Abstract
A replication-dependent histone H2A isotype, H2ac, is upregulated in MCF-7 cells and in estrogen receptor-positive clinical breast cancer tissues. Cellular depletion of this H2A isotype leads to defective estrogen signaling, loss of cell proliferation and cell cycle arrest at G0/G1 phase. H2ac mediates regulation of estrogen receptor target genes, particularly BCL2 and c-MYC, by recruiting estrogen receptor alpha through its HAR domain and facilitating the formation of a chromatin loop between the promoter, enhancer and 3′-untranslated region of the respective genes. These findings reveal a new role for histone isotypes in the regulation of gene expression in cancer cells, and suggest that these molecules may be targeted for anti-cancer drug discovery.
Highlights
Eukaryotic DNA is packaged into chromatin through association with histones [1]
Because MCF-7 cells are estrogen receptor alpha (ERa)+ breast cancer cells, we examined whether H2ac is overexpressed in estrogen receptor (ER)+
To clarify whether ERa was required for the E2induced recruitment of H2ac to the BCL2 and c-MYC chromatin, we examined the recruitment of H2ac and ERa to the enhancer and 30-untranslated region (30-UTR) regions following treatment with the ERa antagonists ICI 182580 or TAM
Summary
Eukaryotic DNA is packaged into chromatin through association with histones [1]. The basic chromatin unit, the nucleosome core particle, consists of 146-base pair units wrapped around a histone octamer composed of two molecules of each of the core histone proteins, H2A, H2B, H3 and H4 [2]. In the recent years, N-terminal tail-modifications of histones, including methylation, acetylation and phosphorylation, have been extensively studied. These modifications regulate cell proliferation, growth and differentiation by altering chromatin structure and gene activity [4,5,6]. The largest group, replicationdependent histones, is cell cycle regulated, and their expression is replication-dependent. The second group, replacement variants, exhibits replication-independent expression throughout the cell cycle. These different histone variants contribute to the creation of distinct or unique nucleosomal architectures. H2A.Z has been implicated in the transcriptional regulation and gene silencing that involves modulation of the nucleosome array [7,8,9,10,11]
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