Skip to main content
NCBI home page
Cell Cycle logoLink to Cell Cycle
. 2013 May 15;12(12):1828–1834. doi: 10.4161/cc.24992

Enforcing the pause

Transcription factor Sp3 limits productive elongation by RNA polymerase II

Alvaro Valin 1, Grace Gill 1,*
PMCID: PMC3735696  PMID: 23676218

Abstract

The transition of paused RNA polymerase II into productive elongation is a highly dynamic process that serves to fine-tune gene expression in response to changing cellular environments. We have recently reported that the transcription factor Sp3 inhibits the transition of paused RNA Pol II to productive elongation at the promoter of the cyclin-dependent kinase inhibitor p21CIP1 and other Sp3-repressed genes. Our studies support the view that Sp3 has three modes of action: activation, SUMO-Sp3-mediated heterochromatin silencing and SUMO-independent inhibition of elongation. At the p21CIP1 promoter, binding of the positive elongation factor P-TEFb kinase was not affected by Sp3. In contrast, Sp3 promoted binding of the protein phosphatase PP1 to the p21CIP1 promoter, suggesting that Sp3-dependent regulation of the local balance between kinase and phosphatase activities may contribute to gene expression. Our findings show that the transition of paused RNA Pol II to productive elongation is an important step regulated by both promoter-specific activators and repressors to finely modulate mRNA expression levels.

Keywords: Sp3, pause, elongation, repression, NELF, P-TEFb, phosphorylation, phosphatase

Introduction

Although transcription initiation was previously assumed to be the rate-limiting step for expression of most genes, recent studies have provided evidence that regulation of transcriptional elongation by RNA polymerase II is a prevalent mechanism for fine-tuning expression of inducible genes in response to developmental cues, cell signaling pathways and stress stimuli.1-5 Transcription of a gene by RNA Pol II is a multi-step process that involves a host of accessory factors. After RNA Pol II binds to a promoter and initiates RNA synthesis, RNA Pol II enters an early elongation phase, which is generally subject to promoter proximal pausing. Pausing is an intrinsic property of RNA Pol II that is influenced by features of the template, including the DNA sequence and the positioning of nucleosomes. The transition of paused RNA Pol II into productive elongation involves an exchange of associated factors that favors polymerase processivity and mRNA maturation, orchestrated in part by the phosphorylation of specific residues in the RNA Pol II C-terminal domain (CTD). This transition involves multiple steps and is regulated both positively and negatively by a large number of trans-acting factors,6-8 providing an opportunity for gene-specific regulation.

Transcription Factor Sp3 Regulates RNA Polymerase II Recruitment and the Transition of Paused Polymerase into Elongation

Sp3 is a broadly expressed zinc-finger transcription factor required for post-natal survival and differentiation of bone, tooth and hematopoietic lineages in mice.9,10 Sp3 and the related transcription factor Sp1 share a highly conserved zinc-finger DNA-binding domain that allows them to interact with the same GC-rich motif to control the expression of genes implicated in diverse processes, including cell cycle, hormone response, tissue-specific and housekeeping genes. A major distinctive feature of Sp3 is its ability to both activate and repress transcription depending on the promoter context. As illustrated in Figure 1, Sp3 can both positively and negatively regulate RNA Pol II binding to promoters. Sp3 activates transcription by promoting the recruitment of RNA Pol II,11 likely through interaction of the glutamine-rich motifs present in the N-terminal region of Sp3, with components of the general transcription factor machinery, similar to what has been described for Sp1.12,13 In contrast, Sp3 post-translationally modified by the small ubiquitin-related modifier (SUMO) blocks RNA Pol II binding to promoters by promoting a repressive chromatin structure (see below). In addition to these effects on RNA Pol II recruitment, we have recently found that Sp3 can repress expression of genes by regulating the transition of paused RNA Pol II into transcriptional elongation (Fig. 1).

graphic file with name cc-12-1828-g1.jpg

Open in a new tab

Figure 1. Transcription factor Sp3 can regulate transcription by three different mechanisms. Sp3 is shown bound to a GC-box promoter element. (A) Activation. Sp3 can promote RNA Pol II initiation by interacting with and recruiting factors of the general transcription machinery. (B) Silencing. Sp3 post-translationaly modified by SUMO recruits co-repressors (CoR) that promote heterochromatin formation thereby inhibiting recruitment of RNA Pol II, and (C) Inhibition. Sp3 acts post- RNA Pol II recruitment to inhibit the release of paused RNA Pol II into productive elongation.

Using shRNA to specifically knockdown Sp3 in HeLa cells, we have shown that Sp3 represses the expression of the negative regulator of the cell cycle p21CIP1. Knockdown of Sp3 led to increased p21CIP1 mRNA associated with an accumulation of cells in G0/G1 phase of the cell cycle.11 p21CIP1 expression is well established to be regulated at the level of transcription elongation14 and therefore served as a model for our investigations of regulation of RNA Pol II elongation by Sp3. RNA Pol II is highly enriched near the p21CIP1 promoter, in contrast to low levels across the transcribed region, a hallmark of polymerase stalling.2,15,16 Interestingly, knockdown of Sp3 did not reduce the level of RNA Pol II bound near the promoter, suggesting that Sp3 regulates RNA Pol II activity post-recruitment and, further, that loss of Sp3-dependent repression did not eliminate proximal-promoter pausing of RNA Pol II as a rate-limiting step of p21CIP1 transcription. In agreement with the presence of paused RNA Pol II, ChIP analysis across the p21CIP1gene showed enrichment of H3K4me3 histone modification at 5′ positions of the gene, suggesting an open chromatin structure1,11 in the presence and absence of Sp3-dependent repression. In contrast, when Sp3 levels were reduced, the elongation mark H3K36me3, increased significantly throughout the body of the gene. Furthermore, there was a relative enrichment of RNA Pol II phosphorylated at Ser2 of the C-terminal domain (CTD) at more 3′ positions of the p21CIP1 gene upon Sp3 knockdown, consistent with the model that Sp3 acts to inhibit the rate of escape of paused RNA Pol II into productive elongation. Paused RNA Pol II and features of open chromatin were found at many Sp3-repressed genes, suggesting that Sp3-dependent inhibition of elongation may occur broadly.

