Skip to main content
NCBI home page
Wiley Open Access Collection logoLink to Wiley Open Access Collection
. 2024 Dec 20;117(1):e2400096. doi: 10.1111/boc.202400096

Phosphoinositide signaling in the nucleus: Impacts on chromatin and transcription regulation

Nesrine Hifdi 1, Mathilde Vaucourt 1, Karim Hnia 1, Ganna Panasyuk 2, Marie Vandromme 1,✉
PMCID: PMC11771838  PMID: 39707648

Abstract

Phosphoinositides also called Polyphosphoinositides (PPIns) are small lipid messengers with established key roles in organelle trafficking and cell signaling in response to physiological and environmental inputs. Besides their well‐described functions in the cytoplasm, accumulating evidences pointed to PPIns involvement in transcription and chromatin regulation. Through the description of previous and recent advances of PPIns implication in transcription, this review highlights key discoveries on how PPIns modulate nuclear factors activity and might impact chromatin to modify gene expression. Finally, we discuss how PPIns nuclear and cytosolic metabolisms work jointly in orchestrating key transduction cascades that end in the nucleus to modulate gene expression.

Polyphosphoinositides (PPIns) are derivates of phosphatidylinositol (PtdIns) through reversible phosphorylation of the myoinositol ring by kinases and phosphatases. This gives rise to seven PPIns that are involved in multiple cascades such as occurring at plasma membrane under physiological and stressor signals but also in the nucleus to regulate gene expression. This review aims to discuss how nuclear PPIns metabolism contributes to chromatin regulation and transcription programs.

graphic file with name BOC-117-e2400096-g002.jpg

INTRODUCTION

Polyphosphoinositides (PPIns), also named phosphoinositides (PIs), are phosphorylated derivates of phosphatidylinositol (PtdIns). They are small lipid messengers composed of a hydrophobic diacylglycerol backbone coupled by a phosphodiester linkage to a hydrophilic myo‐inositol ring that can be reversibly phosphorylated on three distinct hydroxyl groups. The combination of these phosphorylations leads to the formation of seven distinct species of PPIns that are either monophosphorylated on the 3rd (PI3P), 4th (PI4P), or 5th (PI5P) position of the inositol head group; bisphosphorylated on the 3rd and 4th (PI(3,4)P2), 3rd and 5th (PI(3,5)P2) or 4th and 5th positions (PI(4,5)P2), or trisphosphorylated (PI(3,4,5)P3). The PPIns phosphorylation status dictates their cellular distribution and functions on particular cytosolic membrane compartments and organelles (Bilanges et al., 2019). The production and turnover of PPIns are orchestrated by specialized lipid kinases and phosphatases that mediate phosphorylation–dephosphorylation of the inositol ring at the 3rd, 4th, or 5th position (Bilanges et al., 2019). Phosphorylated inositol headgroups in PPIns serve as docking sites for effector proteins that contain binding domains such as FYVE (Fab1, YOTB/ZK632.12, Vac1, and EEA1) (Burd & Emr, 1998; Stenmark et al., 2002, 1996), PH (Pleckstrin homomology domain) (Ferguson et al., 1995; Harlan et al., 1994; Paterson et al., 1995), and PX (Phox homology domain) (Chandra et al., 2019; Ellson et al., 2002; Kanai et al., 2001). These PPIns–effectors interactions allow the transformation of binding signatures into specific biological outputs (Posor et al., 2022; Toker, 2002).

In addition to their well‐established roles in membrane organelle trafficking (Figure 1a), the ensemble of data pointed to the involvement of PPIns in transcription and chromatin regulation as well as DNA damage response (DDR) signaling (Casalin et al., 2024; Chen et al., 2020; Fiume et al., 2019; Hamann & Blind, 2018; Jones et al., 2006; Poli et al., 2019; Vidalle et al., 2023; Wang & Sheetz, 2022). Notably, at the exception of PI(3,5)P2, all PPIns (Figure 1b) as well as several of their metabolizing enzymes have been detected in the nucleus (Figure 1c) (Boronenkov et al., 1998; Cocco et al., 1987; Divecha et al., 1991; Fáberová et al., 2020; Gillooly, 2000; Irvine & Divecha, 1992; Osborne et al., 2001; Payrastre et al., 1992; Watt et al., 2002). PPIns were found in nuclear membranes as well as associated with membraneless structures such as nucleolus, nuclear speckles, chromatin nuclear matrix, and nucleoplasm (Figure 1b). However, despite past and recent advances, our understanding of PPIns nuclear pool functioning remains still limited. This review highlights and discusses key previous and past discoveries on the roles of nuclear PPIns in transcriptional regulation with a particular attention to their possible impact on chromatin architecture.

FIGURE 1.

FIGURE 1

Open in a new tab

Cytoplasmic and nuclear PPIns metabolism. (a) PPIns act as second messengers of transduction cascades and organelle trafficking at the plasma membrane and endomembranes. PPIns mark organelles identity allowing endomembrane dynamics to ensure key process such as endocytosis, exocytosis, and autophagy. The major PPIns organelle signature are indicated in yellow. At the plasma membrane, PI(4,5)P2 and PI(3,4)P2 are the most abundant PPIns. The PI(4,5)P2 and PI(3,4,5)P3 interconversion cycle is controlled by the Class‐I PI3Ks and PTEN, a major signaling cascades involved in cell growth. Generation of PI(3,4)P2 mainly by the Class‐II PI3K occurs on nascent endocytic carriers such as clathrin‐coated pits before conversion to PI3P in early endosomal compartments. PI3P conversion to PI(3,5)P2 marks the late endosomes and the lysosomes. PI(3,5)P2 and PI3P are also involved in the genesis of autophagosomes, a degradative organelle that emerges from the endoplasmic reticulum, the major reservoir of PtdIns. The PI4P is highly present at the Golgi apparatus, a compartment where main exocytosis vesicles emerge. The PI4P‐positive vesicles emanating from the Golgi could also fuel additional cell membranes compartment such as the ER through anterograde and retrograde trafficking. (b) Subnuclear distribution of PPIns in different nuclear compartments. Note that PPIns such as PI5P and PI(4,5)P2 are redundant in many compartments suggesting multiple nuclear functions. (c) PPIns (polyphosphoinositide)‐kinases (in blue) and phosphatases (in red) isoforms that are active for PPIns interconversion in the nucleus. Two distinct nomenclatures are indicated.

EPIGENETIC REGULATION OF TRANSCRIPTION

The eucaryotic genome is packaged into a nucleoprotein complex called chromatin, formed by the association of DNA, RNA and proteins, mainly histones. The basic unit of chromatin is known as the nucleosome composed of 146 pb of DNA wrapped around a histone octamer (two units of H2A–H2B and H3–H4 dimers). Epigenetic mechanisms, including DNA methylation, post‐translational modifications of histones and nucleosome positioning, enable chromatin to switch between closed, inaccessible to DNA binding effectors, and an open transcription‐permissive state. Chromatin compaction is controlled by the chromatin‐modifying enzymes that add (writers) or remove (erasers) specific chromatin marks to histones or DNA, and effector proteins (readers) that interpret these marks to regulate transcription. Posttranslational modifications of histones often occur on their N‐terminal tails. The most abundant histone modifications are acetylation, phosphorylation, methylation, and ubiquitylation, although many others have been reported (Millán‐Zambrano et al., 2022; Yao et al., 2024; Zhang et al., 2015). Histone acetylation is “written” by histone acetyl transferase (HAT), “erased” by histone deacetylase (HDAC) and “read” by bromodomain (BRD) containing proteins (encoded by 42 distinct genes in human) (Filippakopoulos & Knapp, 2014; Gao et al., 2022; Gong et al., 2016). Besides, several domains can bind acetylated lysines, including double PHD fingers, noncanonical BRD and the YEATS domain (Arrowsmith & Schapira, 2019). Furthermore, histone methylation occurs on lysine (Black et al., 2012) and arginine residues (Blanc & Richard, 2017). Lysine methylation/demethylation is mediated by lysine histone methyltransferases (KMT) and lysine histone demethylases (KDM), respectively (Hyun et al., 2017; Verrier et al., 2011). It impacts transcription either positively or negatively depending on the position of the lysine residue that is methylated and its degree of methylation (me1, me2, and me3). For example, trimethylation of histone H4 (H3K4me3) at the promoter region and transcription start site marks active transcription, while trimethylation of lysine 9 of histone H3 (H3K9me3) is a hallmark of heterochromatin and transcriptional repression. Methylated lysines serve as a platform to recruit proteins harboring methyl‐lysine‐binding motifs, including PHD, chromo, Tudor, PWWP, WD40, BAH, ADD, ankyrin repeat, MBT, and zf‐CW domains that differentially bind to lysine methylation state and surrounding amino‐acid sequence (Arrowsmith & Schapira, 2019; Qin & Min, 2014; Sanchez & Zhou, 2011). PHD was initially described as a nuclear PI5P receptor, establishing a link between chromatin, transcription, and PPIns metabolism (Gozani et al., 2003).

Histone marks readers include ATP‐dependent chromatin remodelers that regulate DNA accessibility by repositioning, ejecting, or modifying nucleosomes. These remodelers were grouped into the following four families: SWI/SNF (switch/sucrose‐nonfermenting), ISWI (imitation switch), IN080 (inositol requiring 80), and CHD (chromodomain‐helicase‐DNA binding) (Reyes et al., 2021; Tyagi et al., 2016). Chromatin complexes are targeted to genomic loci by interacting with transcription factors and/or through their binding to chromatin marks. Finally, to establish concerted changes in chromatin structure for coherent transcriptional outcomes, multiprotein chromatin complexes can contain both readers, writers, or/and erasers such as the COMPASS family containing H3K4 methyltransferases (Cenik & Shilatifard, 2021), or the NURD, Sin3, or CoREST containing HDAC complexes (Asmamaw et al., 2024; Lee et al., 2022).

