Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Crosstalk between the RNA methylation and histone binding activities of MePCE regulates P-TEFb activation on chromatin

ABSTRACT: The switch of RNAP II from the paused to the productive transcription elongation state is a pivotal regulatory step requiring specific phosphorylations catalyzed by the P-TEFb kinase. Nucleosolic P-TEFb activity is inhibited by its interaction with the ribonuclear protein complex built around the 7SK small nuclear RNA (7SK snRNP). MePCE is the RNA methyltransferase that methylates and stabilizes 7SK in the nucleosol. Here we report that MePCE also binds chromatin through the tail of histone H4 to serve as a P-TEFb activator at specific genes important for cellular identity. Notably, this histone binding abolishes MePCE’s RNA methyltransferase activity towards 7SK, explaining why MePCE-bound P-TEFb on chromatin may not be associated with the full 7SK snRNP and is competent for RNAP II activation. Overall, our results suggest that a crosstalk between the histone binding and RNA methylation activities of MePCE regulates P-TEFb activation on chromatin in a 7SK- and Brd4-independent manner.

ORGANISM(S): Homo sapiens

PROVIDER: GSE108830 | GEO | 2018/02/05

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Integrative Proteomics Identifies MePCE as a Substrate of CDK9 for Releasing P-TEFb from 7SK snRNP Under Genotoxic Stress

Project description:The dynamic phosphorylation process regulated by the positive transcription elongation factor b (P-TEFb), a CDK9-cyclin T heterodimer, is critical for transcription elongation of numerous mammalian genes. Most P-TEFb in cells are normally sequestered in the 7SK snRNP, and their release from this complex is well-controlled to maintain proper cell homeostasis and growth. The comprehensive profiling of CDK9 substrates is essential for understanding diverse functions of P-TEFb in controlling gene expression. Here, integrative proteomics methodologies are developed to globally identify the potential substrates of CDK9 in vivo. Our results show that the 7SK methylphosphate capping enzyme MePCE is directly phosphorylated by CDK9 within the 7SK snRNP, which is known to exhibit little kinase activity toward other known CDK9 substrates. Upon ultraviolet radiation, MePCE becomes phosphorylated, leading to the dissociation of 7SK snRNP and release of P-TEFb to activate transcription. Meanwhile, the phosphorylation of MePCE does not affect its methyltransferase activity toward 7SK RNA. Our data suggest that even though CDK9 in 7SK snRNP has little kinase activity toward external substrates, it can phosphorylate the snRNP integral component MePCE, which is required to release P-TEFb. This novel inside-to-outside mode of P-TEFb activation may serve as a critical checkpoint in regulating gene transcription under stressful conditions.

2024-07-03 | PXD053627 |

RBM7 activates P-TEFb for a pro-survival transcriptional response to DNA damage

Project description:DNA damage response (DDR) involves dramatic transcriptional alterations, the mechanisms of which remain obscure. Here we show that following DNA damage, the RNA-binding motif protein 7 (RBM7) stimulates RNA polymerase II (Pol II) elongation and increases cell viability by activating the positive transcription elongation factor b (P-TEFb). This is mediated by DNA damage-enhanced binding of RBM7 to 7SK, the scaffold of the 7SK small nuclear ribonucleoprotein (snRNP) that inhibits P-TEFb. As a result, P-TEFb relocates from 7SK snRNP to chromatin to activate transcription of key DDR genes and multiple classes of non-coding RNAs. By alleviating the inhibition of P-TEFb, RBM7 thus promotes Pol II elongation to activate a transcriptional response that is crucial for cell fate upon genotoxic insult. Our work highlights a novel paradigm in stress-dependent control of Pol II pause release, and offers the promise of combating cancer by RBM7 and P-TEFb antagonists in combination with established DNA damage-inducing chemotherapeutics.

2018-06-01 | E-MTAB-6475 | biostudies-arrayexpress

The 7SK/P-TEFb snRNP controls ultraviolet radiation-induced transcriptional reprogramming

Project description:Releasing promoter-proximally-paused RNA polymerase II (RNAPII) by the positive transcription elongation factor b (P-TEFb) is a central regulatory step of eukaryotic mRNA synthesis. The nuclear activity of P-TEFb is controlled mainly by the 7SK small nuclear RNP (snRNP) which sequesters active P-TEFb into inactive 7SK/P-TEFb snRNP. Here we demonstrate that under normal culture conditions, the lack of 7SK snRNP has only a minor impact on global RNAPII transcription and promoter-proximal pausing without detectable consequences on cell growth and proliferation. However, upon ultraviolet (UV) light-induced DNA damage, cells lacking 7SK have a defective transcriptional response and highly reduced viability. Both UV-induced release of ‘lesion-scanning’ polymerases and activation of key early responsive genes are compromised in the absence of 7SK. We show that proper induction of 7SK-dependent UV-responsive genes, namely efficient release of paused RNAPII and recruitment of key elongation factors, requires P-TEFb activity directly mobilized from the nucleoplasmic 7SK/P-TEFb snRNP.