Previous studies by our laboratory and others demonstrated that Sp3 is post-translationally modified by SUMO, and this modification plays an important role in the repressor activity of Sp317,18 (Fig. 1). In most cases, SUMO conjugation of transcription factors has been associated with repression of transcription mediated by non-covalent interaction with SUMO-binding co-repressors.19 Consistent with this protein-protein interaction model, Suske and colleagues20-22 recently demonstrated that SUMOylation of Sp3 promotes the recruitment of corepressors, including the chromatin remodeler Mi2, chromatin-associated proteins L3MBTL1, L3MBTL2 and heterochromatin protein HP1, as well as histone methyltransferases SETDB1/ESET and SUV4–20H. Sp3-SUMO-mediated recruitment of these factors correlated with the establishment of a repressive chromatin structure characterized by H3K9me3- and H4K20me3-modified histones. This mechanism has been shown to play a role in the silencing of spermatocyte- and neuron-specific genes in other tissues, suggesting that SUMOylation of Sp3 contributes to tissue-specific gene silencing.20

Interestingly, although Sp3-deficient mice display defects in multiple tissues at late stages of embryonic development and die immediately after birth due to respiratory failure,9,10 mice expressing SUMO-defective Sp3 were fertile, born at the expected Mendelian frequency and exhibited no obvious phenotypes.20 One explanation for this observation is that the defect observed in Sp3-null animals is largely due to the activation function, which can be provided by the SUMOylation-deficient Sp3 protein. However, we found that the relative number of genes repressed and activated by Sp3 in HeLa cells is similar, consistent with an important role for the repressive function of Sp3.11 Our recent investigations suggest an alternative explanation. We found that non-SUMOylatable Sp3 was able to repress expression of genes such as p21CIP1, where Sp3 acts to limit the transition of paused RNA Pol II into elongation. Therefore, the ability of SUMO-defective Sp3 to rescue the mouse knockout phenotype may be due not only to Sp3-dependent activation, but also to the SUMO-independent inhibitory role of Sp3 on transcriptional elongation.

Distinct Promoter-Specific Transcription Factors Regulate the Formation, Maintenance and Release of Paused RNA Pol II

Many transcriptional activators, including Myc, NFkB and p53, have been shown to stimulate the transition of paused RNA Pol II into productive elongation.23-25 In contrast, the negative regulation of elongation mediated by promoter-specific factors is less well described. In Drosophila, many genes with stalled RNA Pol II, such as hsp70, have binding sites for the GAGA binding factor (GAF).26-29 In fact, over a fifth of all stalled promoters in Drosophila contain the combination of GAGA, initiator (Inr) and downstream promoter element (DPE)/pause button (PB) motifs.6 GAGA factor has been suggested to promote the formation of paused RNA Pol II by facilitating pre-initiation complex formation and the establishment of an open chromatin structure through the recruitment of components of the basal transcriptional machinery, such as TFIID,6 and chromatin remodeling complexes, such as NURF and FACT.30-33 Thus, GAF has been suggested to promote the recruitment of RNA Pol II that subsequently stalls.

Similar to GAGA factor, transcription factor Sp1 can facilitate pre-initiation complex formation in mammalian cells through interactions with components of the general transcriptional machinery and other cofactors.12,34-41 Sites for Sp1/Sp3 are associated with a wide spectrum of genes, and promoter proximal pausing occurs on a stably transfected synthetic promoter containing only a binding site for Sp1 and a core promoter element, either a TATA box or an Inr element.42 Consistent with the idea that some transcription factors are essential for recruitment of RNA Pol II, whereas others work subsequently to release paused RNA Pol II to achieve robust expression,35,42,43 Sp1 has been shown to promote pre-initiation complex formation and initiation at the A20 promoter,44,45 although full transcriptional induction is triggered by the post-initiation activity of NFκB. Similarly, for primary response genes in macrophage cells, a low level of basal transcription occurs upon recruitment of RNA Pol II by Sp1, although full induction by LPS requires the participation of NFκB.46 These data support a role for Sp1 in promoting recruitment of RNA Pol II, which subsequently stalls, and suggest that additional factors are necessary to release paused RNA Pol II to achieve full expression.35,42

Our recent investigations showed that at some Sp3-repressed genes, Sp3 neither promoted nor inhibited RNA Pol II binding to the promoter.11 These findings revealed Sp3 function to be distinct from that of GAF. We also found that Sp1 and Sp3 can bind independently to promoters. Our data are consistent with a model in which, at promoters such as p21CIP1, Sp1 or another factor promotes the recruitment of RNA Pol II that subsequently pauses, while Sp3 favors maintenance of the pause by limiting the rate of release into elongation. This model allows p21CIP1 to keep basal expression low and still be poised for rapid induction in response to stress, such as DNA damage, when p53 binding to the promoter stimulates the transition to productive elongation.14,23 At some promoters, however, Sp3 functions similarly to Sp1 to promote RNA Pol II binding. While the presence of paused RNA Pol II is likely a key feature that distinguishes Sp3 activation and repression targets, our analysis of the promoter sequences of Sp3-repressed and activated genes did not allow us to identify obvious sequence features correlating with the activity of Sp3 in these different contexts (A. Valin and G. Gill, unpublished work).

Sp3 Promotes Occupancy of the NELF Complex

Recent genome-wide studies have revealed that paused RNA Pol II appears to represent an active and tunable mechanism, remaining as a rate-limiting step even for highly transcribed genes.47 Following initiation, RNA Pol II falls under the control of negative elongation factors, including DRB (5,6-ichlorobenzimidazole riboside) sensitivity-inducing factor (DSIF) and the negative elongation factor complex (NELF). NELF is the major factor associated with the early pausing of RNA Pol II. NELF is a complex of four subunits, NELF-A, B, C/D and E, that is conserved in higher eukaryotes, but has not been reported in C. elegans, S. cerevisiae or Arabidopsis thaliana.48 Multiple transcription factors, such as BRCA1, ER-α and AP-1 family members, can promote pausing through the recruitment of NELF to promoters.3,49,50 ChIP-chip analysis of RNA Pol II binding in NELF-depleted Drosophila cells revealed that loss of NELF-mediated pausing reduced RNA Pol II promoter occupancy at most, but not all, promoters,2 globally implicating NELF in inhibition of early elongation. The high sensitivity of the global run-on-sequencing (GRO-seq) technique,51 allowed the determination that even active genes undergo transient pausing of RNA Pol II,47,52 suggesting that NELF-mediated pausing may be a general feature of the transcription mechanism. Furthermore, these studies suggest that the efficiency of pause release, rather than the establishment of pausing, plays a major role in determining gene expression levels.