PHOSPHOINOSITIDE TRAFFICKING INTO THE NUCLEUS

While PPIns are mainly found at the cytoplasmic leaflet of plasma membrane and organelles, part of these lipids as well as their metabolizing enzymes (PI‐kinases and phosphatases) are also detected in the nucleus advocating for their nuclear synthesis/conversion (Figure 1). However, it was also suggested that some PPIns could traffic through the nuclear envelope (NE). Notably, this is supported by the findings of PPIns binding to the orphan nuclear receptors Steroidogenic factor‐1 (SF‐1/NR5A1) and LRH1/NR5A2. SF‐1 collaborates with other transcription factors to regulate gene expression along the hypothalamic pituitary adrenal and gonadal axes (Campbell et al., 2024). Early studies indicated that NR5A subfamily members were able to bind phospholipids since they copurified with bacterial phospholipids (Li et al., 2005; Ortlund et al., 2005). Later, SF‐1 was shown to bind preferentially and with high‐affinity PI(4,5)P2 and PI(3,4,5)P3 (Blind et al., 2014, 2012; Krylova et al., 2005). This interaction was dependent on the hydrophobic ligand binding domain (LBD), revealed by the crystal structure of the SF‐1‐PI(4,5)P2/PI(3,4,5)P3 or LHR‐1‐PI(3,4,5)P3 complexes. In the complex of PPIns with SF1 or LHR‐1, the acyl tails are engulfed into the interior of the hydrophobic pocket whereas the polar head is positioned towards the solvent‐exposed surface (Blind et al., 2012; Bryant et al., 2021; Sablin et al., 2015). Mechanistically, it was proposed that positioning of fatty acid chains within the LBD domain may affect SF‐1 receptor conformation modifying its association with cofactors or DNA binding proteins, and, therefore, potentially impacting its transcriptional activity (Bryant et al., 2021). Moreover, the headgroup of PI(3,4,5)P3 was suggested to act as a new molecular docking surface on solvent‐exposed edges of the LBD mediating interaction with nuclear co‐regulators bearing PPIns binding domains (Blind et al., 2014). Strikingly, in vitro study showed that the SF‐1/PI(4,5)P2 complex favors a dynamic interconversion of PI(4,5)P2 to PI(3,4,5)P3 by the action of the inositol polyphosphate multikinase (IPMK) and the phosphatase and tensin homolog lipid phosphatase (PTEN), respectively. Indeed, decreasing PI(3,4,5)P3 by IPMK inhibition or by PTEN overexpression reduced the transcriptional activity of SF‐1 in human embryonic kidney HEK 293 cells (Blind et al., 2012; Figure 2). Attempting to co‐localize SF‐1 and PI(4,5)P2 in cells, a recent study showed that SF‐1 overexpression seemed to enhance PI(4,5)P2 immunostaining while the mutation of its LBD that interfered with PI(4,5)P2 binding, did not have such effect. However the authors did not reveal any notable impact on PI(3,4,5)P3 suggesting that SF‐1‐binding to PI(4,5)P2 may protect or stabilize the lipid only when SF‐1 transcriptional activity is downregulated (Chi et al., 2023). Collectively, these data support a transcriptional regulation by PPIns through a lipid–protein interaction in a nonmembranous environment and point to the role of orphan nuclear receptor for docking–trafficking of nuclear PPIns. Because NR5A receptors have a restricted tissue distribution, this model per se does not apply to all cells, and other proteins must contribute to PtdIns and PPIns docking–trafficking from the cytoplasm to the nucleus or inside the nucleus. Noticeably, preprint publications recently described PtdIns transfer proteins PTIPα and β  (Ashlin et al., 2021; Hsuan & Cockcroft, 2001) as important players of nuclear PtdIns/PPIns transport and metabolism, through their association with the transcription factor p53 (Carrillo et al., 2024), the poly(A) polymerase Star‐PAP (Wen et al., 2024), and likely other nuclear proteins that remain to be identified.

FIGURE 2.

FIGURE 2

Open in a new tab

PPIns regulate the transcriptional activity of SF‐1. The steroidogenic factor 1(SF‐1) and the liver hormone receptor (LHR‐1) belong to the NR5A family of orphan nuclear receptors. PI(4,5)P2 binds to the ligand binding domain of SF‐1 (LBD) through its acyl chains. PI(4,5)P2 is converted to PI(3,4,5)P3 by the inositol polyphosphate multikinase (IPMK), resulting in SF‐1 transcriptional activation. The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) acts antagonistically to IPMK to shut down SF‐1 transcriptional activity. The inositol headgroup of PI(3,4,5)P3 that faces the cytosol may recruit additional, yet unknown, nuclear transcription factors.

PPINS BINDING DOMAINS/MOTIFS ON TRANSCRIPTION MACHINERY CONNECT PPINS TO CHROMATIN

Plant homeodomain domain (PHD)

PHD‐finger of ING2

Pioneer study on the role of PI5P in transcription identified the Plant Homeodomain (PHD) finger domain of the Inhibitor of Growth protein 2 (ING2) as a new PPIns‐binding domain (Gozani et al., 2003; Figure 3). Nuclear PI5P levels are tightly controlled and regulate cell proliferation and cellular adaptation to stress. Notably, nuclear PI5P levels were shown to fluctuate during the cell cycle and cell differentiation, as well as in response to genotoxic stress such as UV irradiation, DNA damage, or oxidative stress‐inducing agents (Rameh & Blind, 2023; Viaud et al., 2014). ING2 belongs to the ING family that includes five members (ING1 to ING5) and are components and regulators of chromatin‐modifying complexes containing histone acetyl‐transferases or deacetylases (Dantas et al., 2019). The PHD domain is a conserved Cys4‐His‐Cys3 zinc finger domain, found in many nuclear proteins with established role in chromatin regulation (Arrowsmith & Schapira, 2019; Gozani et al., 2003). PI5P binds to ING2 PHD through a positively charged polybasic patch constituted by three consecutive lysines positioned at the surface of the PHD domain as well as a stretch of basic residues (polybasic region [PBR]) present at the very end of the ING2 PHD finger (Gozani et al., 2003). Mutation of the three lysine residues lowered the association of PI5P to the ING2 PHD domain while mutation of the PBR abolished binding. Moreover, the expression of Shigella flexneri virulence factor IpgD, a lipid phosphatase that converts PI(4,5)P2 to PI5P at the plasma membrane, was able to trigger localization of ectopically expressed ING2‐PHD, but not a mutant version unable to bind PI5P, to the plasma membrane, supporting the idea that the PHD finger of ING2 can bind physiological levels of PI5P. Mechanistically, the binding of PI5P to ING2 PHD finger promoted the acetylation of p53 and induced apoptosis (Gozani et al., 2003). Furthermore, ING2 association with chromatin seems to depend on PI5P nuclear levels. Indeed, overexpression of the nuclear PtdIns‐5‐phosphate 4‐kinase type‐II β (PIP4KII‐β also named PI5P4Kβ or PIP4K2B), which converts PI5P into PI(4,5)P2, reduced ING2 chromatin association. Noticeably, PI5P nuclear levels increased and were enriched in the chromatin fraction in response to UV irradiation and treatment with the DNA damaging agent Etoposide. Both these genotoxic stressors activate p38MAPK that phosphorylates and inhibits PIP4K2B resulting in increased content of nuclear PI5P and promoting an association of ING2 to chromatin (Jones et al., 2006). Another route to produce nuclear PI5P is by dephosphorylation of PI(4,5)P2 by type I 4‐phosphatase (PIP4PI/TMEM55B). In resting cells, PIP4PI is mainly localized at endosomal and lysosomal membranes. However, upon genotoxic stress, a fraction of PIP4PI was shown to translocate to the nucleus to dephosphorylate PI(4,5)P2 resulting in increased nuclear PI5P levels (Ungewickell et al., 2005; Zou et al., 2007). Thus, genotoxic stressors trigger the inhibition of PIP4K2B by p38MAPK, and nuclear translocation of PIP4PI by an unknown mechanism, which increases PI5P‐ING2 PHD binding and activation of p53‐dependent genotoxic stress response (Figure 4).

FIGURE 3.

FIGURE 3

Open in a new tab

PI5P links transcription factors to chromatin. The transcription factors ING‐2, TAF‐3, and UHRF1 are regulated by PI5P binding. The PHD domain is present in all proteins, although it was involved in the interaction with PI5P only for ING2 and TAF3. A stretch of polybasic residues (illustrated by a yellow star) is present in the C‐terminal part of both ING2 and TAF3 PHD and is required for PI5P binding. The PHD domain is also involved in the recognition of H3K4me3, associated with active transcription. PI5P enhances the recruitment of ING2 and TAF3 on chromatin via binding of the PHD to H3K4me3. ING2 binds to the Sin3 deacetylase complex that leads to transcriptional repression of p53‐dependent genes by histone deacetylation. TAF3 is a general transcription factor, which forms with TRF3 the pre‐initiation complex required for muscle‐specific gene activation. UHRF1 binds to PI5P via a polybasic region (PBR) independently of the PHD domain. The binding of PI5P to the PBR induces a conformational change that frees the TTD domain from the PBR‐containing region, allowing the TTD to bind to H3K9me3. This configuration triggers the recruitment of the DNA methyltransferase 1 (DNMT1) that interacts with UHRF‐1 to methylate DNA during S‐phase or promotes the repression of transcription of tumor suppressor genes. The hydrophobic diacylglycerol tail of PPIns should be protected from the hydrophilic environment of nucleoplasm, which implies its association with proteins containing hydrophobic pockets such as SF‐1 or PITPs. LZL, leucine zipper‐like domain; PHD, plant homeodomain zinc finger; RING, really interesting new gene domain; SRA, SET and RING‐associated domain; TTD, tandem tudor domain; UBL, ubiquitin‐like domain. Image created with Biorender.

FIGURE 4.

FIGURE 4

Open in a new tab

PI5P nuclear levels are modulated by stressors. The antagonizing enzymes PIP4K2B and PIP4PI (PI(4,5)P2‐4‐phosphatase I) regulate nuclear PI5P levels. PIP4K2B is inhibited through direct phosphorylation by p38‐MAPK that is stimulated by genotoxic stress. In addition, in response to genotoxic stress, a fraction of PIP4PI was shown to translocate to the nucleus through an unknown mechanism to dephosphorylate PI(4,5)P2. Alternatively, p38MAPK activates the ubiquitination of PIP4K2B and potentially UHRF‐1 through activation of the SPOP (speckle‐type POZ domain protein)‐Cullin3 (Cul3) E3 ubiquitin ligase complex.

Besides its binding to PI5P, the PHD finger of ING2 was later reported to bind to trimethylated lysine 4 on histone H3 (H3K4me3) (Shi et al., 2006), a hallmark of active transcription (Peña et al., 2006). H3K4me3 enrichment is found at promoters of actively transcribed genes together with hyperacetylation of histones that maintain an open state of chromatin permitting RNA polymerase II occupancy. The interaction between ING2 and H3K4me3 allows the recruitment of the Sin3A corepressor complexes at target gene promoters resulting in histone deacetylation and gene repression (Doyon et al., 2006). The core subunits include the histone deacetylases HDAC1 and HDAC2, the retinoblastoma‐binding proteins RbAp46 and RbAp48, Sin3A/Sin3B, Sin3A‐associated protein 18 (SAP18), and SAP30 (Asmamaw et al., 2024). SAP30/SAP30L subunits are important in recruiting and stabilizing Sin3 complexes on nucleosome substrates. Interestingly, the nuclear localization signal (NLS) sequence of SAP30 and SAP30L was shown to bind to monophosphorylated PPIns, with a higher affinity toward PI5P. PI5P binding to the NLS, rich in basic residues, inhibited SAP30/SAP30L binding to chromatin and, by competing with the NLS, led to the relocalization of SAP30/SAP30L to the cytoplasm (Viiri et al., 2009). In response to DNA damage, ING2 is recruited to a panel of genes related to the DNA damage response to trigger transcriptional repression. Interestingly, ectopic expression of ING2 mutants unable to bind PI5P but that still bind H3K4me3 affects several ING2 regulated genes (estimated to 10%). Thus, PI5P seems to be required for the regulation of a subset of genes in response to DNA damage (Bua et al., 2013). Why PI5P‐ING2‐PHD binding drives only a subset of ING2‐targeted genes is still unknown and requires further investigations. Also, given the dynamic changes of H3K4me3 levels correlating with the transcriptional rate (Karlić et al., 2010), it would be informative to characterize genome‐wide H3K4me3 levels at PI5P‐ING2‐PHD bound promoters (prior to Etoposide treatment). Finally, it is also possible that PI5P‐ING2‐PHD binding mediates the assembly of specific multiprotein complexes at gene promoters both in a p53‐dependent or independent manner.