2021-03-30 | GSE147055 | GEO

SR Proteins Collaborate with 7SK and Promoter-Associated Nascent RNA to Release Paused Polymerase

Project description:RNAP II is frequently paused near gene promoters in mammals and its transition to productive elongation requires active recruitment of P-TEFb, a cyclin-dependent kinase for RNAP II and other key transcription elongation factors. A fraction of P-TEFb is sequestered in an inhibitory complex containing the 7SK noncoding RNA, but it has been unclear how P-TEFb is switched from the 7SK complex to RNAP II during transcription activation. We report that SRSF2 (also known as SC35, an SR splicing factor) is part of the 7SK complex assembled at gene promoters and plays a direct role in transcription pause release. We demonstrate RNA-dependent, coordinated release of SRSF2 and P-TEFb from the 7SK complex and transcription activation via SRSF2 binding to promoter-associated nascent RNA. These findings reveal an unanticipated SR protein function, a role for promoter-proximal nascent RNA in gene activation, and an analogous mechanism to HIV Tat/TAR for activating cellular genes. SR ChIP-seq, Pol II ChIP-seq, and Gro-seq

2013-05-09 | E-GEOD-45517 | biostudies-arrayexpress

SR Proteins Collaborate with 7SK and Promoter-Associated Nascent RNA to Release Paused Polymerase

2013-05-09 | GSE45517 | GEO

KAP1 Recruitment of the 7SK snRNP to Promoters Enables Transcription Elongation by RNA Polymerase II

Project description:The transition from transcription initiation into elongation at promoters of primary response genes (PRG) in metazoan cells is controlled by inducible transcription factors, which utilize P-TEFb to phosphorylate RNA Polymerase II (Pol II) in response to stimuli. Prior to stimulation, a fraction of P-TEFb is recruited to promoters in a catalytically inactive state bound to the 7SK small nuclear ribonucleoprotein (snRNP). However, it remains unclear how and why the 7SK snRNP is assembled at promoters. Here we report that the transcriptional regulator KAP1 directly recruits the 7SK snRNP to facilitate localized release of P-TEFb, promoting rapid Pol II elongation and PRG synthesis in response to stimuli. Collectively, we have discovered and characterized a novel complex, which we term the KEC, which dictates rapid and robust PRG induction upon stimuli.

2015-10-09 | GSE72622 | GEO

Interaction of 7SK with the Smn complex modulates snRNP production

Project description:Gene expression requires tight coordination of the molecular machineries that mediate transcription and splicing. While the interplay between transcription kinetics and spliceosome fidelity has been investigated before, less is known about mechanisms regulating the assembly of the spliceosomal machinery in response to transcription changes. Here we report an association of the Smn complex, which mediates spliceosomal snRNP biogenesis, with the 7SK complex involved in transcriptional regulation. We found that Smn interacts with the 7SK core components Larp7 and Mepce and specifically associates with 7SK subcomplexes containing hnRNP R. The association between Smn and 7SK complexes is enhanced upon transcriptional inhibition leading to reduced production of snRNPs. Taken together, our findings reveal a functional association of Smn and 7SK complexes that is governed by global changes in transcription. Thus, in addition to its canonical nuclear role in transcriptional regulation, 7SK has cytosolic functions in fine-tuning spliceosome production according to transcriptional demand.

2021-01-26 | PXD021360 | Pride

AFF4 globally affects the release of paused RNA polymerase II in HEL cells [PRO-seq]

Project description:P-TEFb, a heterodimer of kinase, CDK9, and Cyclin T1, is a critical regulator of promoter-proximal pause release of Pol II in metazoans. It is capable of forming three larger multiprotein complexes, including the super elongation complex (SEC), the BRD4/P-TEFb complex and the 7SK snRNP. In the SEC or the BRD4/P-TEFb, P-TEFb is enzymatically active, while in the 7SK snRNP, its activity is inhibited. The SEC consists of AFF1 or 4, ENL or AF9, ELL1, 2 or 3 and EAF1 or 2 in addition to P-TEFb, the only subunit with catalytic activity, and the noncatalytic subunits have been found to be able to regulate pause release through P-TEFb. One recent study showed that in human DLD-1 cells, the SEC only regulates pause release of heat shock (HS) genes, whereas the BRD4/P-TEFb complex regulates pause release of the rest of the genes. In this study, we found that AFF4 knockdown in human HEL cells decreased not only cellular level but also global chromatin occupancy of CTD serine 2 phosphorylated Pol II, and notably, increased promoter-proximal pause of Pol II on several hundred HS and thousands of non-HS genes. Mechanistically, AFF4 facilitates pause release likely by facilitating the binding of P-TEFb to Pol II. These results suggest that the extent of impact of AFF4 on pause release is likely to be context-dependent or cell-type dependent.

2024-06-10 | GSE234619 | GEO

AFF4 globally affects the release of paused RNA polymerase II in HEL cells [RNA-seq]

2024-06-10 | GSE234617 | GEO

AFF4 globally affects the release of paused RNA polymerase II in HEL cells [ChIP-seq]

2024-06-10 | GSE235444 | GEO