We observed high levels of RNA Pol II and NELF at promoters of Sp3-repressed genes, including p21CIP1 and sod2, together with high levels of H3K4me3-modified histones, a mark generally associated with open chromatin structure1,11 (Fig. 2). After Sp3 knockdown, NELF occupancy was significantly reduced at p21CIP1, sod2 and other promoters, and this likely contributed to the observed increase in the levels of transcription of these genes11 (Fig. 2A). We did not observe direct interactions of Sp3 with the NELF complex, suggesting that Sp3 acts indirectly to regulate NELF occupancy. We should note, however, that we did not detect loss of NELF occupancy upon Sp3 knockdown at all Sp3-repressed genes. Thus, Sp3 may be regulating the transient release of RNA Pol II at these genes via effects on factors other than NELF, such as DSIF, and/or without a significant effect on NELF occupancy as determined by ChIP.2 Accumulating evidence supports a model wherein paused RNA Pol II is not a stable repressed state, but rather a highly dynamic state, whose effective duration can be regulated in response to signals and changing cellular environments. The duration of pausing has been shown to be modulated during activation of the Drosophila heat shock genes and at several genes involved in the DNA damage response.2,5 Moreover, recent investigations show that LPS induces a burst of transcription of the murine TNF-α gene mediated by a transient reduction in pausing.53 Thus, depletion of Sp3 could allow a highly dynamic release of RNA Pol II, promoting a burst of transcription with a rapid restoration of high levels of RNA Pol II at the promoter and varying kinetics of restoring NELF occupancy.

graphic file with name cc-12-1828-g2.jpg

Open in a new tab

Figure 2. Transcription factor Sp3 inhibits CDK9 (P-TEFb) activity at sod2. (A) RT-qPCR analysis demonstrated increased expression of sod2 upon Sp3 knockdown in HeLa cells (Sp3i; gray bars). Values are relative to that for GFPi (black bars), set at 1 and normalized to the value for hprt1. (B) HeLa cells were transfected with shRNA targeting either control (GFPi; black bars) or Sp3 (Sp3i; gray bars), and treated with DMSO or the CDK9 inhibitor DRB. Left: ChIP analysis demonstrated that CDK9 was bound under repressed conditions (black bars) and CDK9 occupancy did not increase upon de-repression by Sp3 depletion (gray bars). In fact, CDK9 binding was reduced upon Sp3 knockdown (GFPi vs.Sp3i; *p < 0.05). Inhibition of CDK9 activity by DRB led to increased binding (GFPi, DMSO vs. DRB; *p < 0.05) and blocked the reduction in CDK9 binding seen upon depletion of Sp3, suggesting that reduced CDK9 occupancy under these conditions was likely due to association of active P-TEFb with the elongating polymerase. Right: ChIP revealed that Sp3 knockdown led to reduced NELF-A binding at the sod2 promoter and this reduction was prevented by DRB (***p < 0.001), indicating that, upon Sp3 depletion, NELF binding is regulated by the activity of promoter bound P-TEFb. Since Sp3 does not block P-TEFb binding, these data suggest that Sp3 limits P-TEFb activity. Data represent mean ± SEM of three independent experiments.

Sp3 Regulates the Balance of Kinase and Phosphatase Activities at the Promoter

The positive transcription elongation factor b (P-TEFb) is a central player during the transition of RNA Pol II into productive elongation.54,55 P-TEFb, composed of CDK9 and cyclinT, functions to antagonize the negative elongation factors NELF and DSIF. The kinase activity of P-TEFb phosphorylates subunits of DSIF and NELF as well as serine 2 of the RNA Pol II CTD, thereby relieving repression and promoting the transition to productive elongation. Probably the best-described mechanism for gene-specific and signal-dependent regulation of pausing and elongation is through the recruitment of P-TEFb by interaction with transcriptional activators such as Myc, NFκB and p53,23-25 or specific chromatin-binding factors such as Brd4.8 We investigated whether P-TEFb binding at Sp3-repressed target genes was affected by depletion of Sp3. We found that loss of Sp3-dependent repression did not increase P-TEFb binding at p21CIP1 or sod2 or other promoters examined11 (Fig. 2B, left). Furthermore, we found that DRB, an inhibitor of the P-TEFb kinase, blocked the reduction in NELF occupancy upon Sp3 knockdown at p21CIP1 and sod2 (Fig. 2B, right) suggesting that Sp3 inhibits P-TEFb-dependent release of NELF without blocking binding of P-TEFb. Thus, our data support the view that recruitment of P-TEFb may not be sufficient for the transition of paused RNA Pol II to productive elongation.

Both the recruitment and activity of P-TEFb are tightly regulated in vivo through assembly into multiprotein complexes and posttranslational modifications of P-TEFb subunits.56-58 A major mechanism of P-TEFb regulation is through association with a large inhibitory complex containing 7SK-RNA, MEPCE, LARP7 and HEXIM1 (7SK/HEXIM/P-TEFb complex) that inhibits recruitment of P-TEFb to promoters.8,15,59 Several additional P-TEFb containing complexes have also been described including a super elongation complex (SEC),58 which contains P-TEFb, the elongation factors ELL1 to ELL3 and several other chromosomal translocation partners of the mixed lineage leukemia (MLL) gene, including AFF1, AFF4, ENL and AF9. SEC localizes at Hsp70 gene upon stress, and this complex is also involved in HIV proviral transcription.58,60,61 In addition, the misexpression of HOX genes in leukemia could result from the stabilized recruitment of SEC, giving rise to the unregulated release of RNA Pol II.62 Two additional P-TEFb-containing complexes have been identified, SEC-L2 and SEC-L363 whose subunit composition and in vitro activity are similar to SEC. However, only SEC, but not SEC-L2 or SEC-L3, controls the proper expression of the Hsp70 gene upon stress and genome-wide analyses demonstrated that each member of the SEC family of complexes regulates the expression of a different subset of genes. These findings highlight the importance of different P-TEFb-containing multiprotein complexes for gene-specific regulation of P-TEFb recruitment and activity. Thus, the transcription output mediated by promoter-specific factors such as Sp3 may be determined, in part, by the subunit composition of the P-TEFb complex recruited to each gene.

