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Biological Function and Histone Recognition of Family IV Bromodomain‐Containing Proteins
Author(s) -
Lloyd Jonathan T.,
Poplawaski Amanda,
Lubula Mulu Y.,
Carlson Samuel,
Gay Jamie,
Glass Karen C.
Publication year - 2017
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.31.1_supplement.755.7
Subject(s) - bromodomain , pcaf , histone , histone acetyltransferases , acetylation , chemistry , histone code , epigenetics , histone methylation , histone methyltransferase , nucleosome , histone acetyltransferase , biochemistry , microbiology and biotechnology , biology , dna , gene expression , gene , dna methylation
Bromodomain proteins function as epigenetic readers that recognize acetylated histone tails to facilitate transcription of target genes. There are approximately 60 known human bromodomains, and these are split into 8 sub‐families based on structural conservation. The bromodomain‐containing proteins in family IV consist of 7 members (BRPF1, BRPF2, BRPF3, BRD7, BRD9, ATAD2a, and ATAD2b). The bromodomains of each of these proteins recognize and bind acetyllysine residues on histone tails protruding from the nucleosome. However, the histone marks recognized by each bromodomain protein, can be very different. Our research revealed that the BRPF1 subunit of the MOZ histone acetyltransferase (HAT) recognizes histone acetylated at H2AK5ac, H4K12ac, H3K14ac, H4K8ac and H4K5ac1. While the bromodomain of BRD7, a member of the SWI/SNF complex, was shown to preferentially recognize histones H3K9ac, H3K14ac, H4K8ac, H4K12ac and H4K16ac2. The bromodomains of BRPF2 and BRPF3 are very similar in amino acid sequence, and function as part of the HBO1 HAT complex, but there is limited data on which histone ligands they bind3. Similarly, there is little known about the histone targets of the BRD9 and ATAD2b bromodomain proteins. Interestingly, the ATAD2a bromodomain was recently shown to preferentially bind to H4K5acK12ac in newly synthesized histones following DNA replication4. ATAD2 is a co‐activator of the estrogen and androgen receptors, and has also been shown to stimulate MYC and E2F‐dependent cell proliferation. Additionally, ATAD2a is overexpressed in a range of cancers including lung, breast, and prostate cancer, as well as ovarian and hepatocellular carcinoma. However, despite the physiological importance of the family IV bromodomains, little is known about how they function at the molecular or atomic level. Here, we summarize our understanding of how family IV bromodomains recognize and select for acetyllysine marks by providing the molecular details of ligand binding, which will be critical for the development of new therapeutic interventions targeting these bromodomains. Support or Funding Information Supported by a National Institutes of Health grant, NIGMS 1R15GM104865, and an ACPHS scholarship of discovery grant.