PHD finger of TAF3

Given that the PHD domain is present in more than 100 proteins within the human genome, fruitful attempts were made to screen for transcriptional regulators that could bind PPIns. Out of the 32 tested PHD fingers containing proteins, 17 were shown to bind PPIns with variable affinity (Divecha, 2016; Stijf‐Bultsma et al., 2015). Among them, specific binding of the TATA‐box‐associated factor 3 (TAF3) with PI5P was reported (Figure 3). Similar to ING2, binding to PPIns is mediated by a PBR present at the c‐terminal end of the PHD finger. TAF3 was identified as a subunit specifically associated with the TBP (TATA‐box binding protein) related factor TRF3 to activate skeletal muscle‐specific gene expression (Deato et al., 2008; Deato & Tjian, 2007). In proliferative and undifferentiated cells, PIP4K2Β that converts PI5P to PI(4,5)P2 localizes to the nucleus. However, upon induction of myoblast differentiation, cytoplasmic localization of PIP4K2B triggers an increase in nuclear PI5P levels that activates TAF3 further promoting differentiation. The PHD domain of TAF3 is known to bind H3K4me3, enriched around the transcription start site. Therefore, it was suggested that TAF3–PI5P interaction may modulate TAF3 interaction with H3K4me3 by impacting PHD finger conformation (Divecha, 2016; Stijf‐Bultsma et al., 2015). According to this model, inhibition of PIP4Κ2Β in myoblasts induces muscle differentiation, whereas knockdown of the other cytosolic members PIP4K2A/C inhibits this process (Mansat et al., 2024; Stijf‐Bultsma et al., 2015). More recently, cytoplasmic PI5P levels were reported to decrease during skeletal muscle cell differentiation. Notably, it contradicts the observations in differentiating myotubes of an increased expression of the cytoplasmic 3‐phosphatase MTM1, which converts PI(3,5)P2 to PI5P (Mansat et al., 2024). It is possible that cytoplasmic PIP4K2B converts PI5P into PI(4,5)P2 in differentiated cells, lowering PI5P cytoplasmic pool in myotubes compared to myoblasts. MTM1 was shown to generate close to the plasma membrane PI5P that is then converted into PI(4,5)P2 by PIP4K2A (also known as PIPKIIα/PI5P4Kα) to drive PI(4,5)P2 enrichment in podosome‐like protrusions (PLPs), a process involved in myoblast fusion into multinucleated myotubes (Mansat et al., 2024). These findings illustrate that distinct PI5P pools and related metabolizing enzymes can have different functions. However, if MTM1‐dependent PI5P pool could also orchestrate transcriptional events during myogenesis remains to be addressed. Then, the intriguing question is how PI5P is generated in the nuclei. Neither MTM1 nor the PI5‐kinase PIKfyve, have NLS or have been localized in the nucleus. A possible scenario is a nuclear translocation of these proteins with the help of protein partners having NLS. This also requires the presence of the PtdIns precursor for PIKfyve to generate PI5P in the nucleus. Indeed, PtdIns is synthesized in the endoplasmic reticulum (ER), which is in physical continuity with the NE (Bahmanyar, 2015; Blunsom & Cockcroft, 2020). PtdIns could be produced as well by highly mobile ER‐derived vesicles (Kim et al., 2011). PtdIns is then delivered to cytoplasmic membranes by vesicular transport, or/and MCS (membrane contact sites) (Phillips & Voeltz, 2016) mainly through PtdIns transfer proteins (PITPs) (Ashlin et al., 2021; Hsuan & Cockcroft, 2001). Indeed, PITPα and β were recently suggested as a source for nuclear PPIns in two independent studies (preprint publications) (Carrillo et al., 2024; Wen et al., 2024). However, further work is needed to explore molecular machineries involved in PtdIns‐PI5P conversion between ER and nuclear compartments.

Altogether, the role of PHD domain in PI5P‐dependent regulation of transcription emerged with some physiological output in myogenesis and cell‐stress responses, calling for further investigations in other cellular contexts.

POLYBASIC REGION OF UBIQUITIN‐LIKE WITH PHD AND RING FINGER DOMAINS 1

The binding of PPIns to several proteins is not exclusively dictated by the presence of known PPIns binding domain. The presence of PBRsmotifs (rich in His, Arg, and Lys) can be involved in functional PPIns binding. This was exemplified by studies showing that PI5P bound to the ubiquitin‐like with PHD and ring finger domains 1 (UHFR1) also known as Np95 in mouse and ICBP90 in human (Gelato et al., 2014; Reynoird & Gozani, 2014). Strikingly, UHFR1‐PI5P binding is mediated by a polybasic motif (PBR) in the C‐terminus of UHFR1 (Figure 3). UHRF1 coordinates the maintenance of DNA methylation pattern by the DNA methytransferase DNMT1 and plays a crucial role during genome duplication in S‐phase. It is preferentially localized at the pericentric heterochromatin hallmarked by DNA methylation and the presence of H3K9me3 (Liu et al., 2013). In addition, UHRF1 represses the transcription of tumor suppressor genes, through DNMT1‐ and DNMT3a/b‐mediated DNA methylation at the CpG dinucleotide (meCpG) as well as G9a‐ and Suv39h‐mediated H3K9 methylation (Bronner et al., 2019; Gu et al., 2024; Rajakumara et al., 2011). As depicted in Figure 3, UHRF1 harbors five distinct domains including a N‐terminal ubiquitin‐like domain (UBL) that directs ubiquitination activity of UHRF1 toward histone H3, a tandem tudor domain (TTD) that binds H3K9me3, a PHD finger that binds the unmodified H3R2, a SET and RING‐associated (SRA) domain that recognizes hemimethylated DNA substrates resulting from DNA replication, and finally a C‐terminal really interesting new gene (RING) domain that catalyzes the monoubiquitination of H3K23/H3K18, required for DNMT1 binding (Song et al., 2023). In addition, a PBR was identified in the linker region between the SRA and RING domains and shown to bind PI5P. Binding of PI5P to the PBR induces conformational changes that free the TTD enabling its H3K9me3 binding and recruitment of DNMT1 to DNA methylation sites (Gelato et al., 2014; Mandal et al., 2022; Reynoird & Gozani, 2014). Thus, PI5P facilitates the recruitment of UHRF1 to DNA sites for their methylation.

On the other hand, the negative impact of PI5P on UHRF1 was also reported (Poli et al., 2023). In cells growing on soft substrates, the decrease of PIP4K2B, which converts PI5P into PI(4,5)P2, leads to a decrease in UHRF1 mRNA and protein levels. These culture conditions are known to induce the inactivation of the transcription co‐factors YAP/TAZ by the Hippo pathway (see below). Therefore, the decrease in PIP4K2B protein levels, likely through the proteasome degradation pathway, triggers a downregulation of UHFR1, which in turn might promote the chromatin decompaction and changes in NE tension. This results in YAP nuclear extrusion and defective cell adhesion and migration. Since YAP also regulates UHFR1 transcription, its inactivation leads to a decrease in UHFR1 mRNA level. Complementing cells with soluble PI5P induced UHRF1 degradation in few hours supporting the idea that PI5P could regulate UHRF1 protein turnover (Poli et al., 2023). Accordingly, it was reported that PI5P activated the ubiquitination of SPOP (speckle‐type POZ domain protein)‐Cullin3 (Cul3) E3 ubiquitin ligase substrates through activation of the p38MAPK cascade (Bunce et al., 2008). Thus, PI5P has a dual role on UHRF1, first, by directing recognition of H3K9me3 via allosteric regulation (Figure 3) and second, by controlling its degradation through p38MAPK‐SPOP cascades, a process that also takes part in the control of PIP4K2B level (Figure 4). Another example of a protein harboring is a PHD finger and regulated by PPIns is the histone demethylase PHF8 (PHD finger protein 8). By binding to a polybasic motif, PI(4,5)P2 inhibits its demethylase activity against H3K9me2 on nucleolar ribosomal genes and activates their transcription (Ulicna et al., 2018).

Finally, the PBR motif was found in many nuclear proteins independent of PHD domain presence. As such, PI(4,5)P2 was shown to increase the association of the ATP‐dependent Brg1/Brm associated factor (BAF) chromatin remodeling complex to the nuclear matrix (Zhao et al., 1998). Mechanistically, PI(4,5)P2 binds to a PBR in the catalytic subunit Brg1 (Brahma‐related gene 1; also known as SMARCA4), to regulate its interaction with nuclear actin (Rando et al., 2002). The co‐repressor BASP1 contains in its N‐terminus a myristoylation motif and a bipartite NLS (rich in K/R residues) that are both required for its interaction with PI(4,5)P2. PI(4,5)P2 binding triggers its association with HDAC1 and repression of target genes (Toska et al., 2012).

Also, a quantitative proteomic approach was employed to identify PPIns binding partners using PPIns‐coupled beads and protein extracts of isolated nuclei. To further gain in specificity, the samples were treated with Neomycin that competed with PPIns binding. Among the 349 nuclear proteins released by Neomycin and thus putative PPIns partners, the vast majority contained lysine/arginine‐rich patches with the following motif, K/R‐(X n = 3–7)‐K‐X‐K/R‐K/R, while a smaller subset harbored known PPIns‐binding modules such as PH or PHD domains (Lewis et al., 2011). This study identified 28 nuclear proteins that were specifically pulled down by PI(4,5)P2 beads, with 19 harboring K/R motifs. Functional classification of these proteins pointed to roles in mRNA transcription regulation, mRNA splicing and protein folding (Lewis et al., 2011). An independent study identified around 100 PI(4,5)P2 and/or PI4P nuclear partners through immunoprecipitation with specific anti‐PI4P or anti‐PI(4,5)P2 antibodies followed by mass spectrometry analysis (Fáberová et al., 2020). The majority of the identified proteins are involved in mRNA processing, mainly splicing. Noticeably, 23 proteins were found more enriched and 12 were identified only in the PI4P immunoprecipitate, suggesting specific roles for PI4P in mRNA processing. This was in line with the described localization and function of PI(4,5)P2 (Boronenkov et al., 1998; Osborne et al., 2001) and PI4P (Fáberová et al., 2020) in nuclear speckles, a nuclear compartment dedicated to mRNA processing events. Another proteomic approach based on neomycin extraction recently identified 179 PI(3,4,5)P3 nuclear interactors (Mazloumi Gavgani et al., 2021), with several proteins previously pulled down and characterized from whole cell extracts (Jungmichel et al., 2014). Among these PI(3,4,5)P3‐binding proteins were enriched nucleolar components, in agreement with known nucleolar localization of PI(3,4,5)P3 (Karlsson et al., 2016). Moreover, a large proportion of these proteins contained one or several K/R motifs/PBR shown to be enriched in the PI(4,5)P2 interactome. Altogether these data support a possible larger role of PBR motifs in PPIns‐nuclear function.

Other potential nuclear PPIns binding domains

WD40‐repeat domain (WDR) is among the most abundant protein interaction domains in the human proteome (Arrowsmith & Schapira, 2019). The WDR domain is folded as a donut‐shaped seven‐bladed β‐propeller. β‐propellers that bind phosphoinositides (PROPPINs) display an essential function in autophagy conserved from yeast to human. The WD‐repeat protein interacting with PPIns (WIPI 1–4) contains two individual PPIns binding sites that can bind both to PI3P and PI(3,5)P2, through a conserved cluster of basic amino acids (Baskaran et al., 2012; Thumm et al., 2013). Interestingly, WD40 repeat domain is found in many proteins participating in gene expression regulation. Among these, 15 are components of chromatin complexes, including EED (embryonic ectoderm development), WDR5 (WD40 Repeat protein 5), RbAp46/48 (retinoblastoma‐associated proteins 46 and 48 also known as RBBP4/7), and CAF‐1 (chromatin assembly factor 1) that serve as scaffold to assemble chromatin multiprotein complexes. EED and RbAp46/48 are found in the PRC2 complex that methylates H3K27 to inhibit transcription (Glancy et al., 2021). RbAp46/48 are also components of several other chromatin‐related complexes, including NuRD (nucleosome remodeling HDAC complex), a multi‐subunit complex containing an ATP‐dependent chromatin remodeling and HDAC activity involved in transcriptional repression (Asmamaw et al., 2024). RbAp46/48 is also present in the Sin3 complex, which associates with ING2 to inhibit transcription (Meier & Brehm, 2014). WDR5 that harbors seven WD40 domains is a scaffolding component of SET domain‐containing histone methyltransferase (SET1 and MLL1‐4 complexes) complexes responsible for H3K4 methylation. WDR5 is also a component of the acetyltransferase complexes KAT8 to activate transcription (Guarnaccia & Tansey, 2018). Finally, CAF‐1 deposits H3–H4 directly onto newly synthesized DNA (Sauer et al., 2018). Collectively, the binding of these epigenetic factors to PPIns remains still to be investigated, which could open new routes to connect PPIns to chromatin marks readers.

