Skip to main content
NCBI home page
Cell Cycle logoLink to Cell Cycle
. 2016 Mar 17;15(10):1317–1324. doi: 10.1080/15384101.2016.1160984

Epigenetic regulation by BAF (mSWI/SNF) chromatin remodeling complexes is indispensable for embryonic development

Huong Nguyen a,#, Godwin Sokpor a,#, Linh Pham a, Joachim Rosenbusch a, Anastassia Stoykova b,c, Jochen F Staiger a,c, Tran Tuoc a,c
PMCID: PMC4889280  PMID: 26986003

ABSTRACT

The multi-subunit chromatin-remodeling SWI/SNF (known as BAF for Brg/Brm-associated factor) complexes play essential roles in development. Studies have shown that the loss of individual BAF subunits often affects local chromatin structure and specific transcriptional programs. However, we do not fully understand how BAF complexes function in development because no animal mutant had been engineered to lack entire multi-subunit BAF complexes. Importantly, we recently reported that double conditional knock-out (dcKO) of the BAF155 and BAF170 core subunits in mice abolished the presence of the other BAF subunits in the developing cortex. The generated dcKO mutant provides a novel and powerful tool for investigating how entire BAF complexes affect cortical development. Using this model, we found that BAF complexes globally control the key heterochromatin marks, H3K27me2 and -3, by directly modulating the enzymatic activity of the H3K27 demethylases, Utx and Jmjd3. Here, we present further insights into how the scaffolding ability of the BAF155 and BAF170 core subunits maintains the stability of BAF complexes in the forebrain and throughout the embryo during development. Furthermore, we show that the loss of BAF complexes in the above-described model up-regulates H3K27me3 and impairs forebrain development and embryogenesis. These findings improve our understanding of epigenetic mechanisms and their modulation by the chromatin-remodeling SWI/SNF complexes that control embryonic development.

KEYWORDS: BAF (mSWI/SNF) complexes, brain development, Chromatin remodeling, epigenetics, embryogenesis, H3K27me2/3

Introduction

Embryogenesis and organogenesis are determined by the combined effects of myriad developmental events. In recent years, we have made substantial advances in understanding how embryonic development is regulated.1,2 The early development are coordinated by different molecular programs, in which epigenetic and chromatin-related controls are known to play crucial roles.2 Epigenetic regulation, which modulates the chromatin structure without altering the DNA sequence, has profoundly heritable influences on transcriptional programs.3 These changes in chromatin organization activate or repress gene expression programs either globally or locally, and may thus shape specific developmental events. Epigenetic mechanisms and chromatin regulation influence the ability of transcription factors (TFs) to access regulatory elements in their target genes. This occurs primarily via histone modification4 or the action of ATP-dependent chromatin remodeling complexes, such as SWI/SNF (BAF) complexes.5-8 In addition, recent studies have shown that DNA methylation9 and long non-coding RNA (lncRNA)-based mechanisms10 also contribute to the complexity of epigenetic regulation during development.

The types of covalent histone modification include histone acetylation, methylation, ubiquitination and phosphorylation.4,11 Histone modification (epigenetic marks) is catalyzed by 2 enzyme classes: histone writers (e.g., histone acetyltransferases, methyltransferases, kinases, and ubiquitin ligases) and histone erasers (e.g., histone deacetylases, demethylases, phosphatases, and deubiquitinases). The mis-regulation of histone writers and erasers will typically alter the epigenetic program and have profound effects on development.4,11

A number of non-covalent, energy-dependent chromatin remodeling complexes modulate the dynamicity of chromatin structures. Among them, the SWI/SNF complexes are the best characterized in both development and disease. Mammalian SWI/SNF (BAF) complexes are made up of 2 switchable ATPase subunits (Brg1 or Brm), core subunits (BAF47, BAF155, and BAF170) and a variety of lineage-specific subunits.7,12-14 The Brg1 and Brm ATPases hydrolyze adenosine triphosphate (ATP) and utilize the obtained energy to alter chromatin (nucleosome) structures, thereby modulating cellular processes such as gene expression.15-17 The various subunits (at least 15 have been identified) are capable of undergoing combinatorial assembly,7,18 yielding hundreds of distinct BAF complexes that can direct specific transcriptional events during development in vivo. The exceptional diversity of BAF complexes allows them to have functional specificity in biological processes. To investigate the roles of BAF complexes in development, researchers have focused on phenotypic analyses of model animals harboring mutations in single BAF subunits.2,19,20 However, although BAF complexes are known to play essential roles in development, studies using knockout mouse models for individual BAF subunits have yielded incomplete information regarding the functions of these complexes.

