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PMID: 21555454 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

The Brd4 extraterminal domain confers transcription activation independent of pTEFb by recruiting multiple proteins, including NSD3.

Molecular and cellular biology ·Vol. 31 ·No. 13 ·2011-07-00 ·Pages 2641-52

Rahman S, Sowa ME, Ottinger M, Smith JA, Shi Y, Harper JW, Howley PM

Abstract

Bromodomain protein 4 (Brd4) plays critical roles in development, cancer progression, and virus-host pathogenesis. To gain mechanistic insight into the various biological functions of Brd4, we performed a proteomic analysis to identify and characterize Brd4-associated cellular proteins. We found that the extraterminal (ET) domain, whose function has to date not been determined, interacts with NSD3, JMJD6, CHD4, GLTSCR1, and ATAD5. These ET-domain interactions were also conserved for Brd2 and Brd3, the other human BET proteins tested. We demonstrated that GLTSCR1, NSD3, and JMJD6 impart a pTEFb-independent transcriptional activation function on Brd4. NSD3 as well as JMJD6 is recruited to regulated genes in a Brd4-dependent manner. Moreover, we found that depletion of Brd4 or NSD3 reduces H3K36 methylation, demonstrating that the Brd4/NSD3 complex regulates this specific histone modification. Our results indicate that the Brd4 ET domain through the recruitment of the specific effectors regulates transcriptional activity. In particular, we show that one of these effectors, NSD3, regulates transcription by modifying the chromatin microenvironment at Brd4 target genes. Our study thus identifies the ET domain as a second important transcriptional regulatory domain for Brd4 in addition to the carboxyl-terminal domain (CTD) that interacts with pTEFb.

MeSH Terms
Amino Acid Sequence Cell Cycle Proteins Cell Line Chromosomal Proteins, Non-Histone Histone-Lysine N-Methyltransferase/metabolism Humans Jumonji Domain-Containing Histone Demethylases Molecular Sequence Data Nuclear Proteins/genetics,metabolism Positive Transcriptional Elongation Factor B/metabolism Protein Structure, Tertiary/genetics Transcription Factors/genetics,metabolism Transcriptional Activation Tumor Suppressor Proteins/metabolism
Chemicals
BICRA protein, human BRD4 protein, human Cell Cycle Proteins Chromosomal Proteins, Non-Histone Nuclear Proteins Transcription Factors Tumor Suppressor Proteins JMJD6 protein, human Jumonji Domain-Containing Histone Demethylases Histone-Lysine N-Methyltransferase NSD3 protein, human Positive Transcriptional Elongation Factor B
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Rahman Shaila
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Sowa Mathew E
Ottinger Matthias
Smith Jennifer A
Shi Yang
Harper J Wade
Howley Peter M
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
1098-5549
DOI
10.1128/MCB.01341-10
Published
2011-07-00
Epub
2011-00-09
Pages
2641-52
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC3133372
Subset
IM
Grants
NCI NIH HHS · T32CA009361 · United States
NCI NIH HHS · R01CA116720 · United States
NIA NIH HHS · R01 AG011085 · United States
NIGMS NIH HHS · R01 GM070565 · United States
NIGMS NIH HHS · GM054137 · United States
NCI NIH HHS · T32 CA009361 · United States
NIGMS NIH HHS · R01 GM054137 · United States
NCI NIH HHS · R01 CA116720 · United States
NIA NIH HHS · AG011085 · United States
External Links
PubMed source DOI: 10.1128/MCB.01341-10 PMC Full Text View journal details
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