PPIns nuclear and cytoplasmic signaling orchestrate gene transcription

PI(3,4,5)P3‐p53 signalosome

Class‐I PI3K (PI3KI) converts PI(4,5)P2 into PI(3,4,5)P3 that recruits at membranes AKT, PDK1, and mTORC2 via their respective PH domains. In turn, PDK1 and mTORC2 phosphorylate AKT at Thr308 and Ser473, respectively, triggering its activation. Active AKT resides both in the cytoplasm and in the nucleus. Notably, its nuclear activation can be either due to its nuclear translocation following its activation at the plasma membrane (Andjelkovic et al., 1997; Meier et al., 1997), or by its activation in the nucleus in response to genotoxic stress (Borgatti et al., 2003; Martelli et al., 2012; Wang & Brattain, 2006). Akt phosphorylates and represses the transcription factors FOXOs, which control apoptotic and senescence‐associated gene expression in response to genotoxic stress (Farhan et al., 2017; Rodriguez‐Colman et al., 2024). The tumor suppressor p53 controls the transcription of numerous genes involved in apoptosis, cell‐cycle arrest, senescence, and DNA repair thereby maintaining genome integrity. Previous reports indicate that genotoxic stress increases nuclear levels of both p53, PI(4,5)P2, and PI(3,4,5)P3 (Choi et al., 2019; Wang et al., 2017). p53 associates with the type I PtdIns 4‐phoshate 5 kinase alpha (PIPKIα also named PIP5KIα) and its product PI(4,5)P2, which leads to p53 stabilization (Choi et al., 2019; Wang & Sheetz, 2022). Moreover, nuclear IPMK and PTEN were reported to drive dynamic interconversion of p53‐PI(4,5)P2 and p53‐PI(3,4,5)P3. Mechanistically, the p53‐bound PI(3,4,5)P3 serves as a nuclear platform to recruit AKT, PDK1, and mTORC2 through their PH domain, promoting AKT activity. Preprint results also indicate that PITPα and β associate with p53 in the nucleus to directly transfer PtdIns to P53 and initiate P53–PIPns signaling (Carrillo et al., 2024). Thus, the nuclear p53‐PPIns signalosome represents a link between PI3K–AKT signaling and FOXO activity, DNA repair, and cell survival (Chen et al., 2022). Altogether, these findings revealed a surprising mechanism of AKT activation independent of the plasma membrane PI3K–AKT cascade and underlie the role of p53 in nuclear AKT activation and its spatial confinement to p53‐targeting sites under genotoxic stress.

The Hippo pathway

The Hippo pathway is classically activated at the plasma membrane and regulates gene expression by controlling the cytoplasmic to nuclear transport of the transcriptional co‐regulators YAP/TAZ. In mammals, the Hippo pathway is composed by the upstream regulatory kinases; mammalian STE20‐like kinase 1/2 (MST1/2) and its chaperone Salvador homologue 1 (SAV1), the large tumor suppressor kinase 1/2 (LATS1/2), and its associated chaperone MOBKL1A/B (MOB1A/B), the transcriptional regulators including Yes‐associated protein 1 (YAP), the WW‐domain‐containing transcription regulator 1 (TAZ), and the transcriptional enhanced associated domain (TEAD) family. When the Hippo pathway is active, MST1/MST2 phosphorylates LATS1/2, which phosphorylates YAP/TAZ triggering its cytoplasmic sequestration or degradation. However, Hippo pathway inhibition leads to YAP dephosphorylation followed by its nuclear translocation where it co‐activates the TEAD transcription factors for target gene expression (Figure 5). The Hippo pathway is modulated by a variety of upstream signals, such as cell polarity, mechanical cues, cell density, soluble factors, and stress signals. It is often deregulated in cancer, resulting in the expression of YAP‐target genes encoding pro‐oncogenic proteins (Harvey et al., 2013; Zheng & Pan, 2019).

FIGURE 5.

FIGURE 5

Open in a new tab

Cytosolic and nuclear PPIns regulate the Hippo pathway. The Hippo pathway is activated at the plasma membrane by a variety of upstream signals, such as ligands that stimulate tyrosine‐kinase receptors (RTK) or G‐protein‐coupled receptors (GPCR), cell density, or stress signals. The Hippo pathway is activated by phosphorylation cascades that promote YAP/TAZ cytoplasmic sequestration and degradation. When dephosphorylated, YAP/TAZ translocate to the nucleus and associate with TEAD transcription factors to activate target gene expression. PPIns regulate the Hippo pathway at different levels. PI4P, transported from the endoplasmic reticulum (ER) to the plasma membrane by the Phosphatidylinositol transfer proteins (PITPs), restrains the Hippo pathway through an unknown mechanism that may involve NF2, an upstream regulator of the Hippo pathway. Upon osmotic stress, a plasma membrane pool of PI4P is converted to PI(4,5)P2 by the PIP5KI that is stimulated by ARF6. This leads to the recruitment of NF2 to the plasma membrane, its binding to PI(4,5)P2, and the activation of the Hippo pathway. In the cytoplasm, MST‐1/2 phosphorylates and inhibits PI5P4K/PIP4K2, the PI‐kinase that converts PI5P to PI(4,5)P2, which leads to an increase of a cytosolic PI5P pool. PI5P enhances the association of LATS1 to its chaperone MOBP1, triggering the inhibitory phosphorylation of YAP/TAZ. In the nucleus, PI(4,5)P2 and PI(3,4,5)P3 interact with YAP/TAZ, enhance its association with TEAD promoting the transcription of their target genes. This nuclear regulation requires a local production of PI(4,5)P2 and PI(3,4,5)P3 by the PI4P‐5 kinase (PIPKIα) and the PI3‐kinase IPMK. The hydrophobic diacylglycerol tail of PPIns should be protected from the hydrophilic environment of nucleoplasm, which implies its association with proteins containing hydrophobic pockets. To simplify, it was not drawn. LATS1/2, large tumor suppressor kinase 1/2; MOB1A/B, MOB kinase activator 1 A/B; MST1/2, mammalian STE20‐like kinase 1/2; TEAD, transcriptional enhanced associated domain transcription factor; YAP‐1, yes‐associated protein 1; ZAP, WW‐domain‐containing transcription regulator. Image created with Biorender.

A recent study reported the enhanced interaction of YAP/TAZ with TEAD by its binding to PI(4,5)P2 and PI(3,4,5)P3 within the nucleus (Jung et al., 2024). Notably, this local nuclear production of PI(4,5)P2 and PI(3,4,5)P3 was mediated by PI4P‐5 kinase (PIPKIα) and PI3‐kinase IPMK, respectively. Moreover, the authors identified a polybasic domain on YAP sequence required for PI(4,5)P2 and PI(3,4,5)P3 binding. Interestingly, they found that the acyl chains of these PPIns were also embedded into the hydrophobic pocket formed at the interaction interface of the YAP/TEAD complex (Figure 5). Functionally, the binding of YAP–TEAD to PPIns stabilized the nuclear complex, thus enhancing its transcriptional activity. Interestingly, increased expression of PIPKIα and IPMK is observed in breast cancer cells, which may explain the deregulation of YAP/TAZ–TEAD target gene expression (Jung et al., 2024)

Additionally, it was proposed that PI4P could also regulate the Hippo pathway at the plasma membrane. Indeed, Microcolin A/B, a natural compound identified by a large screen of the Hippo pathway was shown to block YAP phosphorylation. Its synthetic analog, VT01454 showed binding affinity to the StAR‐related lipid transfer domain‐like PITPs, PITPα/β. Thus, PITPs are likely responsible for the localization of PI4P to the plasma membrane, which is needed to restrict the Hippo pathway and activate YAP (Li et al., 2022). The underlying molecular mechanism of PI4P–Hippo interaction and function is not fully determined. However, one of the possibilities is that NF2, an upstream regulator of the Hippo pathway, could bind PI4P, thus mediating the regulatory role of PI4P (Li et al., 2022). Since PITPα was found in the nucleus (Carrillo et al., 2024; De Vries et al., 1995; Hsuan & Cockcroft, 2001), it is tempting to hypothesize that PITPα could also provide nuclear PI4P allowing the production of PI(4,5)P2 and direct regulation of YAP/TEAD complex transcriptional activity. Other nuclear proteins identified as PI4P partners, involved in transcriptional control and nucleocytoplasmic shuttling, could also be involved (Fáberová et al., 2020). Intriguingly, NF2 was suggested to be inhibited by PI4P and shown to be activated by PI(4,5)P2. Indeed, NF2 is recruited at the plasma membrane in response to osmotic stress through its binding to PI(4,5)P2 generated by the phosphorylation of PI4P by PIP5KIα/γ (Hong et al., 2020). Finally, MST1/2 kinases were shown to phosphorylate and inhibit PIP4K2A (also named PIPKIIα/PI5P4Kα) involved in the conversion of PI5P into PI(4,5)P2 resulting in increased cytosolic PI5P pool. PI5P binds to MOB1 and increases its interaction with LATS1, to activate the Hippo pathway (Baumann, 2024; Hirsch et al., 2024; Palamiuc et al., 2024). Finally, recent computational analysis of gene expression revealed upregulation of PIP4K2A in many types of cancer including invasive breast cancer carcinoma, ovarian, colorectal adenocarcinoma, prostate and head/neck cancers which correlated with higher expression of YAP and EMT signature (Palamiuc et al., 2024). Collectively, these findings establish a crosstalk between the Hippo pathway with PI(4,5)P2 and PI(3,4,5)P3 as well as pointing to the interconnection between plasma membrane and nuclear PPIns in transcriptional control (Figure 5).

CONCLUDING REMARKS AND FUTURE CHALLENGES

Beside their well‐described roles in cellular trafficking, PPIns have been involved in transcription and chromatin regulation. While cytosolic PPIns are included in membranes via their acyl chains with the phosphorylated inositol ring facing the cytoplasm, nuclear PPIns are present in membraneless structures including nucleoplasm, nucleolus, nuclear speckles, nuclear matrix, and chromatin. Although PPIns metabolizing enzymes are present in the nucleus, the route of PtdIns precursor and PPIns entry into the nucleus remains enigmatic. The NR5A orphan nuclear receptors family represents the only example of transcription factors that bind PPIns via their acyl chains. In addition, PITPs were recently shown to play key roles in PPIns nuclear signaling. As such, these PPIns “docking” proteins might act as trafficking proteins in a nonmembranous environment facilitating transcriptional regulation by PPIns via a lipid–protein interaction. PPIns interact also with nuclear proteins via their hydrophilic headgroup. For instance, the role of the PHD domain in PI5P‐dependent regulation of transcription started to emerge with some biological and physiological output in myogenesis and cancer, calling for further investigations in other cellular contexts. The PBR, which is composed of a stretch of basic residues, also constitutes a binding motif in numerous proteins with functions in transcription. In addition, the WD40 domain, a well‐described PPIns cytosolic binding domain, is also present in several components of chromatin regulator complexes. The binding of these epigenetic factors to PPIns still remains to be investigated, which could open new routes to connect PPIns to gene transcription. Thus, nuclear PPIns have a regulatory role seemingly independent of their well‐known function in cytosolic compartments. This is exemplified by the roles of nuclear PPIns in the activation of AKT by p53 as well as in the regulation of the YAP/TAZ transcriptional activity.