While the epigenetic machinery and chromatin-remodeling complexes are known to play essential roles in development, we know little about how they interact to coordinate developmental processes during embryogenesis and organogenesis. Recently, our group developed cortex-specific BAF155/BAF170cKO mouse mutant and showed that BAF complexes did not form in the cortices of these mice. We further showed that the known BAF subunits undergo proteasome-mediated degradation in the developing cortices of these mutants. Finally, we found that, during corticogenesis, BAF complexes globally control key heterochromatin marks (H3K27me2/3) by directly interacting with and modulating the enzymatic activity of the H3K27 demethylases. Here, we discuss these recent discoveries21 and present additional evidence suggesting that the BAF155 and BAF170 core subunits cooperate to stabilize the BAF complex and maintain the global level of H3K27me3 both in the developing forebrain and throughout the embryo. Our new findings indicate that BAF complexes act as key regulators of embryogenesis.

Results and discussion

BAF155 and BAF170 are indispensable for brain development and embryogenesis

By employing cortex-specific conditional mouse mutagenesis, we showed that the dual loss of the BAF155 and BAF170 subunits in double conditional knock-out (dcKO) mutants severely perturbed the growth of cortical structures, blocked the proliferation, differentiation and cell-cycle progression of cortical progenitors, and triggered a massive increase in the number of apoptotic cells.21 To further investigate how the loss of both BAF155 and BAF170 affects forebrain development, we generated forebrain-specific BAF155 and BAF170 dcKO mice by crossing mice floxed for BAF15522 and BAF17023 (BAF155fl/fl, BAF170fl/fl) with a FoxG1-Cre line.24 In FoxG1-Cre mice, the Cre-recombinase is driven in all telencephalic cells [including those of the cortex (Cx) and basal ganglia (BG)], but not in other parts of the brain [e.g., in the diencephalon (Di)].24 Remarkably, we found that the dcKO_FoxG1-Cre mutants completely lacked all telencephalic structures at E16.5.21 This indicated that the expressions of BAF155 and BAF170 are required for brain development.

To address whether BAF155 and BAF170 are essential for embryogenesis, we generated and analyzed a line harboring a full dcKO_CAG-Cre mutant with the tamoxifen (TAM)-inducible ubiquitous deleter, CAG-Cre line25 (Fig. 1). The dcKO_CAG-Cre mutants were injected with either TAM or corn oil (vehicle solution, control) at E9.5. Following TAM induction, we observed Cre-recombinase activation in all cells of the body.25 The mutants died between E14.5-E15.5, and exhibited a severe developmental retardation (Fig. 1). Together, these results show that the expressions of BAF155 and BAF170 are critical for determining overall embryogenesis, including the formations of the forebrain and cortex

Figure 1.

Figure 1.

Open in a new tab

The expressions of BAF155 and BAF170 are indispensable for embryonic development. dcKO_CAG-Cre embryos treated with TAM at E9.5 remained alive and showed roughly preserved morphology at E13.5, but thereafter died between E14.5 and E15.5. Scale bars = 1000 μm.

BAF155 and BAF170 control the stability of BAF complexes in both cultured cells and embryos

Hundreds of distinct BAF complexes are predicted to form in vivo by the combinatorial assembly of at least 15 identified BAF subunits.2 The functional specificity of a BAF complex is believed to reflect the composite surfaces of its integrated subunits, which are essential for the ability of these complexes to target the genome and interact with transcriptional factors (TFs), co-activators, co-repressors, and signaling pathways.2 We recently reported that BAF155 and BAF170 act as scaffolding subunits and are required to ensure the stability of the entire BAF complex in the developing cortex.21 The loss of BAF155 and BAF170 in cortex-specific dcKO mutants leads to the dissociation of all other BAF subunits from the complex. The free BAF subunits are subsequently ubiquitinated and degraded by the proteasome system.

In an effort to extend our analysis to other parts of the brain, we examined the expression levels of various BAF subunits (e.g., Brg1, Brm, BAF47, BAF60, and BAF250) following the loss of BAF155/BAF170 in telencephalon of dcKO_FoxG1-Cre embryos (Fig. 2). Consistent with the Cre-recombinase activity in the Cx and BG of dcKO_FoxG1-Cre mice, there was no detectable expression of BAF155 or BAF170 in these structures. In contrast, their expression levels were preserved in the Di, where Cre is inactive (Fig. 2A, B). Similar to the reported effects in cortical tissues,21 the loss of BAF155 and BAF170 in the telencephalon abrogated the expression of all BAF subunits throughout this structure, including in the BG (Fig. 2C-G). To investigate whether both BAF155 and BAF170 are required to stabilize BAF complexes throughout the embryo, the expression of BAF subunits was examined in ubiquitously inducible dcKO_CAG-Cre embryos with global loss of BAF155/BAF170 (Fig. 3). These dcKO_CAG-Cre mutants were injected with either TAM or corn oil (vehicle solution, as control) at E9.5 and analyzed at E13.5, when the mutants were still viable. Following treatment with TAM, the expression levels of BAF155 and BAF170 were considerably ablated (Fig. 3A–D, Table S1). Moreover, the expression levels of the tested BAF subunits (Brg1, Brm, BAF47, and BAF250) were severely diminished throughout the dcKO_CAG-Cre embryos, as compared to controls (Fig. 3E-L, Table S1). These findings suggest that BAF155 and BAF170 are required to maintain the expression levels of BAF subunits in living animals.