Posttranslational modifications, and particularly phosphorylation, also regulate P-TEFb activity. For example, dephosphorylation of the Thr186 residue in the T-loop of CDK9 by the serine/threonine phosphatase PP1 is necessary for the release of P-TEFb from the large inhibitory 7SK/HEXIM/P-TEFb complex.64 However, phosphorylation of CDK9 at this same residue, Thr186 and other residues is required for full enzymatic activity at promoters.64-69 These studies suggest dynamic cycles of phosphorylation and dephosphorylation regulate P-TEFb activity to control the release of the RNA Pol II into productive elongation.

While the role of protein kinases in transcription elongation has been the subject of intensive studies, the involvement of protein phosphatases in the regulation of this process is less well described. Protein phosphatases are recruited to genes as part of complexes containing histone-modifying or chromatin-remodeling activities,70 for example HDAC complexes,71,72 and by transcription factors such as REST/NRSF73 or the HIV-1 Tat protein.74 We found that both protein phosphatases PP1 and PP2A interact with the transcription factor Sp3. We have demonstrated that PP1 is recruited to the p21CIP1 promoter and other Sp3-repressed genes in a Sp3-dependent manner.11 Previous studies have shown that PP2A localizes at the p21CIP1 promoter, where it counteracts phosphorylation of the histone H3S10 residue mediated by MSK1 and MSK2 kinases.75 H3S10 phosphorylation-dependent recruitment of the phospho-binding protein 14-3-3ζ at the the p21CIP1 promoter has been suggested to stabilize the dual mark of H3S10 phosphorylation/H3K14 acetylation, resulting in prolonged expression of the p21CIP1 gene.75 In this regard, phosphorylation of H3S10 and the recruitment of 14-3-3 has been reported to be part of a cascade of histone modifications and protein interactions to promote Brd4-dependent recruitment of P-TEFb.76,77 Our data also support a role for PP1 and/or PP2A as the H3S10 phosphatase.11,78-80 However, we found that while Sp3 inhibits H3S10 phosphorylation, Sp3 does not block P-TEFb recruitment, suggesting an alternative function for Sp3-regulated H3S10 phosphorylation. Additional pathways for H3S10ph-mediated activation have been proposed, including a role in maintaining the active state of a gene, in part by preventing the spreading of H3K9me2 and HP1 and thus counteracting heterochromatin formation.81-83 Thus, while the molecular events regulated by the dephosphorylation of H3S10 mediated by PP1 are currently unclear, our data suggest that phosphatase activities recruited by Sp3 play an important role in limiting the transition of RNA Pol II into productive elongation.

There are many stimulatory phosphorylation events that could be antagonized by promoter-bound PP1, including P-TEFb-dependent phosphorylation of NELF and DSIF, or the phosphorylation of RNA Pol II CTD by P-TEFb and other kinases (Fig. 3). Since P-TEFb itself is regulated by phosphorylation, it is tempting to speculate that Sp3-dependent recruitment of PP1 could inhibit productive transcriptional elongation by controlling the phosphorylation pattern of P-TEFb at promoters. Notably, PP1 consists of a constant catalytic subunit and a variable regulatory subunit that determines the localization, activity and substrate-specificity of the phosphatase.84 Thus, the activity of the Sp3-recruited PP1 toward specific substrates will depend on the associated regulatory subunits,85,86 a complexity that opens additional possibilities for regulation.

graphic file with name cc-12-1828-g3.jpg

Open in a new tab

Figure 3. Model of Sp3-dependent inhibition of transcription elongation. Multiple phosphorylation events (shown as “P”) directed by P-TEFb and other kinases regulate the release of paused RNA Pol II into productive elongation. Our data suggest that recruitment of PP1 (and perhaps PP2A) phosphatase by the promoter-specific transcription factor Sp3 helps to maintain paused RNA polymerase. Protein phosphatases recruited by Sp3 regulate the phosphorylation state of histone H3Ser10 at the p21CIP1 promoter (continuous line) and may also regulate phosphorylation of additional substrates including P-TEFb, the negative elongation factors DSIF and NELF, or the RNA Pol II CTD (discontinuous line). According to this model, Sp3-dependent regulation of the local balance between kinase and phosphatase activities provides an additional level of control that contributes to the precise regulation of gene expression.

Challenges Ahead

The ability of cells to respond to diverse internal and external stimuli requires exquisite control in the level and timing of transcription of groups of genes. Studies by our laboratory and others have shown that Sp3 can regulate gene expression through diverse mechanisms, from SUMO-dependent chromatin silencing to SUMO-independent activation and inhibition of elongation, providing further insight into the functional complexity of Sp3. Regulation of transcription elongation is a widely used mechanism controlling the pattern of gene expression during development and in response to different stimuli and stresses. Our investigations of Sp3-dependent repression mechanisms suggest that regulation of the levels and activity of promoter-bound kinases, such as P-TEFb, and phosphatases, such as PP1 and PP2A, contributes to the regulation of RNA Pol II pausing and elongation. Identifying the regulatory subunits associated with the protein phosphatases recruited by Sp3 will help to better understand the role of this transcription factor during RNA Pol II elongation. Furthermore, additional studies are needed to understand how promoter sequence, chromatin structure and factor binding at the promoter determine the context for Sp3-dependent activation, inhibition of elongation and silencing. Overall, our recent study offers evidence for additional levels of regulation to provide precise control of the levels of expression for each gene.

Acknowledgments

We thank Jian Ouyang and Sohini Mazumdar for helpful comments on the manuscript. A.V. was supported in part by a fellowship from the Spanish Ministerio de Educacion y Ciencias. This work was supported in part by a grant from the National Institutes of Health (R01 GM077689) to G.G.

