title: H4K12ac is regulated by estrogen receptor-alpha and is associated with BRD4 function and inducible transcription.
abstract: Hormone-dependent gene expression requires dynamic and coordinated epigenetic changes. Estrogen receptor-positive (ER+) breast cancer is particularly dependent upon extensive chromatin remodeling and changes in histone modifications for the induction of hormone-responsive gene expression. Our previous studies established an important role of bromodomain-containing protein-4 (BRD4) in promoting estrogen-regulated transcription and proliferation of ER+ breast cancer cells. Here, we investigated the association between genome-wide occupancy of histone H4 acetylation at lysine 12 (H4K12ac) and BRD4 in the context of estrogen-induced transcription. Similar to BRD4, we observed that H4K12ac occupancy increases near the transcription start sites (TSS) of estrogen-induced genes as well as at distal ERα binding sites in an estrogen-dependent manner. Interestingly, H4K12ac occupancy highly correlates with BRD4 binding and enhancer RNA production on ERα-positive enhancers. Consistent with an importance in estrogen-induced gene transcription, H4K12ac occupancy globally increased in ER-positive cells relative to ER-negative cells and these levels were further increased by estrogen treatment in an ERα-dependent manner. Together, these findings reveal a strong correlation between H4K12ac and BRD4 occupancy with estrogen-dependent gene transcription and further suggest that modulators of H4K12ac and BRD4 may serve as new therapeutic targets for hormone-dependent cancers.
authors: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.
authors: Sankari
authors: S
authors: Nagarajan
authors: Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany.
authors: Eva
authors: E
authors: Benito
authors: Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany.|Research Group for Epigenetics in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE) Göttingen, Göttingen, Germany.
authors: Andre
authors: A
authors: Fischer
authors: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.
authors: Steven A
authors: SA
authors: Johnsen
mesh_terms: D000107:Acetylation; D001665:Binding Sites; D001943:Breast Neoplasms / Q000378:metabolism; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D019295:Computational Biology; D044127:Epigenesis, Genetic; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006657:Histones / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D009687:Nuclear Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D047628:Estrogen Receptor alpha; D004967:Estrogens; D006657:Histones; D009687:Nuclear Proteins; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C506487:ESR1 protein, human
keywords: bromodomain; chromatin; epigenetics; estrogen; histone acetylation