Figure 2.

Figure 2.

Open in a new tab

Expression of BAF subunits in telencephalon-specific dcKO_FoxG1-Cre mutants (A-G) Images show immunohistochemical (IHC) analyses for various core subunits of BAF complexes, including BAF155 (A), BAF170 (B), Brg1 (C), Brm (D), BAF47 (E), BAF60 (F), and BAF250 (G), in the forebrains of dcKO_FoxG1-Cre mutants at E11.5. The indicated BAF subunits are not detected in the BAF155/BAF170-knockout telencephalon. Scale bars = 500 μm. Abbreviations: Cx, cortex; BG, basal ganglia; and Di, diencephalon.

Figure 3.

Figure 3.

Open in a new tab

Expression of BAF subunits in embryos of TAM-inducible full dcKO_CAG-Cre mutants (A/C/E/G/I/K) E13.5 dcKO_CAG-Cre mutant embryos were treated with TAM at E9.5, and whole-embryo sections were immunostained with antibodies against BAF155 (A), BAF170 (C), Brg1 (E), Brm (G), BAF47 (I), and BAF250a (K). (B/D/F/H/J/L) Quantifications of fluorescent signal intensities obtained from the sections described (A/C/E/G/I/G) (see also Table S1 for statistical analysis). The results revealed that the protein expression levels of BAF155 and BAF170 were reduced throughout the TAM-treated dcKO_CAG-Cre mutant embryos, confirming the double knockdown of BAF155/BAF170. The expression levels of the other tested BAF subunits were also diminished in mutant embryos compared to controls. Scale bars = 500 μm.

In different tissues and cell lineages, BAF155 is highly expressed in proliferating stem/progenitor cells but generally down-regulated upon differentiation.23,26,27 Conversely, little BAF170 is expressed in stem/progenitor cells (e.g., embryonic stem cells, or ESCs) and at higher levels in differentiated cells (e.g., neurons).23,26,27 We hypothesized that although only low expression levels are detected for BAF170 in proliferating ESCs and for BAF155 in post-mitotic neurons, this expression is necessary and sufficient to stabilize the embryonic stem cell (es)BAF and neuronal (n)BAF complexes. Indeed, when we derived ESC lines from blastocysts and primary neurons from forebrains (both representing the dcKO_CAG-Cre genotype), we found that the depletion of BAF155 and BAF170 in these cultured cells led to the loss of BAF subunit expression at the protein level.21

These results collectively indicate that the knockout of BAF155/BAF170 in dcKO mutants eliminates the presence of known BAF complex subunits both in vitro and in vivo. Thus, the dcKO mutants provide a potent tool for investigating the roles of entire BAF complexes during development.

The loss of BAF complexes induces the accumulation of H3K27me2/3-marked heterochromatin

Previous studies suggested that the loss of individual BAF subunits has a local (not global) influence on chromatin marks.23,28 However, when we examined epigenetic marks in cortex-specific dcKO_Emx1-Cre mice, which lacked entire BAF complexes, we observed a global reduction in euchromatin along with increased H3K27me2/3 and decreased H3K9Ac in the developing cortex during both embryonic and perinatal stages, as assessed by assays such as ChIP-Seq, immunohistochemistry, and western blotting.21 Thus, our data showed for the first time that the presence of BAF complexes is needed to maintain the balance between global repression and local activation of epigenetic programs during cortical development.21

The intriguing observation that BAF complexes are lost from the telencephalon-specific dcKO_FoxG1-Cre and inducible full dcKO_CAG-Cre mutants prompted us to study how this BAF155/BAF170 loss-of-function affects the H3K27me3 repressive mark. We performed protein gel blotting (WB) on telencephalic tissue lysates from E11.5 dcKO_FoxG1-Cre mutants using an antibody against H3K27me3. Similar to our observation in cortical tissues, we found that the loss of BAF155 and BAF170 increased the level of H3K27me3 in telencephalon (Fig. 4A/C, Table S2). Likewise compared to control (non-injected) embryos, the H3K27me3 level was augmented in E13.5 dcKO_CAG-Cre embryos that had been injected with TAM at E9.5 (Fig. 4B/C; Table S2).