Glossary

Abbreviations:

CDK

cyclin-dependent kinase

CTD

C-terminal domain of the RNA polymerase II

DSIF

DRB sensitivity-inducing factor

H3K4me3

histone H3 trimethylated at lysine 4

H3K36me3

histone H3 trimethylated at lysine 36

H3S10

histone H3 serine 10

NELF

negative elongation factor complex

P-TEFb

positive transcription elongation factor b

PP

protein phosphatase

p21CIP1

cyclin-dependent kinase inhibitor 1A, RNA Pol II, RNA polymerase II

SUMO

small ubiquitin-related modifier

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Footnotes

References

  • 1.Guenther MG, Levine SS, Boyer LA, Jaenisch R, Young RA. A chromatin landmark and transcription initiation at most promoters in human cells. Cell. 2007;130:77–88. doi: 10.1016/j.cell.2007.05.042. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Muse GW, Gilchrist DA, Nechaev S, Shah R, Parker JS, Grissom SF, et al. RNA polymerase is poised for activation across the genome. Nat Genet. 2007;39:1507–11. doi: 10.1038/ng.2007.21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Aiyar SE, Sun JL, Blair AL, Moskaluk CA, Lu YZ, Ye QN, et al. Attenuation of estrogen receptor alpha-mediated transcription through estrogen-stimulated recruitment of a negative elongation factor. Genes Dev. 2004;18:2134–46. doi: 10.1101/gad.1214104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Aida M, Chen Y, Nakajima K, Yamaguchi Y, Wada T, Handa H. Transcriptional pausing caused by NELF plays a dual role in regulating immediate-early expression of the junB gene. Mol Cell Biol. 2006;26:6094–104. doi: 10.1128/MCB.02366-05. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Rasmussen EB, Lis JT. Short transcripts of the ternary complex provide insight into RNA polymerase II elongational pausing. J Mol Biol. 1995;252:522–35. doi: 10.1006/jmbi.1995.0517. [DOI] [PubMed] [Google Scholar]
  • 6.Hendrix DA, Hong JW, Zeitlinger J, Rokhsar DS, Levine MS. Promoter elements associated with RNA Pol II stalling in the Drosophila embryo. Proc Natl Acad Sci USA. 2008;105:7762–7. doi: 10.1073/pnas.0802406105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Saunders A, Core LJ, Lis JT. Breaking barriers to transcription elongation. Nat Rev Mol Cell Biol. 2006;7:557–67. doi: 10.1038/nrm1981. [DOI] [PubMed] [Google Scholar]
  • 8.Brès V, Yoh SM, Jones KA. The multi-tasking P-TEFb complex. Curr Opin Cell Biol. 2008;20:334–40. doi: 10.1016/j.ceb.2008.04.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Van Loo PF, Bouwman P, Ling KW, Middendorp S, Suske G, Grosveld F, et al. Impaired hematopoiesis in mice lacking the transcription factor Sp3. Blood. 2003;102:858–66. doi: 10.1182/blood-2002-06-1848. [DOI] [PubMed] [Google Scholar]
  • 10.Göllner H, Dani C, Phillips B, Philipsen S, Suske G. Impaired ossification in mice lacking the transcription factor Sp3. Mech Dev. 2001;106:77–83. doi: 10.1016/S0925-4773(01)00420-8. [DOI] [PubMed] [Google Scholar]
  • 11.Valin A, Ouyang J, Gill G. Transcription factor Sp3 represses expression of p21CIP¹ via inhibition of productive elongation by RNA polymerase II. Mol Cell Biol. 2013;33:1582–93. doi: 10.1128/MCB.00323-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Gill G, Pascal E, Tseng ZH, Tjian R. A glutamine-rich hydrophobic patch in transcription factor Sp1 contacts the dTAFII110 component of the Drosophila TFIID complex and mediates transcriptional activation. Proc Natl Acad Sci USA. 1994;91:192–6. doi: 10.1073/pnas.91.1.192. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Hoey T, Weinzierl RO, Gill G, Chen JL, Dynlacht BD, Tjian R. Molecular cloning and functional analysis of Drosophila TAF110 reveal properties expected of coactivators. Cell. 1993;72:247–60. doi: 10.1016/0092-8674(93)90664-C. [DOI] [PubMed] [Google Scholar]
  • 14.Espinosa JM, Verdun RE, Emerson BM. p53 functions through stress- and promoter-specific recruitment of transcription initiation components before and after DNA damage. Mol Cell. 2003;12:1015–27. doi: 10.1016/S1097-2765(03)00359-9. [DOI] [PubMed] [Google Scholar]
  • 15.Price DH. Poised polymerases: on your mark...get set...go! Mol Cell. 2008;30:7–10. doi: 10.1016/j.molcel.2008.03.001. [DOI] [PubMed] [Google Scholar]
  • 16.Gilchrist DA, Nechaev S, Lee C, Ghosh SK, Collins JB, Li L, et al. NELF-mediated stalling of Pol II can enhance gene expression by blocking promoter-proximal nucleosome assembly. Genes Dev. 2008;22:1921–33. doi: 10.1101/gad.1643208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Ross S, Best JL, Zon LI, Gill G. SUMO-1 modification represses Sp3 transcriptional activation and modulates its subnuclear localization. Mol Cell. 2002;10:831–42. doi: 10.1016/S1097-2765(02)00682-2. [DOI] [PubMed] [Google Scholar]
  • 18.Sapetschnig A, Rischitor G, Braun H, Doll A, Schergaut M, Melchior F, et al. Transcription factor Sp3 is silenced through SUMO modification by PIAS1. EMBO J. 2002;21:5206–15. doi: 10.1093/emboj/cdf510. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Ouyang J, Gill G. SUMO engages multiple corepressors to regulate chromatin structure and transcription. Epigenetics. 2009;4:440–4. doi: 10.4161/epi.4.7.9807. [DOI] [PubMed] [Google Scholar]
  • 20.Stielow B, Krüger I, Diezko R, Finkernagel F, Gillemans N, Kong-a-San J, et al. Epigenetic silencing of spermatocyte-specific and neuronal genes by SUMO modification of the transcription factor Sp3. PLoS Genet. 2010;6:e1001203. doi: 10.1371/journal.pgen.1001203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Stielow B, Sapetschnig A, Krüger I, Kunert N, Brehm A, Boutros M, et al. Identification of SUMO-dependent chromatin-associated transcriptional repression components by a genome-wide RNAi screen. Mol Cell. 2008;29:742–54. doi: 10.1016/j.molcel.2007.12.032. [DOI] [PubMed] [Google Scholar]
