HIST1H2AC (also known as H2ac) is a replicative histone H2A isoform that is overexpressed in breast cancer (Shann et al, 2008). HIST1H2AC and HIST1H2AA, unique among HIST1H2 family members, contains a HAR domain that in yeast has been shown mediate interaction with histone H3 and to regulate gene expression (Zheng et al, 2010). Estrogen-dependent recruitment of HIST1H2AC to target genes contributes to the proliferative response to estrogen, and siRNA depletion of HIST1H2AC abrogates expression of genes including MYC, CCND1 and BCL2, among others, and results in cell cycle arrest at G0/G1. By ChIP, both the estrogen receptor and HIST1H2AC are present at distal enhancer elements and in the 3' UTR of target genes upon estrogen stimulation, and the proteins physically interact both in vitro and in vivo. HIST1H2AC and ESR1 contribute to target gene activation by promoting the formation of long distance chromatin loops between disparate regulatory regions (Su et al, 2013). Overexpression of HIST1H2AC additionally decreases the levels of the repressive epigenetic modification H3K9me2 that is associated with estrogen-responsive signaling, and HIST1H2AC contributes to the recruitment of the histone demethylase KDM1A (Perillo et al, 2008; Su et al, 2014).