Figure 4.

Figure 4.

Open in a new tab

BAF complexes control the level of H3K27me3 in the brain and whole embryo during development (A) WB analysis of E11.5 telencephalons from telencephalon-specific dcKO_FoxG1-Cre mutants revealed that the lost expressions of BAF155 and BAF170 elevated the level of H3K27me3. (B) dcKO_CAG-Cre embryos treated with TAM at E9.5 showed upregulation of H3K27me3 at E13.5, compared to untreated control embryos. (C) Densitometric quantification of the WB bands shown in (A and B; see also Table S2 for statistical analysis). (D) Schematic indicating how altered levels of H3K27me2/3 demethylases (UTX/Kdm6a and JMJD3/Kdm6b), BAF complexes, and the H3K27 methyltransferase Ezh2 subunit of the PRC2 complex collectively modulate histone methylation, developmental defects and diseases (e.g., tumorgenesis).

H3K27me2 and -3 are chromatin modifications that have been linked to the down-regulation of gene expression.29,30 Thus, the massive enhancement of H3K27me3 in the dcKO mutants would be expected to trigger obvious repression of gene expression. Indeed, gene expression profiling of developing cortices from dcKO mutants revealed that most of the transcripts were downregulated, with only a few showing up-regulation.21 Remarkably, BAF complexes were found to positively regulate most of the genes that are repressed by the H3K27 methyltransferase, Ezh2.21,30

To directly examine the apparent opposing activity of BAF complexes and the Ezh2 subunit of the PRC2 complex, we treated dcKO mutants with an Ezh2 inhibitor and examined gene expression in developing cortex. We found that inhibition of the H3K27 methyltransferase partially rescued the expression of certain BAF-complex target genes.21 In mechanistic terms, our results suggested that this process involves binding of the BAF155 and BAF170 core subunits of the BAF complex to the JmjC domains of UTX/Kdm6a and JMJD3/Kdm6b, which are required for the H3K27me2/3 demethylase activities of these proteins.21

Ezh2 (or PRC2)29-31 and UTX/Kdm6a/JMJD3/Kdm6b32-38 are the only enzymes known to methylate and demethylate H3K27, respectively. These enzymes play essential roles in development and diseases by modulating gene expression programs through changes in the methylation of H3K27. Studies have shown that homozygous-null Ezh2 mutants die prior to completing gastrulation, conditional loss of maternal Ezh2 results in severe growth retardation among neonates,39,40 and EZH2 overexpression causes tumorigenesis.41,42 Phenotypic analysis revealed that mouse embryos dcKO for Utx and Jmjd3 (which encode the H3K27 demethylases) exhibit lethality at mid-gestation. Moreover, the expression levels of Jmjd3 and Utx are significantly decreased in several types of primary tumors.43 The BAF complexes, which we identified as important cofactors of the H3K27 demethylases, are known to be key players in development2,19-21 and tumor suppression.19,44-46 Thus, any alteration in the balance among the BAF complexes, H3K27 demethylases, and methyltransferase will result in severe developmental defects and/or diseases such as cancer (Fig. 4C).2,47-49

Conclusion

We herein present evidence suggesting that BAF155 and BAF170 act as scaffolding subunits to maintain the stability of BAF complexes. The loss of BAF complexes in BAF155/BAF170 double mutants is associated with severe defects in global epigenetic and gene expression programs during cortical development21 and embryogenesis (this study). Our results further suggest that manipulation of the endogenous expression and activity levels of the chromatin-remodeling BAF complexes, the H3K27me2/3 demethylases (UTX/Kdm6a and JMJD3/Kdm6b), and the H3K27me2/3 methyltransferase (polycomb repressive complex 2) might enable to alter global gene expression programs. The crosstalk between BAF complexes and epigenetic factors revealed herein may shed light on how cells acquire their fates. This work could thus contribute to the establishment of protocols aimed at differentiating specific lineages from pluripotent cells and/or treating diseases.

Materials and methods

Transgenic mice

Floxed BAF155,22 floxed BAF170,23 FoxG1-Cre24 and CAG-Cre25 mouse lines were kept in a C57BL6/J background. All animal research was conducted in accordance with the local regulations for animal protection.

