Transcriptional elongation control of hypoxic response

被引：6

作者：

Soliman, Shimaa Hassan AbdelAziz ^{[1
]}

Iwanaszko, Marta ^{[1
]}

Zheng, Bin ^{[1
]}

Gold, Sarah ^{[1
]}

Howard, Benjamin Charles ^{[1
]}

Das, Madhurima ^{[1
]}

Chakrabarty, Ram Prosad ^{[1
,2
]}

Chandel, Navdeep S. ^{[1
,2
]}

Shilatifard, Ali ^{[1
]}

机构：

[1] Northwestern Univ, Simpson Querrey Inst Epigenet, Feinberg Sch Med, Dept Biochem & Mol Genet, Chicago, IL 60611 USA

[2] Northwestern Univ, Dept Med, Div Pulm & Crit Care, Chicago, IL 60611 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2024年 / 121卷 / 15期

关键词：

transcription; gene expression; epigenetic mechanisms; chromatin; RNA polymerase II; RNA-POLYMERASE-II; BROMODOMAIN PROTEIN BRD4; INDUCIBLE FACTOR-I; SEQ DATA; P-TEFB; OXYGEN; COMPLEX; BINDING; HIF-1-ALPHA; RESISTANCE;

D O I：

10.1073/pnas.2321502121

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The release of paused RNA polymerase II (RNAPII) from promoter- proximal regions is tightly controlled to ensure proper regulation of gene expression. The elongation tor PTEF-b is known to release paused RNAPII via phosphorylation of the RNAPII C - terminal domain by its cyclin- dependent kinase component, CDK9. However, the nal and stress- specific roles of the various RNAPII- associated macromolecular complexes containing PTEF- b/CDK9 are not yet clear. Here, we identify and characterize the CDK9 complex required for transcriptional response to hypoxia. Contrary to previous reports, our data indicate that a CDK9 complex containing BRD4 but not AFF1/4 is essential for this hypoxic stress response. We demonstrate that BRD4 bromodomains (BET) dispensable for the release of paused RNAPII at hypoxia- activated genes and that inhibition by JQ1 is insufficient to impair hypoxic gene response. Mechanistically, demonstrate that the C - terminal region of BRD4 is required for Polymerase- Associated Factor - 1 Complex (PAF1C) recruitment to establish an elongation- competent RNAPII complex at hypoxia- responsive genes. PAF1C disruption using a small- molecule inhibitor (iPAF1C) impairs hypoxia- induced, BRD4- mediated RNAPII release. Together, our results provide insight into potentially targetable mechanisms that control the hypoxia- responsive transcriptional elongation.

引用

页数：12