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PMID: 24360279 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Cell ·Vol. 155 ·No. 7 ·2013-12-19 ·Pages 1581-1595

Liu W, Ma Q, Wong K, Li W, Ohgi K, Zhang J, Aggarwal A, Rosenfeld MG

Abstract

Distal enhancers characterized by the H3K4me(1) mark play critical roles in developmental and transcriptional programs. However, potential roles of specific distal regulatory elements in regulating RNA polymerase II (Pol II) promoter-proximal pause release remain poorly investigated. Here, we report that a unique cohort of jumonji C-domain-containing protein 6 (JMJD6) and bromodomain-containing protein 4 (Brd4) cobound distal enhancers, termed anti-pause enhancers (A-PEs), regulate promoter-proximal pause release of a large subset of transcription units via long-range interactions. Brd4-dependent JMJD6 recruitment on A-PEs mediates erasure of H4R3me(2(s)), which is directly read by 7SK snRNA, and decapping/demethylation of 7SK snRNA, ensuring the dismissal of the 7SK snRNA/HEXIM inhibitory complex. The interactions of both JMJD6 and Brd4 with the P-TEFb complex permit its activation and pause release of regulated coding genes. The functions of JMJD6/ Brd4-associated dual histone and RNA demethylase activity on anti-pause enhancers have intriguing implications for these proteins in development, homeostasis, and disease.

MeSH Terms
Cell Cycle Proteins Enhancer Elements, Genetic HEK293 Cells Humans Jumonji Domain-Containing Histone Demethylases/metabolism Nuclear Proteins/metabolism Promoter Regions, Genetic RNA Polymerase II/metabolism RNA, Small Nuclear/metabolism Transcription Factors/metabolism Transcription, Genetic
Chemicals
BRD4 protein, human Cell Cycle Proteins Nuclear Proteins RNA, Small Nuclear Transcription Factors JMJD6 protein, human Jumonji Domain-Containing Histone Demethylases RNA Polymerase II
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Liu Wen
School of Pharmaceutical Science, Xiamen University, Xiang'an South Road, Xiamen, Fujian 361102, China. | Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Ma Qi
Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. | Graduate Program in Bioinformatics and System Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Wong Kaki
Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Li Wenbo
Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Ohgi Kenny
Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Zhang Jie
Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Aggarwal Aneel
Department of Structural and Chemical Biology, Mount Sinai School of Medicine, Box 1677, 1425 Madison Avenue, New York, NY 10029, USA.
Rosenfeld Michael G
Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2013.10.056
Published
2013-12-19
Pages
1581-1595
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3886918
Subset
IM
Grants
NINDS NIH HHS · R01 NS034934 · United States
NIDDK NIH HHS · R37 DK039949 · United States
Howard Hughes Medical Institute · United States
NIDDK NIH HHS · DK18477 · United States
NCRR NIH HHS · P41 RR011823 · United States
NIDDK NIH HHS · R01 DK018477 · United States
NCI NIH HHS · P30 CA023100 · United States
NIDDK NIH HHS · R01 DK039949 · United States
NCI NIH HHS · CA173903 · United States
NIDDK NIH HHS · DK097748 · United States
NINDS NIH HHS · NS34934 · United States
NIDDK NIH HHS · P01 DK074868 · United States
NCI NIH HHS · R01 CA173903 · United States
NHLBI NIH HHS · HL065445 · United States
NHLBI NIH HHS · R01 HL065445 · United States
NIDDK NIH HHS · DK39949 · United States
Databases
GEO
GSE51633
External Links
PubMed source DOI: 10.1016/j.cell.2013.10.056 PMC Full Text View journal details
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