Immunohistochemistry (IHC) and Western blotting (WB)

IHC and WB were performed as previously described.50,51 The following polyclonal (pAb) and monoclonal (mAb) primary antibodies used in this study were obtained from the indicated commercial sources: Brg1 rabbit pAb (Santa Cruz), Brg1 mouse mAb (Santa Cruz), Brm mouse mAb (BD Biosciences), Brm rabbit pAb (Abcam), BAF250 mouse mAb (Sigma), BAF170 rabbit pAb (Bethyl), BAF170 rabbit pAb (Sigma), BAF155 rabbit pAb (Santa Cruz), BAF155 mouse mAb (Santa Cruz), BAF60a mouse mAb (BD Biosciences), GAPDH rabbit pAb (Santa Cruz), ß-actin rabbit pAb (Sigma), and H3K27me3 rabbit pAb (Upstate). The utilized secondary antibodies included peroxidase-conjugated goat anti-rabbit IgG (1:10,000; Covance), peroxidase-conjugated goat anti-mouse IgG (1:5000; Covance), and Alexa 488- or Alexa 568-conjugated IgG (various species,1: 400; Molecular Probes).

Imaging and quantitative and statistical analyses

Imaging was performed with an Axio Imager M2 (Zeiss) with a Neurolucida system (Version 11; MBF Bioscience) and confocal fluorescence microscopes (TCS SP5; Leica). Pictures were analyzed further with Adobe Photoshop. Densitometric quantification of WB bands and quantitative analysis of IHC signal intensities were performed using the ImageJ software, as described previously.21,51 Statistical analyses were carried out using the Student's t-test. The results are presented as the mean ± SEM.

Supplementary Material

Supplemental Files

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

We acknowledge T. Huttanus, H. Fett, and U. Teichmann for their support with the animal breeding. We thank R. H. Seong, S. K. McConnell, and A. P. McMahon for providing the transgenic lines.

Funding

This work was supported by the Research Program at the Faculty of Medicine, Georg-August University Goettingen (to TT), DFG grants (TU432/1-1 and TU432/3-1 to TT), and DFG-CNMPB (to TT, JS, and AS). The authors declare that they have no competing financial interest.

