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BRD4 通过与乙酰化组蛋白相互作用,辅助编码 RNA 和增强子 RNA 的延伸。

BRD4 assists elongation of both coding and enhancer RNAs by interacting with acetylated histones.

机构信息

1] Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA. [2] Program in Genomics of Differentiation, National Institutes of Child Health and Human Development, Bethesda, Maryland, USA.

Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.

出版信息

Nat Struct Mol Biol. 2014 Dec;21(12):1047-57. doi: 10.1038/nsmb.2912. Epub 2014 Nov 10.


DOI:10.1038/nsmb.2912
PMID:25383670
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4720983/
Abstract

Small-molecule BET inhibitors interfere with the epigenetic interactions between acetylated histones and the bromodomains of the BET family proteins, including BRD4, and they potently inhibit growth of malignant cells by targeting cancer-promoting genes. BRD4 interacts with the pause-release factor P-TEFb and has been proposed to release RNA polymerase II (Pol II) from promoter-proximal pausing. We show that BRD4 occupies widespread genomic regions in mouse cells and directly stimulates elongation of both protein-coding transcripts and noncoding enhancer RNAs (eRNAs), in a manner dependent on bromodomain function. BRD4 interacts with elongating Pol II complexes and assists Pol II in progression through hyperacetylated nucleosomes by interacting with acetylated histones via bromodomains. On active enhancers, the BET inhibitor JQ1 antagonizes BRD4-associated eRNA synthesis. Thus, BRD4 is involved in multiple steps of the transcription hierarchy, primarily by facilitating transcript elongation both at enhancers and on gene bodies independently of P-TEFb.

摘要

小分子 BET 抑制剂干扰乙酰化组蛋白与 BET 家族蛋白的溴结构域之间的表观遗传相互作用,包括 BRD4,并通过靶向促进癌症的基因强烈抑制恶性细胞的生长。BRD4 与暂停释放因子 P-TEFb 相互作用,并被提议从启动子近端暂停释放 RNA 聚合酶 II (Pol II)。我们表明 BRD4 在小鼠细胞中占据广泛的基因组区域,并直接刺激蛋白质编码转录本和非编码增强子 RNA (eRNA) 的延伸,这种方式依赖于溴结构域的功能。BRD4 与延伸的 Pol II 复合物相互作用,并通过溴结构域与乙酰化组蛋白相互作用,协助 Pol II 通过超乙酰化核小体进行进展。在活性增强子上,BET 抑制剂 JQ1 拮抗 BRD4 相关的 eRNA 合成。因此,BRD4 参与转录层次的多个步骤,主要是通过在增强子和基因体上独立于 P-TEFb 促进转录本的延伸。

相似文献

[1]
BRD4 assists elongation of both coding and enhancer RNAs by interacting with acetylated histones.

Nat Struct Mol Biol. 2014-11-10

[2]
BRD4 coordinates recruitment of pause release factor P-TEFb and the pausing complex NELF/DSIF to regulate transcription elongation of interferon-stimulated genes.

Mol Cell Biol. 2013-4-15

[3]
Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells.

J Biol Chem. 2012-10-19

[4]
RNAs interact with BRD4 to promote enhanced chromatin engagement and transcription activation.

Nat Struct Mol Biol. 2018-8-3

[5]
Affinity map of bromodomain protein 4 (BRD4) interactions with the histone H4 tail and the small molecule inhibitor JQ1.

J Biol Chem. 2014-2-4

[6]
Bromodomain and extra-terminal (BET) bromodomain inhibition activate transcription via transient release of positive transcription elongation factor b (P-TEFb) from 7SK small nuclear ribonucleoprotein.

J Biol Chem. 2012-9-5

[7]
A BRD4-mediated elongation control point primes transcribing RNA polymerase II for 3'-processing and termination.

Mol Cell. 2021-9-2

[8]
Distinct layers of BRD4-PTEFb reveal bromodomain-independent function in transcriptional regulation.

Mol Cell. 2023-8-17

[9]
The BET bromodomain inhibitor JQ1 activates HIV latency through antagonizing Brd4 inhibition of Tat-transactivation.

Nucleic Acids Res. 2012-10-18

[10]
Acetylation on histone H3 lysine 9 mediates a switch from transcription initiation to elongation.

J Biol Chem. 2017-9-1

引用本文的文献

[1]
The extra-terminal domain drives the role of BET proteins in transcription.

bioRxiv. 2025-5-14

[2]
Brd4 expression in CD4 T cells and in microglia promotes neuroinflammation in experimental autoimmune encephalomyelitis.

J Neuroinflammation. 2025-6-2

[3]
BRD4 regulates mA of ESPL1 mRNA interaction with ALKBH5 to modulate breast cancer progression.

Acta Pharm Sin B. 2025-3

[4]
The ESCRT protein CHMP5 promotes T cell leukemia by enabling BRD4-p300-dependent transcription.

Nat Commun. 2025-5-3

[5]
Molecular and clinical aspects of histone-related disorders.

Hum Genomics. 2025-4-29

[6]
Pro-Inflammatory Properties of Salivary Gland-Derived Fibroblasts-Implications in Sjögren's Disease.

Cells. 2025-4-8

[7]
USP10 stabilizes BAZ1A to drive tumor stemness via an epigenetic mechanism in head and neck squamous cell carcinoma.

Cell Death Dis. 2025-4-10

[8]
Studies on Gene Enhancer with KSHV mini-chromatin.

bioRxiv. 2025-3-24

[9]
Prior epigenetic status predicts future susceptibility to seizures in mice.

bioRxiv. 2025-3-23

[10]
Identification of a SNAI1 enhancer RNA that drives cancer cell plasticity.

Nat Commun. 2025-3-25

本文引用的文献

[1]
Blockade of oncogenic IκB kinase activity in diffuse large B-cell lymphoma by bromodomain and extraterminal domain protein inhibitors.

Proc Natl Acad Sci U S A. 2014-7-21

[2]
Bromodomain protein BRD4 is required for estrogen receptor-dependent enhancer activation and gene transcription.

Cell Rep. 2014-7-24

[3]
Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer.

Nature. 2014-4-23

[4]
An atlas of active enhancers across human cell types and tissues.

Nature. 2014-3-27

[5]
Disrupting the interaction of BRD4 with diacetylated Twist suppresses tumorigenesis in basal-like breast cancer.

Cancer Cell. 2014-2-10

[6]
Affinity map of bromodomain protein 4 (BRD4) interactions with the histone H4 tail and the small molecule inhibitor JQ1.

J Biol Chem. 2014-2-4

[7]
Brd4 and JMJD6-associated anti-pause enhancers in regulation of transcriptional pause release.

Cell. 2013-12-19

[8]
Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation.

Cell. 2013-12-19

[9]
Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma.

Cancer Cell. 2013-12-9

[10]
eRNAs promote transcription by establishing chromatin accessibility at defined genomic loci.

Mol Cell. 2013-8-29

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