Given the lack of tools to detect, localize, and follow PI5P, efforts should be employed to find protein domains and motifs that recognize specifically PI5P to confirm its nuclear function and identify new mechanisms of PI5P‐chromatin‐transcription crosstalk. Besides the involvement of the phosphorylated inositol ring, recent lines of evidence pointed to the regulatory role of acyl chains in binding nuclear proteins either individually or in complex interfaces (Jung et al., 2024). These add another level of complexity to how these nuclear PPIns could be integrated in nuclear signal transduction. Moreover, a micelle or micelle‐like structures of some PPIns were described in the nucleus in close interaction with chromatin (Sobol et al., 2018). These nuclear lipid islets were enriched in PI(4,5)P2 and may serve as a scaffolding platform to activate RNA Pol‐II‐dependent transcription (Sobol et al., 2018). This raises the question on a possible role of nuclear PPIns in phase separation (Sztacho et al., 2019), a process that certainly merits further investigations. Finally, given that our knowledge about the dynamics of PPIns–chromatin interaction remains still limited, future approaches for mapping chromatin PPIns networks such as ChIP‐sequencing will be of high interest to determine at which level PPIns, PPIns‐kinases, and phosphatases remain chromatin‐bound and which chromatin loci are targeted.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

ACKNOWLEDGMENTS

Due to the limited space, we could not cite all the studies and review articles in the field. We warmly apologize for that. We thank INSERM, Université Paul Sabatier for their continual support. N.H. was supported by the Agence Nationale de la Recherche (Grant ANR‐21‐CE14‐0056‐02‐MuscLY), M. Vaucourt by a PhD fellowship from AFM‐Téléthon (#24542), G.P. was supported by grants from the European Research Council (Grant no. ERC‐CoG‐MetaboSENS‐819543) and ANR‐PRC (Grant #ANR‐21‐CE14‐0056‐02‐MuscLY to K.H. and G.P.), M. Vandromme and K.H. was financed by an AFM‐telethon grant (#23101 and #25113).

Hifdi, N. , Vaucourt, M. , Hnia, K. , Panasyuk, G. & Vandromme, M. (2025) Phosphoinositide signaling in the nucleus: impacts on chromatin and transcription regulation. Biology of the Cell, 117, e2400096. 10.1111/boc.202400096