References

  • [1].Kojima Y, Tam OH, Tam PP. Timing of developmental events in the early mouse embryo. Semin Cell Dev Biol 2014; 34:65-75; PMID:24954643; http://dx.doi.org/ 10.1016/j.semcdb.2014.06.010 [DOI] [PubMed] [Google Scholar]
  • [2].Ho L, Crabtree GR. Chromatin remodelling during development. Nature 2011; 463:474-84; http://dx.doi.org/ 10.1038/nature08911 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [3].Heard E, Martienssen RA. Transgenerational epigenetic inheritance: myths and mechanisms. Cell 2014; 157:95-109; PMID:24679529; http://dx.doi.org/ 10.1016/j.cell.2014.02.045 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [4].Goldberg AD, Allis CD, Bernstein E. Epigenetics: a landscape takes shape. Cell 2007; 128:635-8; PMID:17320500; http://dx.doi.org/ 10.1016/j.cell.2007.02.006 [DOI] [PubMed] [Google Scholar]
  • [5].MuhChyi C, Juliandi B, Matsuda T, Nakashima K. Epigenetic regulation of neural stem cell fate during corticogenesis. Int J Dev Neurosci 2013; 31:424-33; PMID:23466416; http://dx.doi.org/ 10.1016/j.ijdevneu.2013.02.006 [DOI] [PubMed] [Google Scholar]
  • [6].Wen S, Li H, Liu J. Epigenetic background of neuronal fate determination. Prog Neurobiol 2009; 87:98-117; PMID:19007844; http://dx.doi.org/ 10.1016/j.pneurobio.2008.10.002 [DOI] [PubMed] [Google Scholar]
  • [7].Ronan JL, Wu W, Crabtree GR. From neural development to cognition: unexpected roles for chromatin. Nat Rev Genet 2013; 14:347-59; PMID:23568486; http://dx.doi.org/ 10.1038/nrg3413 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [8].Narlikar GJ, Sundaramoorthy R, Owen-Hughes T. Mechanisms and functions of ATP-dependent chromatin-remodeling enzymes. Cell 2013; 154:490-503; PMID:23911317; http://dx.doi.org/ 10.1016/j.cell.2013.07.011 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [9].Wu H, Zhang Y. Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell 2014; 156:45-68; PMID:24439369; http://dx.doi.org/ 10.1016/j.cell.2013.12.019 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [10].Bohmdorfer G, Wierzbicki AT. Control of Chromatin Structure by Long Noncoding RNA. Trends Cell Biol 2015; 25:623-32; PMID:26410408; http://dx.doi.org/ 10.1016/j.tcb.2015.07.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [11].Strahl BD, Allis CD. The language of covalent histone modifications. Nature 2000; 403:41-5; PMID:10638745; http://dx.doi.org/ 10.1038/47412 [DOI] [PubMed] [Google Scholar]
  • [12].Lessard J, Wu JI, Ranish JA, Wan M, Winslow MM, Staahl BT, Wu H, Aebersold R, Graef IA, Crabtree GR. An essential switch in subunit composition of a chromatin remodeling complex during neural development. Neuron 2007; 55:201-15; PMID:17640523; http://dx.doi.org/ 10.1016/j.neuron.2007.06.019 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [13].Ho L, Ronan JL, Wu J, Staahl BT, Chen L, Kuo A, Lessard J, Nesvizhskii AI, Ranish J, Crabtree GR. An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency. Proc Natl Acad Sci U S A 2009; 106:5181-6; PMID:19279220; http://dx.doi.org/ 10.1073/pnas.0812889106 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [14].Kadoch C, Hargreaves DC, Hodges C, Elias L, Ho L, Ranish J, Crabtree GR. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat Genet 2013; 45:592-601; PMID:23644491; http://dx.doi.org/ 10.1038/ng.2628 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [15].Phelan ML, Sif S, Narlikar GJ, Kingston RE. Reconstitution of a core chromatin remodeling complex from SWI/SNF subunits. Mol Cell 1999; 3:247-53; PMID:10078207; http://dx.doi.org/ 10.1016/S1097-2765(00)80315-9 [DOI] [PubMed] [Google Scholar]
  • [16].Hirschhorn JN, Brown SA, Clark CD, Winston F. Evidence that SNF2/SWI2 and SNF5 activate transcription in yeast by altering chromatin structure. Genes Dev 1992; 6:2288-98; PMID:1459453; http://dx.doi.org/ 10.1101/gad.6.12a.2288 [DOI] [PubMed] [Google Scholar]
  • [17].Laurent BC, Treich I, Carlson M. The yeast SNF2/SWI2 protein has DNA-stimulated ATPase activity required for transcriptional activation. Genes Dev 1993; 7:583-91; PMID:8458575; http://dx.doi.org/ 10.1101/gad.7.4.583 [DOI] [PubMed] [Google Scholar]
  • [18].Wang W, Xue Y, Zhou S, Kuo A, Cairns BR, Crabtree GR. Diversity and specialization of mammalian SWI/SNF complexes. Genes Dev 1996; 10:2117-30; PMID:8804307; http://dx.doi.org/ 10.1101/gad.10.17.2117 [DOI] [PubMed] [Google Scholar]
  • [19].Ko M, Sohn DH, Chung H, Seong RH. Chromatin remodeling, development and disease. Mutat Res 2008; 647:59-67; PMID:18786551; http://dx.doi.org/ 10.1016/j.mrfmmm.2008.08.004 [DOI] [PubMed] [Google Scholar]
