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DNA Damage Induces Dynamic Associations of BRD4/P-TEFb With Chromatin and Modulates Gene Transcription in a BRD4-Dependent and -Independent Manner

Authors
  • Song, Yawei1, 2, 3, 4, 5
  • Hu, Gongcheng2, 3, 4, 5
  • Jia, Jinping2
  • Yao, Mingze2
  • Wang, Xiaoshan2
  • Lu, Wenliang2
  • Hutchins, Andrew P.6
  • Chen, Jiekai2, 3, 5
  • Ozato, Keiko7
  • Yao, Hongjie2, 3, 4, 5
  • 1 School of Life Sciences, University of Science and Technology of China, Hefei , (China)
  • 2 CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou , (China)
  • 3 Bioland Laboratory (Guangzhou Regenerative Medicine and Health GuangDong Laboratory), Guangzhou , (China)
  • 4 Institute of Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing , (China)
  • 5 Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou , (China)
  • 6 Department of Biology, Southern University of Science and Technology, Shenzhen , (China)
  • 7 Division of Developmental Biology, National Institute of Child Health and Human Development, Bethesda, MD , (United States)
Type
Published Article
Journal
Frontiers in Molecular Biosciences
Publisher
Frontiers Media SA
Publication Date
Dec 04, 2020
Volume
7
Identifiers
DOI: 10.3389/fmolb.2020.618088
Source
Frontiers
Keywords
Disciplines
  • Molecular Biosciences
  • Original Research
License
Green

Abstract

The bromodomain-containing protein BRD4 has been thought to transmit epigenetic information across cell divisions by binding to both mitotic chromosomes and interphase chromatin. UV-released BRD4 mediates the recruitment of active P-TEFb to the promoter, which enhances transcriptional elongation. However, the dynamic associations between BRD4 and P-TEFb and BRD4-mediated gene regulation after UV stress are largely unknown. In this study, we found that BRD4 dissociates from chromatin within 30 min after UV treatment and thereafter recruits chromatin. However, P-TEFb binds tightly to chromatin right after UV treatment, suggesting that no interactions occur between BRD4 and P-TEFb within 30 min after UV stress. BRD4 knockdown changes the distribution of P-TEFb among nuclear soluble and chromatin and downregulates the elongation activity of RNA polymerase II. Inhibition of JNK kinase but not other MAP kinases impedes the interactions between BRD4 and P-TEFb. RNA-seq and ChIP assays indicate that BRD4 both positively and negatively regulates gene transcription in cells treated with UV stress. These results reveal previously unrecognized dynamics of BRD4 and P-TEFb after UV stress and regulation of gene transcription by BRD4 acting as either activator or repressor in a context-dependent manner.

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