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

REFERENCES

  1. Andjelkovic, M. , Alessi, D.R. , Meier, R. , Fernandez, A. , Lamb, N.J.C. , Frech, M. , Cron, P. , Cohen, P. , Lucocq, J.M. & Hemmings, B.A. (1997) Role of translocation in the activation and function of protein kinase B. Journal of Biological Chemistry, 272, 31515–31524. Available from: 10.1074/jbc.272.50.31515 [DOI] [PubMed] [Google Scholar]
  2. Arrowsmith, C.H. & Schapira, M. (2019) Targeting non‐bromodomain chromatin readers. Nature Structural & Molecular Biology, 26, 863–869. Available from: 10.1038/s41594-019-0290-2 [DOI] [PubMed] [Google Scholar]
  3. Ashlin, T.G. , Blunsom, N.J. & Cockcroft, S. (2021) Courier service for phosphatidylinositol: PITPs deliver on demand. Biochimica et Biophysica Acta (BBA)—Molecular and Cell Biology of Lipids, 1866, 158985. Available from: 10.1016/j.bbalip.2021.158985 [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Asmamaw, M.D. , He, A. , Zhang, L.‐R. , Liu, H.‐M. & Gao, Y. (2024) Histone deacetylase complexes: structure, regulation and function. Biochimica et Biophysica Acta (BBA)—Reviews on Cancer, 1879, 189150. Available from: 10.1016/j.bbcan.2024.189150 [DOI] [PubMed] [Google Scholar]
  5. Bahmanyar, S. (2015) Spatial regulation of phospholipid synthesis within the nuclear envelope domain of the endoplasmic reticulum. Nucleus, 6, 102–106. Available from: 10.1080/19491034.2015.1010942 [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Baskaran, S. , Ragusa, M.J. , Boura, E. & Hurley, J.H. (2012) Two‐site recognition of phosphatidylinositol 3‐phosphate by PROPPINs in autophagy. Molecular Cell, 47, 339–348. Available from: 10.1016/j.molcel.2012.05.027 [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Baumann, K. (2024) The phosphoinositide PI5P inhibits the Hippo pathway effector YAP. Nature Reviews Molecular Cell Biology, 25, 513–513. Available from: 10.1038/s41580-024-00750-y [DOI] [PubMed] [Google Scholar]
  8. Bilanges, B. , Posor, Y. & Vanhaesebroeck, B. (2019) PI3K isoforms in cell signalling and vesicle trafficking. Nature Reviews Molecular Cell Biology, 20, 515–534. Available from: 10.1038/s41580-019-0129-z [DOI] [PubMed] [Google Scholar]
  9. Black, J.C. , Van Rechem, C. & Whetstine, J.R. (2012) Histone lysine methylation dynamics: establishment, regulation, and biological impact. Molecular Cell, 48, 491–507. Available from: 10.1016/j.molcel.2012.11.006 [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Blanc, R.S. & Richard, S. (2017) Arginine methylation: the coming of age. Molecular Cell, 65, 8–24. Available from: 10.1016/j.molcel.2016.11.003 [DOI] [PubMed] [Google Scholar]
  11. Blind, R.D. , Sablin, E.P. , Kuchenbecker, K.M. , Chiu, H.‐J. , Deacon, A.M. , Das, D. , Fletterick, R.J. & Ingraham, H.A. (2014) The signaling phospholipid PIP3 creates a new interaction surface on the nuclear receptor SF‐1. Proceedings of the National Academy of Sciences USA, 111, 15054–15059. Available from: 10.1073/pnas.1416740111 [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Blind, R.D. , Suzawa, M. & Ingraham, H.A. (2012) Direct modification and activation of a nuclear receptor–PIP2 complex by the inositol lipid kinase IPMK. Science Signaling, 5, ra44. Available from: 10.1126/scisignal.2003111 [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Blunsom, N.J. & Cockcroft, S. (2020) Phosphatidylinositol synthesis at the endoplasmic reticulum. Biochimica et Biophysica Acta (BBA)—Molecular and Cell Biology of Lipids, 1865, 158471. Available from: 10.1016/j.bbalip.2019.05.015 [DOI] [PubMed] [Google Scholar]
  14. Borgatti, P. , Martelli, A.M. , Tabellini, G. , Bellacosa, A. , Capitani, S. & Neri, L.M. (2003) Threonine 308 phosphorylated form of akt translocates to the nucleus of PC12 cells under nerve growth factor stimulation and associates with the nuclear matrix protein nucleolin. Journal Cellular Physiology, 196, 79–88. Available from: 10.1002/jcp.10279 [DOI] [PubMed] [Google Scholar]
  15. Boronenkov, I.V. , Loijens, J.C. , Umeda, M. & Anderson, R.A. (1998) Phosphoinositide signaling pathways in nuclei are associated with nuclear speckles containing pre‐mRNA processing factors. Molecular Biology of the Cell, 9, 3547–3560. Available from: 10.1091/mbc.9.12.3547 [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Bronner, C. , Alhosin, M. , Hamiche, A. & Mousli, M. (2019) Coordinated dialogue between UHRF1 and DNMT1 to ensure faithful inheritance of methylated DNA patterns. Genes, 10, 65. Available from: 10.3390/genes10010065 [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Bryant, J.M. , Malabanan, M.M. , Vanderloop, B.H. , Nichols, C.M. , Haratipour, Z. , Poon, K.T. , Sherrod, S.D. , McLean, J.A. & Blind, R.D. (2021) The acyl chains of phosphoinositide PIP3 alter the structure and function of nuclear receptor steroidogenic factor‐1. Journal of Lipid Research, 62, 100081. Available from: 10.1016/j.jlr.2021.100081 [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Bua, D.J. , Martin, G.M. , Binda, O. & Gozani, O. (2013) Nuclear phosphatidylinositol‐5‐phosphate regulates ING2 stability at discrete chromatin targets in response to DNA damage. Scientific Reports, 3, 2137. Available from: 10.1038/srep02137 [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Bunce, M.W. , Boronenkov, I.V. & Anderson, R.A. (2008) Coordinated activation of the nuclear ubiquitin ligase Cul3‐SPOP by the generation of phosphatidylinositol 5‐phosphate. Journal of Biological Chemistry, 283, 8678–8686. Available from: 10.1074/jbc.M710222200 [DOI] [PubMed] [Google Scholar]
  20. Burd, C.G. & Emr, S.D. (1998) Phosphatidylinositol(3)‐phosphate signaling mediated by specific binding to RING FYVE domains. Molecular Cell, 2, 157–162. Available from: 10.1016/S1097-2765(00)80125-2 [DOI] [PubMed] [Google Scholar]
  21. Campbell, A.N. , Choi, W.J. , Chi, E.S. , Orun, A.R. , Poland, J.C. , Stivison, E.A. , Kubina, J.N. , Hudson, K.L. , Loi, M.N.C. , Bhatia, J.N. , Gilligan, J.W. , Quintanà, A.A. & Blind, R.D. (2024) Steroidogenic factor‐1 form and function: from phospholipids to physiology. Advances in Biological Regulation, 91, 100991. Available from: 10.1016/j.jbior.2023.100991 [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Carrillo, N.D. , Chen, M. , Wen, T. , Awasthi, P. , Wolfe, T.J. , Cryns, V.L. & Anderson, R.A. (2024) Lipid transfer proteins and a PI 4‐kinase initiate nuclear phosphoinositide signaling. bioRxiv (Preprint) Apr 20:2023.05.08.539894 Available from: 10.1101/2023.05.08.539894 [DOI]
  23. Casalin, I. , Ceneri, E. , Ratti, S. , Manzoli, L. , Cocco, L. & Follo, M.Y. (2024) Nuclear phospholipids and signaling: an update of the story. Cells, 13, 713. Available from: 10.3390/cells13080713 [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Cenik, B.K. & Shilatifard, A. (2021) COMPASS and SWI/SNF complexes in development and disease. Nature Reviews Genetics, 22, 38–58. Available from: 10.1038/s41576-020-0278-0 [DOI] [PubMed] [Google Scholar]
  25. Chandra, M. , Chin, Y.K.‐Y. , Mas, C. , Feathers, J.R. , Paul, B. , Datta, S. , Chen, K.‐E. , Jia, X. , Yang, Z. , Norwood, S.J. , Mohanty, B. , Bugarcic, A. , Teasdale, R.D. , Henne, W.M. , Mobli, M. & Collins, B.M. (2019) Classification of the human phox homology (PX) domains based on their phosphoinositide binding specificities. Nature Communications, 10, 1528. Available from: 10.1038/s41467-019-09355-y [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Chen, M. , Choi, S. , Wen, T. , Chen, C. , Thapa, N. , Lee, J.H. , Cryns, V.L. & Anderson, R.A. (2022) A p53–phosphoinositide signalosome regulates nuclear AKT activation. Nature Cell Biology, 24, 1099–1113. Available from: 10.1038/s41556-022-00949-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Chen, M. , Wen, T. , Horn, H.T. , Chandrahas, V.K. , Thapa, N. , Choi, S. , Cryns, V.L. & Anderson, R.A. (2020) The nuclear phosphoinositide response to stress. Cell Cycle, 19, 268–289. Available from: 10.1080/15384101.2019.1711316 [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Chi, E.S. , Stivison, E.A. & Blind, R.D. (2023) SF‐1 induces nuclear PIP2. Biomolecules, 13, 1509. Available from: 10.3390/biom13101509 [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Choi, S. , Chen, M. , Cryns, V.L. & Anderson, R.A. (2019) A nuclear phosphoinositide kinase complex regulates p53. Nature Cell Biology, 21, 462–475. Available from: 10.1038/s41556-019-0297-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Cocco, L. , Gilmour, R.S. , Ognibene, A. , Letcher, A.J. , Manzoli, F.A. & Irvine, R.F. (1987) Synthesis of polyphosphoinositides in nuclei of friend cells. Evidence for polyphosphoinositide metabolism inside the nucleus which changes with cell differentiation. Biochemical Journal, 248, 765–770. Available from: 10.1042/bj2480765 [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Dantas, A. , Al Shueili, B. , Yang, Y. , Nabbi, A. , Fink, D. & Riabowol, K. 2019. Biological functions of the ING proteins. Cancers, 11, 1817. Available from: 10.3390/cancers11111817 [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. De Vries, K.J. , Heinrichs, A.A.J. , Cunningham, E. , Brunink, F. , Westerman, J. , Somerharju, P.J. , Cockcroft, S. , Wirtz, K.W.A. & Snoek, G.T. (1995) An isoform of the phosphatidylinositol‐transfer protein transfers sphingomyelin and is associated with the Golgi system. Biochemical Journal, 310, 643–649. Available from: 10.1042/bj3100643 [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Deato, M.D.E. , Marr, M.T. , Sottero, T. , Inouye, C. , Hu, P. & Tjian, R. (2008) MyoD targets TAF3/TRF3 to activate myogenin transcription. Molecular Cell, 32, 96–105. Available from: 10.1016/j.molcel.2008.09.009 [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Deato, M.D.E. & Tjian, R. (2007) Switching of the core transcription machinery during myogenesis. Genes & Development, 21, 2137–2149. Available from: 10.1101/gad.1583407 [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Divecha, N. (2016) Phosphoinositides in the nucleus and myogenic differentiation: how a nuclear turtle with a PHD builds muscle. Biochemical Society Transactions, 44, 299–306. Available from: 10.1042/BST20150238 [DOI] [PubMed] [Google Scholar]
  36. Divecha, N. , Banfić, H. & Irvine, R.F. (1991) The polyphosphoinositide cycle exists in the nuclei of Swiss 3T3 cells under the control of a receptor (for IGF‐I) in the plasma membrane, and stimulation of the cycle increases nuclear diacylglycerol and apparently induces translocation of protein kinase. The EMBO Journal, 10, 3207–3214. Available from: 10.1002/j.1460-2075.1991.tb04883.x [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Doyon, Y. , Cayrou, C. , Ullah, M. , Landry, A.‐J. , Côté, V. , Selleck, W. , Lane, W.S. , Tan, S. , Yang, X.‐J. & Côté, J. (2006) ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation. Molecular Cell, 21, 51–64. Available from: 10.1016/j.molcel.2005.12.007 [DOI] [PubMed] [Google Scholar]
  38. Ellson, C.D. , Andrews, S. , Stephens, L.R. & Hawkins, P.T. (2002) The PX domain: a new phosphoinositide‐binding module. Journal of Cell Science, 115, 1099–1105. Available from: 10.1242/jcs.115.6.1099 [DOI] [PubMed] [Google Scholar]
  39. Fáberová, V. , Kalasová, I. , Krausová, A. & Hozák, P. (2020) Super‐resolution localisation of nuclear PI(4)P and identification of its interacting proteome. Cells, 9, 1191. Available from: 10.3390/cells9051191 [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Farhan, M. , Wang, H. , Gaur, U. , Little, P.J. , Xu, J. & Zheng, W. (2017) FOXO signaling pathways as therapeutic targets in cancer. International Journal of Biological Sciences, 13, 815–827. Available from: 10.7150/ijbs.20052 [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Ferguson, K.M. , Lemmon, M.A. , Schlessinger, J. & Sigler, P.B. (1995) Structure of the high affinity complex of inositol trisphosphate with a phospholipase C pleckstrin homology domain. Cell, 83, 1037–1046. Available from: 10.1016/0092-8674(95)90219-8 [DOI] [PubMed] [Google Scholar]
  42. Filippakopoulos, P. & Knapp, S. (2014) Targeting bromodomains: epigenetic readers of lysine acetylation. Nature Reviews Drug Discovery, 13, 337–356. Available from: 10.1038/nrd4286 [DOI] [PubMed] [Google Scholar]