  • [20].Narayanan R, Tuoc TC. Roles of chromatin remodeling BAF complex in neural differentiation and reprogramming. Cell Tissue Res 2014; 356:575-84; PMID:24496512; http://dx.doi.org/ 10.1007/s00441-013-1791-7 [DOI] [PubMed] [Google Scholar]
  • [21].Narayanan R, Pirouz M, Kerimoglu C, Pham L, Wagener RJ, Kiszka KA, Rosenbusch J, Seong RH, Kessel M, Fischer A, et al.. Loss of BAF (mSWI/SNF) Complexes Causes Global Transcriptional and Chromatin State Changes in Forebrain Development. Cell Rep 2015; 13:1842-54; PMID:26655900; http://dx.doi.org/ 10.1016/j.celrep.2015.10.046 [DOI] [PubMed] [Google Scholar]
  • [22].Choi J, Ko M, Jeon S, Jeon Y, Park K, Lee C, Lee H, Seong RH. The SWI/SNF-like BAF complex is essential for early B cell development. J Immunol 2012; 188:3791-803; PMID:22427636; http://dx.doi.org/ 10.4049/jimmunol.1103390 [DOI] [PubMed] [Google Scholar]
  • [23].Tuoc TC, Boretius S, Sansom SN, Pitulescu ME, Frahm J, Livesey FJ, Stoykova A. Chromatin regulation by BAF170 controls cerebral cortical size and thickness. Dev Cell 2013; 25:256-69; PMID:23643363; http://dx.doi.org/ 10.1016/j.devcel.2013.04.005 [DOI] [PubMed] [Google Scholar]
  • [24].Hebert JM, McConnell SK. Targeting of cre to the Foxg1 (BF-1) locus mediates loxP recombination in the telencephalon and other developing head structures. Dev Biol 2000; 222:296-306; PMID:10837119; http://dx.doi.org/ 10.1006/dbio.2000.9732 [DOI] [PubMed] [Google Scholar]
  • [25].Hayashi S, McMahon AP. Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse. Dev Biol 2002; 244:305-18; PMID:11944939; http://dx.doi.org/ 10.1006/dbio.2002.0597 [DOI] [PubMed] [Google Scholar]
  • [26].Ho L, Ronan JL, Wu J, Staahl BT, Chen L, Kuo A, Lessard J, Nesvizhskii AI, Ranish J, Crabtree GR. An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency. Proc Natl Acad Sci U S A 2009; 106:5181-6; PMID:19279220; http://dx.doi.org/ 10.1073/pnas.0812889106 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [27].Yan Z, Wang Z, Sharova L, Sharov AA, Ling C, Piao Y, Aiba K, Matoba R, Wang W, Ko MS. BAF250B-associated SWI/SNF chromatin-remodeling complex is required to maintain undifferentiated mouse embryonic stem cells. Stem Cells 2008; 26:1155-65; PMID:18323406; http://dx.doi.org/ 10.1634/stemcells.2007-0846 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [28].Ho L, Miller EL, Ronan JL, Ho WQ, Jothi R, Crabtree GR. esBAF facilitates pluripotency by conditioning the genome for LIF/STAT3 signalling and by regulating polycomb function. Nat Cell Biol 2011; 13:903-13; PMID:21785422; http://dx.doi.org/ 10.1038/ncb2285 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [29].Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, Jones RS, Zhang Y. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 2002; 298:1039-43; PMID:12351676; http://dx.doi.org/ 10.1126/science.1076997 [DOI] [PubMed] [Google Scholar]
  • [30].Pereira JD, Sansom SN, Smith J, Dobenecker MW, Tarakhovsky A, Livesey FJ. Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex. Proc Natl Acad Sci U S A 2010; 107:15957-62; PMID:20798045; http://dx.doi.org/ 10.1073/pnas.1002530107 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [31].Shen X, Liu Y, Hsu YJ, Fujiwara Y, Kim J, Mao X, Yuan GC, Orkin SH. EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency. Mol Cell 2008; 32:491-502; PMID:19026780; http://dx.doi.org/ 10.1016/j.molcel.2008.10.016 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [32].Jepsen K, Solum D, Zhou T, McEvilly RJ, Kim HJ, Glass CK, Hermanson O, Rosenfeld MG. SMRT-mediated repression of an H3K27 demethylase in progression from neural stem cell to neuron. Nature 2007; 450:415-9; PMID:17928865; http://dx.doi.org/ 10.1038/nature06270 [DOI] [PubMed] [Google Scholar]
  • [33].Xiang Y, Zhu Z, Han G, Lin H, Xu L, Chen CD. JMJD3 is a histone H3K27 demethylase. Cell Res 2007; 17:850-7; PMID:17923864; http://dx.doi.org/ 10.1038/cr.2007.83 [DOI] [PubMed] [Google Scholar]
  • [34].Lee MG, Villa R, Trojer P, Norman J, Yan KP, Reinberg D, Di Croce L, Shiekhattar R. Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination. Science 2007; 318:447-50; PMID:17761849; http://dx.doi.org/ 10.1126/science.1149042 [DOI] [PubMed] [Google Scholar]
  • [35].Lan F, Bayliss PE, Rinn JL, Whetstine JR, Wang JK, Chen S, Iwase S, Alpatov R, Issaeva I, Canaani E, et al.. A histone H3 lysine 27 demethylase regulates animal posterior development. Nature 2007; 449:689-94; PMID:17851529; http://dx.doi.org/ 10.1038/nature06192 [DOI] [PubMed] [Google Scholar]