  • 22.Stielow B, Sapetschnig A, Wink C, Krüger I, Suske G. SUMO-modified Sp3 represses transcription by provoking local heterochromatic gene silencing. EMBO Rep. 2008;9:899–906. doi: 10.1038/embor.2008.127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Gomes NP, Bjerke G, Llorente B, Szostek SA, Emerson BM, Espinosa JM. Gene-specific requirement for P-TEFb activity and RNA polymerase II phosphorylation within the p53 transcriptional program. Genes Dev. 2006;20:601–12. doi: 10.1101/gad.1398206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Luecke HF, Yamamoto KR. The glucocorticoid receptor blocks P-TEFb recruitment by NFkappaB to effect promoter-specific transcriptional repression. Genes Dev. 2005;19:1116–27. doi: 10.1101/gad.1297105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Rahl PB, Lin CY, Seila AC, Flynn RA, McCuine S, Burge CB, et al. c-Myc regulates transcriptional pause release. Cell. 2010;141:432–45. doi: 10.1016/j.cell.2010.03.030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Shopland LS, Hirayoshi K, Fernandes M, Lis JT. HSF access to heat shock elements in vivo depends critically on promoter architecture defined by GAGA factor, TFIID, and RNA polymerase II binding sites. Genes Dev. 1995;9:2756–69. doi: 10.1101/gad.9.22.2756. [DOI] [PubMed] [Google Scholar]
  • 27.Wilkins RC, Lis JT. Dynamics of potentiation and activation: GAGA factor and its role in heat shock gene regulation. Nucleic Acids Res. 1997;25:3963–8. doi: 10.1093/nar/25.20.3963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Biggin MD, Tjian R. Transcription factors that activate the Ultrabithorax promoter in developmentally staged extracts. Cell. 1988;53:699–711. doi: 10.1016/0092-8674(88)90088-8. [DOI] [PubMed] [Google Scholar]
  • 29.Lee C, Li X, Hechmer A, Eisen M, Biggin MD, Venters BJ, et al. NELF and GAGA factor are linked to promoter-proximal pausing at many genes in Drosophila. Mol Cell Biol. 2008;28:3290–300. doi: 10.1128/MCB.02224-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Tsukiyama T, Wu C. Chromatin remodeling and transcription. Curr Opin Genet Dev. 1997;7:182–91. doi: 10.1016/S0959-437X(97)80127-X. [DOI] [PubMed] [Google Scholar]
  • 31.Wang YV, Tang H, Gilmour DS. Identification in vivo of different rate-limiting steps associated with transcriptional activators in the presence and absence of a GAGA element. Mol Cell Biol. 2005;25:3543–52. doi: 10.1128/MCB.25.9.3543-3552.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Xiao H, Sandaltzopoulos R, Wang HM, Hamiche A, Ranallo R, Lee KM, et al. Dual functions of largest NURF subunit NURF301 in nucleosome sliding and transcription factor interactions. Mol Cell. 2001;8:531–43. doi: 10.1016/S1097-2765(01)00345-8. [DOI] [PubMed] [Google Scholar]
  • 33.Nakayama T, Nishioka K, Dong YX, Shimojima T, Hirose S. Drosophila GAGA factor directs histone H3.3 replacement that prevents the heterochromatin spreading. Genes Dev. 2007;21:552–61. doi: 10.1101/gad.1503407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Tanese N, Saluja D, Vassallo MF, Chen JL, Admon A. Molecular cloning and analysis of two subunits of the human TFIID complex: hTAFII130 and hTAFII100. Proc Natl Acad Sci USA. 1996;93:13611–6. doi: 10.1073/pnas.93.24.13611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Blau J, Xiao H, McCracken S, O’Hare P, Greenblatt J, Bentley D. Three functional classes of transcriptional activation domain. Mol Cell Biol. 1996;16:2044–55. doi: 10.1128/mcb.16.5.2044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Yankulov K, Blau J, Purton T, Roberts S, Bentley DL. Transcriptional elongation by RNA polymerase II is stimulated by transactivators. Cell. 1994;77:749–59. doi: 10.1016/0092-8674(94)90058-2. [DOI] [PubMed] [Google Scholar]
  • 37.Colgan J, Manley JL. Cooperation between core promoter elements influences transcriptional activity in vivo. Proc Natl Acad Sci USA. 1995;92:1955–9. doi: 10.1073/pnas.92.6.1955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Sadovsky Y, Webb P, Lopez G, Baxter JD, Fitzpatrick PM, Gizang-Ginsberg E, et al. Transcriptional activators differ in their responses to overexpression of TATA-box-binding protein. Mol Cell Biol. 1995;15:1554–63. doi: 10.1128/mcb.15.3.1554. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.He S, Weintraub SJ. Stepwise recruitment of components of the preinitiation complex by upstream activators in vivo. Mol Cell Biol. 1998;18:2876–83. doi: 10.1128/mcb.18.5.2876. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Dorris DR, Struhl K. Artificial recruitment of TFIID, but not RNA polymerase II holoenzyme, activates transcription in mammalian cells. Mol Cell Biol. 2000;20:4350–8. doi: 10.1128/MCB.20.12.4350-4358.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Barboric M, Nissen RM, Kanazawa S, Jabrane-Ferrat N, Peterlin BM. NF-kappaB binds P-TEFb to stimulate transcriptional elongation by RNA polymerase II. Mol Cell. 2001;8:327–37. doi: 10.1016/S1097-2765(01)00314-8. [DOI] [PubMed] [Google Scholar]
  • 42.Krumm A, Hickey LB, Groudine M. Promoter-proximal pausing of RNA polymerase II defines a general rate-limiting step after transcription initiation. Genes Dev. 1995;9:559–72. doi: 10.1101/gad.9.5.559. [DOI] [PubMed] [Google Scholar]