  43. Fiume, R. , Faenza, I. , Sheth, B. , Poli, A. , Vidalle, M.C. , Mazzetti, C. , Abdul, S.H. , Campagnoli, F. , Fabbrini, M. , Kimber, S.T. , Mariani, G.A. , Xian, J. , Marvi, M.V. , Mongiorgi, S. , Shah, Z. & Divecha, N. (2019) Nuclear phosphoinositides: their regulation and roles in nuclear functions. International Journal of Molecular Sciences, 20, 2991. Available from: 10.3390/ijms20122991 [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Gao, C. , Glass, K.C. & Frietze, S. (2022) Functional networks of the human bromodomain‐containing proteins. Frontiers in Bioinformatics, 2, 835892. Available from: 10.3389/fbinf.2022.835892 [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Gelato, K.A. , Tauber, M. , Ong, M.S. , Winter, S. , Hiragami‐Hamada, K. , Sindlinger, J. , Lemak, A. , Bultsma, Y. , Houliston, S. , Schwarzer, D. , Divecha, N. , Arrowsmith, C.H. & Fischle, W. (2014) Accessibility of different histone H3‐binding domains of UHRF1 is allosterically regulated by phosphatidylinositol 5‐phosphate. Molecular Cell, 54, 905–919. Available from: 10.1016/j.molcel.2014.04.004 [DOI] [PubMed] [Google Scholar]
  46. Gillooly, D.J. (2000) Localization of phosphatidylinositol 3‐phosphate in yeast and mammalian cells. The EMBO Journal, 19, 4577–4588. Available from: 10.1093/emboj/19.17.4577 [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Glancy, E. , Ciferri, C. & Bracken, A.P. (2021) Structural basis for PRC2 engagement with chromatin. Current Opinion in Structural Biology, 67, 135–144. Available from: 10.1016/j.sbi.2020.10.017 [DOI] [PubMed] [Google Scholar]
  48. Gong, F. , Chiu, L.‐Y. & Miller, K.M. (2016) Acetylation reader proteins: linking acetylation signaling to genome maintenance and cancer. PLoS Genetics, 12, e1006272. Available from: 10.1371/journal.pgen.1006272 [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Gozani, O. , Karuman, P. , Jones, D.R. , Ivanov, D. , Cha, J. , Lugovskoy, A.A. , Baird, C.L. , Zhu, H. , Field, S.J. , Lessnick, S.L. , Villasenor, J. , Mehrotra, B. , Chen, J. , Rao, V.R. , Brugge, J.S. , Ferguson, C.G. , Payrastre, B. , Myszka, D.G. , Cantley, L.C. , Wagner, G. , Divecha, N. , Prestwich, G.D. & Yuan, J. (2003) The PHD finger of the chromatin‐associated protein ING2 functions as a nuclear phosphoinositide receptor. Cell, 114, 99–111. Available from: 10.1016/S0092-8674(03)00480-X [DOI] [PubMed] [Google Scholar]
  50. Gu, L. , Fu, Y. & Li, X. (2024) Roles of post‐translational modifications of UHRF1 in cancer. Epigenetics & Chromatin, 17, 15. Available from: 10.1186/s13072-024-00540-y [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Guarnaccia, A. & Tansey, W. (2018) Moonlighting with WDR5: a cellular multitasker. Journal of Clinical Medicine, 7, 21. Available from: 10.3390/jcm7020021 [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Hamann, B.L. & Blind, R.D. (2018) Nuclear phosphoinositide regulation of chromatin. Journal Cellular Physiology, 233, 107–123. Available from: 10.1002/jcp.25886 [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Harlan, J.E. , Hajduk, P.J. , Yoon, H.S. & Fesik, S.W. (1994) Pleckstrin homology domains bind to phosphatidylinositol‐4,5‐bisphosphate. Nature, 371, 168–170. Available from: 10.1038/371168a0 [DOI] [PubMed] [Google Scholar]
  54. Harvey, K.F. , Zhang, X. & Thomas, D.M. (2013) The Hippo pathway and human cancer. Nature Reviews Cancer, 13, 246–257. Available from: 10.1038/nrc3458 [DOI] [PubMed] [Google Scholar]
  55. Hirsch, E. , Fantastico, E. , Prever, L. & Gulluni, F. (2024) A connection between phosphatidylinositol 5‐phosphate and the Hippo pathway to prevent epithelial‐mesenchymal transition in cancer. Science Signaling, 17, eadp3504. Available from: 10.1126/scisignal.adp3504 [DOI] [PubMed] [Google Scholar]
  56. Hong, A.W. , Meng, Z. , Plouffe, S.W. , Lin, Z. , Zhang, M. & Guan, K.‐L. (2020) Critical roles of phosphoinositides and NF2 in Hippo pathway regulation. Genes & Development, 34, 511–525. Available from: 10.1101/gad.333435.119 [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Hsuan, J. & Cockcroft, S. (2001) The PITP family of phosphatidylinositol transfer proteins. Genome Biology, 2, reviews3011.1. Available from: 10.1186/gb-2001-2-9-reviews3011 [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Hyun, K. , Jeon, J. , Park, K. & Kim, J. (2017) Writing, erasing and reading histone lysine methylations. Experimental & Molecular Medicine, 49, e324–e324. Available from: 10.1038/emm.2017.11 [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Irvine, R.F. & Divecha, N. (1992) Phospholipids in the nucleus—metabolism and possible functions. Seminars in Cell Biology, 3, 225–235. Available from: 10.1016/1043-4682(92)90024-P [DOI] [PubMed] [Google Scholar]
  60. Jones, D.R. , Bultsma, Y. , Keune, W.‐J. , Halstead, J.R. , Elouarrat, D. , Mohammed, S. , Heck, A.J. , D'Santos, C.S. & Divecha, N. (2006) Nuclear PtdIns5P as a transducer of stress signaling: an in vivo role for PIP4Kbeta. Molecular Cell, 23, 685–695. Available from: 10.1016/j.molcel.2006.07.014 [DOI] [PubMed] [Google Scholar]
  61. Jung, O. , Baek, M. , Wooldrik, C. , Johnson, K.R. , Fisher, K.W. , Lou, J. , Ricks, T.J. , Wen, T. , Best, M.D. , Cryns, V.L. , Anderson, R.A. & Choi, S. (2024) Nuclear phosphoinositide signaling promotes YAP/TAZ‐TEAD transcriptional activity in breast cancer. The EMBO Journal, 43, 1740–1769. Available from: 10.1038/s44318-024-00085-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Jungmichel, S. , Sylvestersen, K.B. , Choudhary, C. , Nguyen, S. , Mann, M. & Nielsen, M.L. (2014) Specificity and commonality of the phosphoinositide‐binding proteome analyzed by quantitative mass spectrometry. Cell Reports, 6, 578–591. Available from: 10.1016/j.celrep.2013.12.038 [DOI] [PubMed] [Google Scholar]
  63. Kanai, F. , Liu, H. , Field, S.J. , Akbary, H. , Matsuo, T. , Brown, G.E. , Cantley, L.C. & Yaffe, M.B. (2001) The PX domains of p47phox and p40phox bind to lipid products of PI(3)K. Nature Cell Biology, 3, 675–678. Available from: 10.1038/35083070 [DOI] [PubMed] [Google Scholar]
  64. Karlić, R. , Chung, H.‐R. , Lasserre, J. , Vlahoviček, K. & Vingron, M. (2010) Histone modification levels are predictive for gene expression. Proceedings of the National Academy of Sciences USA, 107, 2926–2931. Available from: 10.1073/pnas.0909344107 [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Karlsson, T. , Altankhuyag, A. , Dobrovolska, O. , Turcu, D.C. & Lewis, A.E. (2016) A polybasic motif in ErbB3‐binding protein 1 (EBP1) has key functions in nucleolar localization and polyphosphoinositide interaction. Biochemical Journal, 473, 2033–2047. Available from: 10.1042/BCJ20160274 [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Kim, Y.J. , Guzman‐Hernandez, M.L. & Balla, T. (2011) A highly dynamic ER‐derived phosphatidylinositol‐synthesizing organelle supplies phosphoinositides to cellular membranes. Developmental Cell, 21, 813–824. Available from: 10.1016/j.devcel.2011.09.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Krylova, I.N. , Sablin, E.P. , Moore, J. , Xu, R.X. , Waitt, G.M. , MacKay, J.A. , Juzumiene, D. , Bynum, J.M. , Madams, K. , Montana, V. , Lebed Eva, L. , Suzawa, M. , Williams, J.D. , Williams, S.P. , Guy, R.K. , Thornton, J.W. , Fletterick, R.J. , Wilson, T.M. & Ingraham, H.A. (2005) Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF‐1 and LRH‐1. Cell, 120, 343–355. Available from: 10.1016/j.cell.2005.01.024 [DOI] [PubMed] [Google Scholar]
  68. Lee, K. , Whedon, S.D. , Wang, Z.A. & Cole, P.A. (2022) Distinct biochemical properties of the class I histone deacetylase complexes. Current Opinion in Chemical Biology, 70, 102179. Available from: 10.1016/j.cbpa.2022.102179 [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Lewis, A.E. , Sommer, L. , Arntzen, M.Ø. , Strahm, Y. , Morrice, N.A. , Divecha, N. & D'Santos, C.S. (2011) Identification of nuclear phosphatidylinositol 4,5‐bisphosphate‐interacting proteins by neomycin extraction. Molecular & Cellular Proteomics, 10, S1–S15. Available from: 10.1074/mcp.M110.003376 [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Li, F.‐L. , Fu, V. , Liu, G. , Tang, T. , Konradi, A.W. , Peng, X. , Kemper, E. , Cravatt, B.F. , Franklin, J.M. , Wu, Z. , Mayfield, J. , Dixon, J.E. , Gerwick, W.H. & Guan, K.‐L. (2022) Hippo pathway regulation by phosphatidylinositol transfer protein and phosphoinositides. Nature Chemical Biology, 18, 1076–1086. Available from: 10.1038/s41589-022-01061-z [DOI] [PubMed] [Google Scholar]
  71. Li, Y. , Choi, M. , Cavey, G. , Daugherty, J. , Suino, K. , Kovach, A. , Bingham, N.C. , Kliewer, S.A. & Xu, H.E. (2005) Crystallographic identification and functional characterization of phospholipids as ligands for the orphan nuclear receptor steroidogenic factor‐1. Molecular Cell, 17, 491–502. Available from: 10.1016/j.molcel.2005.02.002 [DOI] [PubMed] [Google Scholar]
  72. Liu, X. , Gao, Q. , Li, P. , Zhao, Q. , Zhang, J. , Li, J. , Koseki, H. & Wong, J. (2013) UHRF1 targets DNMT1 for DNA methylation through cooperative binding of hemi‐methylated DNA and methylated H3K9. Nature Communications, 4, 1563. Available from: 10.1038/ncomms2562 [DOI] [PubMed] [Google Scholar]
  73. Mandal, P. , Eswara, K. , Yerkesh, Z. , Kharchenko, V. , Zandarashvili, L. , Szczepski, K. , Bensaddek, D. , Jaremko, Ł. , Black, B.E. & Fischle, W. (2022) Molecular basis of hUHRF1 allosteric activation for synergistic histone modification binding by PI5P. Science Advances, 8, eabl9461. Available from: 10.1126/sciadv.abl9461 [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Mansat, M. , Kpotor, A.O. , Chicanne, G. , Picot, M. , Mazars, A. , Flores‐Flores, R. , Payrastre, B. , Hnia, K. & Viaud, J. (2024) MTM1‐mediated production of phosphatidylinositol 5‐phosphate fuels the formation of podosome‐like protrusions regulating myoblast fusion. Proceedings of the National Academy of Sciences USA, 121, e2217971121. Available from: 10.1073/pnas.2217971121 [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Martelli, A.M. , Tabellini, G. , Bressanin, D. , Ognibene, A. , Goto, K. , Cocco, L. & Evangelisti, C. (2012) The emerging multiple roles of nuclear Akt. Biochimica et Biophysica Acta (BBA)—Molecular Cell Research, 1823, 2168–2178. Available from: 10.1016/j.bbamcr.2012.08.017 [DOI] [PubMed] [Google Scholar]
  76. Mazloumi Gavgani, F. , Slinning, M.S. , Morovicz, A.P. , Arnesen, V.S. , Turcu, D.C. , Ninzima, S. , D'Santos, C.S. & Lewis, A.E. (2021) Nuclear phosphatidylinositol 3,4,5‐trisphosphate interactome uncovers an enrichment in nucleolar proteins. Molecular & Cellular Proteomics, 20, 100102. Available from: 10.1016/j.mcpro.2021.100102 [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Meier, K. & Brehm, A. (2014) Chromatin regulation: how complex does it get? Epigenetics, 9, 1485–1495. Available from: 10.4161/15592294.2014.971580 [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Meier, R. , Alessi, D.R. , Cron, P. , Andjelković, M. & Hemmings, B.A. (1997) Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase Bβ. Journal of Biological Chemistry, 272, 30491–30497. Available from: 10.1074/jbc.272.48.30491 [DOI] [PubMed] [Google Scholar]
  79. Millán‐Zambrano, G. , Burton, A. , Bannister, A.J. & Schneider, R. (2022) Histone post‐translational modifications—cause and consequence of genome function. Nature Reviews Genetics, 23, 563–580. Available from: 10.1038/s41576-022-00468-7 [DOI] [PubMed] [Google Scholar]
  80. Ortlund, E.A. , Lee, Y. , Solomon, I.H. , Hager, J.M. , Safi, R. , Choi, Y. , Guan, Z. , Tripathy, A. , Raetz, C.R.H. , McDonnell, D.P. , Moore, D.D. & Redinbo, M.R. (2005) Modulation of human nuclear receptor LRH‐1 activity by phospholipids and SHP. Nature Structural & Molecular Biology, 12, 357–363. Available from: 10.1038/nsmb910 [DOI] [PubMed] [Google Scholar]
  81. Osborne, S.L. , Thomas, C.L. , Gschmeissner, S. & Schiavo, G. (2001) Nuclear PtdIns(4,5)P2 assembles in a mitotically regulated particle involved in pre‐mRNA splicing. Journal of Cell Science, 114, 2501–2511. Available from: 10.1242/jcs.114.13.2501 [DOI] [PubMed] [Google Scholar]
  82. Palamiuc, L. , Johnson, J.L. , Haratipour, Z. , Loughran, R.M. , Choi, W.J. , Arora, G.K. , Tieu, V. , Ly, K. , Llorente, A. , Crabtree, S. , Wong, J.C.Y. , Ravi, A. , Wiederhold, T. , Murad, R. , Blind, R.D. & Emerling, B.M. (2024) Hippo and PI5P4K signaling intersect to control the transcriptional activation of YAP. Science Signaling, 17, eado6266. Available from: 10.1126/scisignal.ado6266 [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Paterson, H.F. , Savopoulos, J.W. , Perisic, O. , Cheung, R. , Ellis, M.V. , Williams, R.L. & Katan, M. (1995) Phospholipase C δ 1 requires a pleckstrin homology domain for interaction with the plasma membrane. Biochemical Journal, 312, 661–666. Available from: 10.1042/bj3120661 [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Payrastre, B. , Nievers, M. , Boonstra, J. , Breton, M. , Verkleij, A.J. & Van Bergen en Henegouwen, P.M. (1992) A differential location of phosphoinositide kinases, diacylglycerol kinase, and phospholipase C in the nuclear matrix. Journal of Biological Chemistry, 267, 5078–5084. [PubMed] [Google Scholar]