  • [36].Hong S, Cho YW, Yu LR, Yu H, Veenstra TD, Ge K. Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases. Proc Natl Acad Sci U S A 2007; 104:18439-44; PMID:18003914; http://dx.doi.org/ 10.1073/pnas.0707292104 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [37].Agger K, Cloos PA, Christensen J, Pasini D, Rose S, Rappsilber J, Issaeva I, Canaani E, Salcini AE, Helin K. UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature 2007; 449:731-4; PMID:17713478; http://dx.doi.org/ 10.1038/nature06145 [DOI] [PubMed] [Google Scholar]
  • [38].De Santa F, Totaro MG, Prosperini E, Notarbartolo S, Testa G, Natoli G. The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell 2007; 130:1083-94; PMID:17825402; http://dx.doi.org/ 10.1016/j.cell.2007.08.019 [DOI] [PubMed] [Google Scholar]
  • [39].Puschendorf M, Terranova R, Boutsma E, Mao XH, Isono KI, Brykczynska U, Kolb C, Otte AP, Koseki H, Orkin SH, et al.. PRC1 and Suv39h specify parental asymmetry at constitutive heterochromatin in early mouse embryos. Nat Genet 2008; 40:411-20; PMID:18311137; http://dx.doi.org/ 10.1038/ng.99 [DOI] [PubMed] [Google Scholar]
  • [40].Erhardt S, Su IH, Schneider R, Barton S, Bannister AJ, Perez-Burgos L, Jenuwein T, Kouzarides T, Tarakhovsky A, Surani MA. Consequences of the depletion of zygotic and embryonic enhancer of zeste 2 during preimplantation mouse development. Development 2003; 130:4235-48; PMID:12900441; http://dx.doi.org/ 10.1242/dev.00625 [DOI] [PubMed] [Google Scholar]
  • [41].Varambally S, Cao Q, Mani RS, Shankar S, Wang X, Ateeq B, Laxman B, Cao X, Jing X, Ramnarayanan K, et al.. Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science 2008; 322:1695-9; PMID:19008416; http://dx.doi.org/ 10.1126/science.1165395 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [42].Takawa M, Masuda K, Kunizaki M, Daigo Y, Takagi K, Iwai Y, Cho HS, Toyokawa G, Yamane Y, Maejima K, et al.. Validation of the histone methyltransferase EZH2 as a therapeutic target for various types of human cancer and as a prognostic marker. Cancer Sci 2011; 102:1298-305; PMID:21539681; http://dx.doi.org/ 10.1111/j.1349-7006.2011.01958.x [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [43].Agger K, Cloos PA, Rudkjaer L, Williams K, Andersen G, Christensen J, Helin K. The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence. Genes Dev 2009; 23:1171-6; PMID:19451217; http://dx.doi.org/ 10.1101/gad.510809 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [44].Wu JI. Diverse functions of ATP-dependent chromatin remodeling complexes in development and cancer. Acta Biochim Biophys Sin (Shanghai) 2012; 44:54-69; PMID:22194014; http://dx.doi.org/ 10.1093/abbs/gmr099 [DOI] [PubMed] [Google Scholar]
  • [45].Helming KC, Wang X, Roberts CW. Vulnerabilities of mutant SWI/SNF complexes in cancer. Cancer Cell 2014; 26:309-17; PMID:25203320; http://dx.doi.org/ 10.1016/j.ccr.2014.07.018 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [46].Masliah-Planchon J, Bieche I, Guinebretiere JM, Bourdeaut F, Delattre O. SWI/SNF chromatin remodeling and human malignancies. Annu Rev Pathol 2015; 10:145-71; PMID:25387058; http://dx.doi.org/ 10.1146/annurev-pathol-012414-040445 [DOI] [PubMed] [Google Scholar]
  • [47].Shi Y. Histone lysine demethylases: emerging roles in development, physiology and disease. Nat Rev Genet 2007; 8:829-33; PMID:17909537; http://dx.doi.org/ 10.1038/nrg2218 [DOI] [PubMed] [Google Scholar]
  • [48].Pedersen MT, Helin K. Histone demethylases in development and disease. Trends Cell Biol 2010; 20:662-71; PMID:20863703; http://dx.doi.org/ 10.1016/j.tcb.2010.08.011 [DOI] [PubMed] [Google Scholar]
  • [49].Kadoch C, Copeland RA, Keilhack H. PRC2 and SWI/SNF chromatin remodeling complexes in health and disease. Biochemistry 2016; 55:1600-14; PMID:26836503. [DOI] [PubMed] [Google Scholar]
  • [50].Tuoc TC, Radyushkin K, Tonchev AB, Pinon MC, Ashery-Padan R, Molnar Z, Davidoff MS, Stoykova A. Selective cortical layering abnormalities and behavioral deficits in cortex-specific Pax6 knockout mice. J Neurosci 2009; 29:8335-49; PMID:19571125; http://dx.doi.org/ 10.1523/JNEUROSCI.5669-08.2009 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [51].Tuoc TC, Stoykova A. Trim11 modulates the function of neurogenic transcription factor Pax6 through ubiquitin-proteosome system. Genes Dev 2008; 22:1972-86; PMID:18628401; http://dx.doi.org/ 10.1101/gad.471708 [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.

Supplementary Materials

Supplemental Files
kccy-15-10-1160984-s001.zip (19.3KB, zip)

Articles from Cell Cycle are provided here courtesy of Taylor & Francis

RESOURCES