  • 43.Levine M. Paused RNA polymerase II as a developmental checkpoint. Cell. 2011;145:502–11. doi: 10.1016/j.cell.2011.04.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Ainbinder E, Revach M, Wolstein O, Moshonov S, Diamant N, Dikstein R. Mechanism of rapid transcriptional induction of tumor necrosis factor alpha-responsive genes by NF-kappaB. Mol Cell Biol. 2002;22:6354–62. doi: 10.1128/MCB.22.18.6354-6362.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Ainbinder E, Amir-Zilberstein L, Yamaguchi Y, Handa H, Dikstein R. Elongation inhibition by DRB sensitivity-inducing factor is regulated by the A20 promoter via a novel negative element and NF-kappaB. Mol Cell Biol. 2004;24:2444–54. doi: 10.1128/MCB.24.6.2444-2454.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Hargreaves DC, Horng T, Medzhitov R. Control of inducible gene expression by signal-dependent transcriptional elongation. Cell. 2009;138:129–45. doi: 10.1016/j.cell.2009.05.047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Min IM, Waterfall JJ, Core LJ, Munroe RJ, Schimenti J, Lis JT. Regulating RNA polymerase pausing and transcription elongation in embryonic stem cells. Genes Dev. 2011;25:742–54. doi: 10.1101/gad.2005511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Narita T, Yamaguchi Y, Yano K, Sugimoto S, Chanarat S, Wada T, et al. Human transcription elongation factor NELF: identification of novel subunits and reconstitution of the functionally active complex. Mol Cell Biol. 2003;23:1863–73. doi: 10.1128/MCB.23.6.1863-1873.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Ye Q, Hu YF, Zhong H, Nye AC, Belmont AS, Li R. BRCA1-induced large-scale chromatin unfolding and allele-specific effects of cancer-predisposing mutations. J Cell Biol. 2001;155:911–21. doi: 10.1083/jcb.200108049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Zhong H, Zhu J, Zhang H, Ding L, Sun Y, Huang C, et al. COBRA1 inhibits AP-1 transcriptional activity in transfected cells. Biochem Biophys Res Commun. 2004;325:568–73. doi: 10.1016/j.bbrc.2004.10.079. [DOI] [PubMed] [Google Scholar]
  • 51.Core LJ, Waterfall JJ, Lis JT. Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters. Science. 2008;322:1845–8. doi: 10.1126/science.1162228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Nechaev S, Fargo DC, dos Santos G, Liu L, Gao Y, Adelman K. Global analysis of short RNAs reveals widespread promoter-proximal stalling and arrest of Pol II in Drosophila. Science. 2010;327:335–8. doi: 10.1126/science.1181421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Adelman K, Kennedy MA, Nechaev S, Gilchrist DA, Muse GW, Chinenov Y, et al. Immediate mediators of the inflammatory response are poised for gene activation through RNA polymerase II stalling. Proc Natl Acad Sci USA. 2009;106:18207–12. doi: 10.1073/pnas.0910177106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Peterlin BM, Price DH. Controlling the elongation phase of transcription with P-TEFb. Mol Cell. 2006;23:297–305. doi: 10.1016/j.molcel.2006.06.014. [DOI] [PubMed] [Google Scholar]
  • 55.Marshall NF, Price DH. Purification of P-TEFb, a transcription factor required for the transition into productive elongation. J Biol Chem. 1995;270:12335–8. doi: 10.1074/jbc.270.21.12335. [DOI] [PubMed] [Google Scholar]
  • 56.Chen R, Liu M, Li H, Xue Y, Ramey WN, He N, et al. PP2B and PP1alpha cooperatively disrupt 7SK snRNP to release P-TEFb for transcription in response to Ca2+ signaling. Genes Dev. 2008;22:1356–68. doi: 10.1101/gad.1636008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Cho S, Schroeder S, Ott M. CYCLINg through transcription: posttranslational modifications of P-TEFb regulate transcription elongation. Cell Cycle. 2010;9:1697–705. doi: 10.4161/cc.9.9.11346. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Lin C, Smith ER, Takahashi H, Lai KC, Martin-Brown S, Florens L, et al. AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. Mol Cell. 2010;37:429–37. doi: 10.1016/j.molcel.2010.01.026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.He N, Zhou Q. New insights into the control of HIV-1 transcription: when Tat meets the 7SK snRNP and super elongation complex (SEC) J Neuroimmune Pharmacol. 2011;6:260–8. doi: 10.1007/s11481-011-9267-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.He N, Liu M, Hsu J, Xue Y, Chou S, Burlingame A, et al. HIV-1 Tat and host AFF4 recruit two transcription elongation factors into a bifunctional complex for coordinated activation of HIV-1 transcription. Mol Cell. 2010;38:428–38. doi: 10.1016/j.molcel.2010.04.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Sobhian B, Laguette N, Yatim A, Nakamura M, Levy Y, Kiernan R, et al. HIV-1 Tat assembles a multifunctional transcription elongation complex and stably associates with the 7SK snRNP. Mol Cell. 2010;38:439–51. doi: 10.1016/j.molcel.2010.04.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Mohan M, Lin C, Guest E, Shilatifard A. Licensed to elongate: a molecular mechanism for MLL-based leukaemogenesis. Nat Rev Cancer. 2010;10:721–8. doi: 10.1038/nrc2915. [DOI] [PubMed] [Google Scholar]
  • 63.Luo Z, Lin C, Guest E, Garrett AS, Mohaghegh N, Swanson S, et al. The super elongation complex family of RNA polymerase II elongation factors: gene target specificity and transcriptional output. Mol Cell Biol. 2012;32:2608–17. doi: 10.1128/MCB.00182-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Chen R, Yang Z, Zhou Q. Phosphorylated positive transcription elongation factor b (P-TEFb) is tagged for inhibition through association with 7SK snRNA. J Biol Chem. 2004;279:4153–60. doi: 10.1074/jbc.M310044200. [DOI] [PubMed] [Google Scholar]