  85. Peña, P.V. , Davrazou, F. , Shi, X. , Walter, K.L. , Verkhusha, V.V. , Gozani, O. , Zhao, R. & Kutateladze, T.G. (2006) Molecular mechanism of histone H3K4me3 recognition by plant homeodomain of ING2. Nature, 442, 100–103. Available from: 10.1038/nature04814 [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Phillips, M.J. & Voeltz, G.K. (2016) Structure and function of ER membrane contact sites with other organelles. Nature Reviews Molecular Cell Biology, 17, 69–82. Available from: 10.1038/nrm.2015.8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Poli, A. , Pennacchio, F.A. , Ghisleni, A. , Di Gennaro, M. , Lecacheur, M. , Nastały, P. , Crestani, M. , Pramotton, F.M. , Iannelli, F. , Beznusenko, G. , Mironov, A.A. , Panzetta, V. , Fusco, S. , Sheth, B. , Poulikakos, D. , Ferrari, A. , Gauthier, N. , Netti, P.A. , Divecha, N. & Maiuri, P. (2023) PIP4K2B is mechanoresponsive and controls heterochromatin‐driven nuclear softening through UHRF1. Nature Communications, 14, 1432. Available from: 10.1038/s41467-023-37064-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Poli, A. , Zaurito, A.E. , Abdul‐Hamid, S. , Fiume, R. , Faenza, I. & Divecha, N. (2019) Phosphatidylinositol 5 phosphate (PI5P): from behind the scenes to the front (nuclear) stage. International Journal of Molecular Sciences, 20, 2080. Available from: 10.3390/ijms20092080 [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Posor, Y. , Jang, W. & Haucke, V. (2022) Phosphoinositides as membrane organizers. Nature Reviews Molecular Cell Biology, 23, 797–816. Available from: 10.1038/s41580-022-00490-x [DOI] [PMC free article] [PubMed] [Google Scholar]
  90. Qin, S. & Min, J. (2014) Structure and function of the nucleosome‐binding PWWP domain. Trends in Biochemical Sciences, 39, 536–547. Available from: 10.1016/j.tibs.2014.09.001 [DOI] [PubMed] [Google Scholar]
  91. Rajakumara, E. , Wang, Z. , Ma, H. , Hu, L. , Chen, H. , Lin, Y. , Guo, R. , Wu, F. , Li, H. , Lan, F. , Shi, Y.G. , Xu, Y. , Patel, D.J. & Shi, Y. (2011) PHD finger recognition of unmodified histone H3R2 links UHRF1 to regulation of euchromatic gene expression. Molecular Cell, 43, 275–284. Available from: 10.1016/j.molcel.2011.07.006 [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Rameh, L.E. & Blind, R.D. (2023) 25 years of PI5P. Frontiers in Cell and Developmental Biology, 11, 1272911. Available from: 10.3389/fcell.2023.1272911 [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Rando, O.J. , Zhao, K. , Janmey, P. & Crabtree, G.R. (2002) Phosphatidylinositol‐dependent actin filament binding by the SWI/SNF‐like BAF chromatin remodeling complex. Proceedings of the National Academy of Sciences USA, 99, 2824–2829. Available from: 10.1073/pnas.032662899 [DOI] [PMC free article] [PubMed] [Google Scholar]
  94. Reyes, A.A. , Marcum, R.D. & He, Y. (2021) Structure and function of chromatin remodelers. Journal of Molecular Biology, 433, 166929. Available from: 10.1016/j.jmb.2021.166929 [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Reynoird, N. & Gozani, O. (2014) Nuclear PI5P, Uhrf1, and the road not taken. Molecular Cell, 54, 901–903. Available from: 10.1016/j.molcel.2014.06.012 [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. Rodriguez‐Colman, M.J. , Dansen, T.B. , Burgering & Boudewijn M.T. (2024) FOXO transcription factors as mediators of stress adaptation. Nature Reviews Molecular Cell Biology, 25, 46–64. Available from: 10.1038/s41580-023-00649-0 [DOI] [PubMed] [Google Scholar]
  97. Sablin, E.P. , Blind, R.D. , Uthayaruban, R. , Chiu, H.‐J. , Deacon, A.M. , Das, D. , Ingraham, H.A. & Fletterick, R.J. (2015) Structure of liver receptor homolog‐1 (NR5A2) with PIP3 hormone bound in the ligand binding pocket. Journal of Structural Biology, 192, 342–348. Available from: 10.1016/j.jsb.2015.09.012 [DOI] [PMC free article] [PubMed] [Google Scholar]
  98. Sanchez, R. & Zhou, M.‐M. (2011) The PHD finger: a versatile epigenome reader. Trends in Biochemical Sciences, 36, 364–372. S0968000411000491. Available from: 10.1016/j.tibs.2011.03.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Sauer, P.V. , Gu, Y. , Liu, W.H. , Mattiroli, F. , Panne, D. , Luger, K. & Churchill, M.E. (2018) Mechanistic insights into histone deposition and nucleosome assembly by the chromatin assembly factor‐1. Nucleic Acids Research, 46, 9907–9917. Available from: 10.1093/nar/gky823 [DOI] [PMC free article] [PubMed] [Google Scholar]
  100. Shi, X. , Hong, T. , Walter, K.L. , Ewalt, M. , Michishita, E. , Hung, T. , Carney, D. , Peña, P. , Lan, F. , Kaadige, M.R. , Lacoste, N. , Cayrou, C. , Davrazou, F. , Saha, A. , Cairns, B.R. , Ayer, D.E. , Kutateladze, T.G. , Shi, Y. , Côté, J. , Chua, K.F. & Gozani, O. (2006) ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature, 442, 96–99. Available from: 10.1038/nature04835 [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Sobol, M. , Krausová, A. , Yildirim, S. , Kalasová, I. , Fáberová, V. , Vrkoslav, V. , Philimonenko, V. , Marášek, P. , Pastorek, L. , Čapek, M. , Lubovská, Z. , Uličná, L. , Tsuji, T. , Lísa, M. , Cvačka, J. , Fujimoto, T. & Hozak, P. (2018) Nuclear phosphatidylinositol 4,5‐bisphosphate islets contribute to efficient RNA polymerase II‐dependent transcription. Journal of Cell Science, 131, jcs211094. Available from: 10.1242/jcs.211094 [DOI] [PubMed] [Google Scholar]
  102. Song, Y. , Liu, H. , Xian, Q. , Gui, C. , Xu, M. & Zhou, Y. (2023) Mechanistic insights into UHRF1‑mediated DNA methylation by structure‑based functional clarification of UHRF1 domains (review). Oncology Letters, 26, 542. Available from: 10.3892/ol.2023.14129 [DOI] [PMC free article] [PubMed] [Google Scholar]
  103. Stenmark, H. , Aasland, R. & Driscoll, P.C. (2002) The phosphatidylinositol 3‐phosphate‐binding FYVE finger. FEBS Letters, 513, 77–84. Available from: 10.1016/S0014-5793(01)03308-7 [DOI] [PubMed] [Google Scholar]
  104. Stenmark, H. , Aasland, R. , Toh, B.‐H. & D'Arrigo, A. (1996) Endosomal localization of the autoantigen EEA1 is mediated by a zinc‐binding FYVE finger. Journal of Biological Chemistry, 271, 24048–24054. Available from: 10.1074/jbc.271.39.24048 [DOI] [PubMed] [Google Scholar]
  105. Stijf‐Bultsma, Y. , Sommer, L. , Tauber, M. , Baalbaki, M. , Giardoglou, P. , Jones, D.R. , Gelato, K.A. , van Pelt, J. , Shah, Z. , Rahnamoun, H. , Toma, C. , Anderson, K.E. , Hawkins, P. , Lauberth, S.M. , Haramis, A.‐P.G. , Hart, D. , Fischle, W. & Divecha, N. (2015) The basal transcription complex component TAF3 transduces changes in nuclear phosphoinositides into transcriptional output. Molecular Cell, 58, 453–467. Available from: 10.1016/j.molcel.2015.03.009 [DOI] [PMC free article] [PubMed] [Google Scholar]
  106. Sztacho, M. , Sobol, M. , Balaban, C. , Escudeiro Lopes, S.E. & Hozák, P. (2019) Nuclear phosphoinositides and phase separation: Important players in nuclear compartmentalization. Advances in Biological Regulation, 71, 111–117. Available from: 10.1016/j.jbior.2018.09.009 [DOI] [PubMed] [Google Scholar]
  107. Thumm, M. , Busse, R.A. , Scacioc, A. , Stephan, M. , Janshoff, A. , Kühnel, K. & Krick, R. (2013) It takes two to tango: PROPPINs use two phosphoinositide‐binding sites. Autophagy, 9, 106–107. Available from: 10.4161/auto.22400 [DOI] [PMC free article] [PubMed] [Google Scholar]
  108. Toker, A. (2002) Phosphoinositides and signal transduction. Cellular and Molecular Life Sciences, 59, 761–779. Available from: 10.1007/s00018-002-8465-z [DOI] [PMC free article] [PubMed] [Google Scholar]
  109. Toska, E. , Campbell, H.A. , Shandilya, J. , Goodfellow, S.J. , Shore, P. , Medler, K.F. & Roberts, S.G.E. (2012) Repression of transcription by WT1‐BASP1 requires the myristoylation of BASP1 and the PIP2‐dependent recruitment of histone deacetylase. Cell Reports, 2, 462–469. Available from: 10.1016/j.celrep.2012.08.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
  110. Tyagi, M. , Imam, N. , Verma, K. & Patel, A.K. (2016) Chromatin remodelers: we are the drivers!! Nucleus, 7, 388–404. Available from: 10.1080/19491034.2016.1211217 [DOI] [PMC free article] [PubMed] [Google Scholar]
  111. Ulicna, L. , Kalendova, A. , Kalasova, I. , Vacik, T. & Hozák, P. (2018) PIP2 epigenetically represses rRNA genes transcription interacting with PHF8. Biochimica et Biophysica Acta (BBA)—Molecular and Cell Biology of Lipids, 1863, 266–275. Available from: 10.1016/j.bbalip.2017.12.008 [DOI] [PubMed] [Google Scholar]
  112. Ungewickell, A. , Hugge, C. , Kisseleva, M. , Chang, S.‐C. , Zou, J. , Feng, Y. , Galyov, E.E. , Wilson, M. & Majerus, P.W. (2005) The identification and characterization of two phosphatidylinositol‐4,5‐bisphosphate 4‐phosphatases. Proceedings of the National Academy of Sciences USA, 102, 18854–18859. Available from: 10.1073/pnas.0509740102 [DOI] [PMC free article] [PubMed] [Google Scholar]
  113. Verrier, L. , Vandromme, M. & Trouche, D. (2011) Histone demethylases in chromatin cross‐talks. Biology of the Cell, 103, 381–401. Available from: 10.1042/BC20110028 [DOI] [PubMed] [Google Scholar]
  114. Viaud, J. , Boal, F. , Tronchère, H. , Gaits‐Iacovoni, F. & Payrastre, B. (2014) Phosphatidylinositol 5‐phosphate: a nuclear stress lipid and a tuner of membranes and cytoskeleton dynamics. BioEssays, 36, 260–272. Available from: 10.1002/bies.201300132 [DOI] [PubMed] [Google Scholar]
  115. Vidalle, M.C. , Sheth, B. , Fazio, A. , Marvi, M.V. , Leto, S. , Koufi, F.‐D. , Neri, I. , Casalin, I. , Ramazzotti, G. , Follo, M.Y. , Ratti, S. , Manzoli, L. , Gehlot, S. , Divecha, N & Fiume, R. (2023) Nuclear phosphoinositides as key determinants of nuclear functions. Biomolecules, 13, 1049. Available from: 10.3390/biom13071049 [DOI] [PMC free article] [PubMed] [Google Scholar]
  116. Viiri, K.M. , Jänis, J. , Siggers, T. , Heinonen, T.Y.K. , Valjakka, J. , Bulyk, M.L. , Mäki, M. & Lohi, O. (2009) DNA‐binding and ‐bending activities of SAP30L and SAP30 are mediated by a zinc‐dependent module and monophosphoinositides. Molecular and Cellular Biology, 29, 342–356. Available from: 10.1128/MCB.01213-08 [DOI] [PMC free article] [PubMed] [Google Scholar]
  117. Wang, R. & Brattain, M.G. (2006) AKT can be activated in the nucleus. Cellular Signalling, 18, 1722–1731. Available from: 10.1016/j.cellsig.2006.01.020 [DOI] [PubMed] [Google Scholar]
  118. Wang, Y.‐H. , Hariharan, A. , Bastianello, G. , Toyama, Y. , Shivashankar, G.V. , Foiani, M. & Sheetz, M.P. (2017) DNA damage causes rapid accumulation of phosphoinositides for ATR signaling. Nature Communications, 8, 2118. Available from: 10.1038/s41467-017-01805-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
  119. Wang, Y.‐H. & Sheetz, M.P. (2022) When PIP2 meets p53: nuclear phosphoinositide signaling in the DNA damage response. Frontiers in Cell and Developmental Biology, 10, 903994. Available from: 10.3389/fcell.2022.903994 [DOI] [PMC free article] [PubMed] [Google Scholar]
  120. Watt, S.A. , Kular, G. , Fleming, I.N. , Downes, C.P. & Lucocq, J.M. (2002) Subcellular localization of phosphatidylinositol 4,5‐bisphosphate using the pleckstrin homology domain of phospholipase C δ1. Biochemical Journal, 363, 657–666. Available from: 10.1042/bj3630657 [DOI] [PMC free article] [PubMed] [Google Scholar]
  121. Wen, T. , Chen, M. , Cryns, V.L. & Anderson, R.A. (2024) Regulation of the poly(A) polymerase star‐PAP by a nuclear phosphoinositide signalosome. bioRxiv (Preprint). Jul 2:2024.07.01.601467 . Available from: 10.1101/2024.07.01.601467 [DOI]
  122. Yao, W. , Hu, X. & Wang, X. (2024) Crossing epigenetic frontiers: the intersection of novel histone modifications and diseases. Signal Transduction and Targeted Therapy, 9, 232. Available from: 10.1038/s41392-024-01918-w [DOI] [PMC free article] [PubMed] [Google Scholar]
  123. Zhang, T. , Cooper, S. & Brockdorff, N. (2015) The interplay of histone modifications—writers that read. EMBO Reports, 16, 1467–1481. Available from: 10.15252/embr.201540945 [DOI] [PMC free article] [PubMed] [Google Scholar]
  124. Zhao, K. , Wang, W. , Rando, O.J. , Xue, Y. , Swiderek, K. , Kuo, A. & Crabtree, G.R. (1998) Rapid and phosphoinositol‐dependent binding of the SWI/SNF‐like BAF complex to chromatin after T lymphocyte receptor signaling. Cell, 95, 625–636. Available from: 10.1016/S0092-8674(00)81633-5 [DOI] [PubMed] [Google Scholar]
  125. Zheng, Y. & Pan, D. (2019) The Hippo signaling pathway in development and disease. Developmental Cell, 50, 264–282. Available from: 10.1016/j.devcel.2019.06.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
  126. Zou, J. , Marjanovic, J. , Kisseleva, M.V. , Wilson, M. & Majerus, P.W. (2007) Type I phosphatidylinositol‐4,5‐bisphosphate 4‐phosphatase regulates stress‐induced apoptosis. Proceedings of the National Academy of Sciences USA, 104, 16834–16839. Available from: 10.1073/pnas.0708189104 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Articles from Biology of the Cell are provided here courtesy of Wiley

RESOURCES