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BRD4 IS A HISTONE ACETYLTRANSFERASE THAT EVICTS NUCLEOSOMES FROM CHROMATIN
Author(s) -
Ballachanda Devaiah Nanjappa,
CaseBorden Chanelle,
Gegonne Anne,
Hsu Chih Hao,
Chen Qingrong,
Meerzaman Daoud,
Dey Anup,
Ozato Keiko,
Singer Dinah
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.802.5
Subject(s) - bromodomain , brd4 , chromatin , nucleosome , histone , microbiology and biotechnology , histone acetyltransferase , chromatin remodeling , chemistry , biology , histone h4 , cancer research , genetics , gene
Bromodomain protein 4 (BRD4) is a master transcriptional and epigenetic regulator which plays a pivotal role in cancer development and immune diseases. As a chromatin binding protein that remains bound during mitosis, BRD4 has been described as a mitotic bookmark. Inhibiting its interaction with chromatin has been a successful therapeutic strategy against many cancers including acute myeloid leukemia, Burkitt's lymphoma, breast, colon and lung cancer. While BRD4 association with chromatin is known to activate transcription of key proto‐oncogenes, the mechanism involved is currently unknown. Here, we report that BRD4 has novel and intrinsic histone acetyltransferase (HAT) activity through which it acetylates histones H3 and H4 in nucleosomes. BRD4 HAT activity maps to two consensus acetyl CoA binding sites and a 40 aa catalytic site. BRD4 HAT activity is distinct from all other known HAT's with a unique lysine acetylation ‘fingerprint’ that includes acetylation of H3K4, H3K9, H3K18 and H3K27 but not H3K14. Most importantly, BRD4 acetylates H3K122, a key lysine residue critical for nucleosome stability located on the dyad axis of the nucleosome. BRD4 HAT activity and H3K122 acetylation is responsible for nucleosome eviction and opening of the chromatin, as evidenced by the ability of BRD4, but not BRD4 HAT mutants, to evict nucleosomes both in vitro and in vivo . Nucleosome clearance by BRD4 is selective and localized to the gene loci it regulates such as c‐Myc, c‐Fos and Aurora B kinase. Consistent with its role in localized chromatin de‐compaction, BRD4 HAT activity regulates transcription at these gene loci as well. BRD4 HAT activity thus plays a key role in chromatin remodeling and transcription. Support or Funding Information This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.