Research Papers:
H4K12ac is regulated by estrogen receptor-alpha and is associated with BRD4 function and inducible transcription
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Abstract
Sankari Nagarajan1, Eva Benito2, Andre Fischer2,3 and Steven A. Johnsen1
1 Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
2 Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany
3 Research Group for Epigenetics in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE) Göttingen, Göttingen, Germany
Correspondence to:
Steven A. Johnsen, email:
Keywords: Histone acetylation, bromodomain, estrogen, epigenetics, chromatin
Received: December 04, 2014 Accepted: January 28, 2015 Published: January 31, 2015
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.
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