  • 65.Fong YW, Zhou Q. Relief of two built-In autoinhibitory mechanisms in P-TEFb is required for assembly of a multicomponent transcription elongation complex at the human immunodeficiency virus type 1 promoter. Mol Cell Biol. 2000;20:5897–907. doi: 10.1128/MCB.20.16.5897-5907.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Garber ME, Mayall TP, Suess EM, Meisenhelder J, Thompson NE, Jones KA. CDK9 autophosphorylation regulates high-affinity binding of the human immunodeficiency virus type 1 tat-P-TEFb complex to TAR RNA. Mol Cell Biol. 2000;20:6958–69. doi: 10.1128/MCB.20.18.6958-6969.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Li Q, Price JP, Byers SA, Cheng D, Peng J, Price DH. Analysis of the large inactive P-TEFb complex indicates that it contains one 7SK molecule, a dimer of HEXIM1 or HEXIM2, and two P-TEFb molecules containing Cdk9 phosphorylated at threonine 186. J Biol Chem. 2005;280:28819–26. doi: 10.1074/jbc.M502712200. [DOI] [PubMed] [Google Scholar]
  • 68.Baumli S, Lolli G, Lowe ED, Troiani S, Rusconi L, Bullock AN, et al. The structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation. EMBO J. 2008;27:1907–18. doi: 10.1038/emboj.2008.121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Kohoutek J. P-TEFb- the final frontier. Cell Div. 2009;4:19. doi: 10.1186/1747-1028-4-19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Bennett D. Transcriptional control by chromosome-associated protein phosphatase-1. Biochem Soc Trans. 2005;33:1444–6. doi: 10.1042/BST20051444. [DOI] [PubMed] [Google Scholar]
  • 71.Canettieri G, Morantte I, Guzmán E, Asahara H, Herzig S, Anderson SD, et al. Attenuation of a phosphorylation-dependent activator by an HDAC-PP1 complex. Nat Struct Biol. 2003;10:175–81. doi: 10.1038/nsb895. [DOI] [PubMed] [Google Scholar]
  • 72.Brush MH, Guardiola A, Connor JH, Yao TP, Shenolikar S. Deactylase inhibitors disrupt cellular complexes containing protein phosphatases and deacetylases. J Biol Chem. 2004;279:7685–91. doi: 10.1074/jbc.M310997200. [DOI] [PubMed] [Google Scholar]
  • 73.Yeo M, Lee SK, Lee B, Ruiz EC, Pfaff SL, Gill GN. Small CTD phosphatases function in silencing neuronal gene expression. Science. 2005;307:596–600. doi: 10.1126/science.1100801. [DOI] [PubMed] [Google Scholar]
  • 74.Ammosova T, Jerebtsova M, Beullens M, Lesage B, Jackson A, Kashanchi F, et al. Nuclear targeting of protein phosphatase-1 by HIV-1 Tat protein. J Biol Chem. 2005;280:36364–71. doi: 10.1074/jbc.M503673200. [DOI] [PubMed] [Google Scholar]
  • 75.Simboeck E, Sawicka A, Zupkovitz G, Senese S, Winter S, Dequiedt F, et al. A phosphorylation switch regulates the transcriptional activation of cell cycle regulator p21 by histone deacetylase inhibitors. J Biol Chem. 2010;285:41062–73. doi: 10.1074/jbc.M110.184481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76.Ivaldi MS, Karam CS, Corces VG. Phosphorylation of histone H3 at Ser10 facilitates RNA polymerase II release from promoter-proximal pausing in Drosophila. Genes Dev. 2007;21:2818–31. doi: 10.1101/gad.1604007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Zippo A, Serafini R, Rocchigiani M, Pennacchini S, Krepelova A, Oliviero S. Histone crosstalk between H3S10ph and H4K16ac generates a histone code that mediates transcription elongation. Cell. 2009;138:1122–36. doi: 10.1016/j.cell.2009.07.031. [DOI] [PubMed] [Google Scholar]
  • 78.Koshibu K, Gräff J, Beullens M, Heitz FD, Berchtold D, Russig H, et al. Protein phosphatase 1 regulates the histone code for long-term memory. J Neurosci. 2009;29:13079–89. doi: 10.1523/JNEUROSCI.3610-09.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Mansuy IM, Shenolikar S. Protein serine/threonine phosphatases in neuronal plasticity and disorders of learning and memory. Trends Neurosci. 2006;29:679–86. doi: 10.1016/j.tins.2006.10.004. [DOI] [PubMed] [Google Scholar]
  • 80.Moorhead GB, Trinkle-Mulcahy L, Ulke-Lemée A. Emerging roles of nuclear protein phosphatases. Nat Rev Mol Cell Biol. 2007;8:234–44. doi: 10.1038/nrm2126. [DOI] [PubMed] [Google Scholar]
  • 81.Cai W, Bao X, Deng H, Jin Y, Girton J, Johansen J, et al. RNA polymerase II-mediated transcription at active loci does not require histone H3S10 phosphorylation in Drosophila. Development. 2008;135:2917–25. doi: 10.1242/dev.024927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Zhang W, Deng H, Bao X, Lerach S, Girton J, Johansen J, et al. The JIL-1 histone H3S10 kinase regulates dimethyl H3K9 modifications and heterochromatic spreading in Drosophila. Development. 2006;133:229–35. doi: 10.1242/dev.02199. [DOI] [PubMed] [Google Scholar]
  • 83.Regnard C, Straub T, Mitterweger A, Dahlsveen IK, Fabian V, Becker PB. Global analysis of the relationship between JIL-1 kinase and transcription. PLoS Genet. 2011;7:e1001327. doi: 10.1371/journal.pgen.1001327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Bollen M, Beullens M. Signaling by protein phosphatases in the nucleus. Trends Cell Biol. 2002;12:138–45. doi: 10.1016/S0962-8924(01)02247-4. [DOI] [PubMed] [Google Scholar]
  • 85.Cohen PT. Protein phosphatase 1--targeted in many directions. J Cell Sci. 2002;115:241–56. doi: 10.1242/jcs.115.2.241. [DOI] [PubMed] [Google Scholar]
  • 86.Virshup DM, Shenolikar S. From promiscuity to precision: protein phosphatases get a makeover. Mol Cell. 2009;33:537–45. doi: 10.1016/j.molcel.2009.02.015. [DOI] [PubMed] [Google Scholar]

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

RESOURCES