The Histone Variant H2A.Z Is a Master Regulator of the Epithelial-Mesenchymal Transition

Abstract

Epithelial-mesenchymal transition (EMT) is a profound example of cell plasticity that is crucial for embryonic development and cancer. Although it has long been suspected that chromatin-based mechanisms play a role in this process, no master regulator that can specifically regulate EMT has been identified to date. Here, we show that H2A.Z can coordinate EMT by serving as either an activator or repressor of epithelial or mesenchymal gene expression, respectively. Following induction of EMT by TGF-β, we observed an unexpected loss of H2A.Z across both downregulated epithelial and upregulated mesenchymal promoters. Strikingly, the repression of epithelial gene expression was associated with reduction of H2A.Z upstream of the transcription start site (TSS), while the activation of mesenchymal gene expression was dependent on removal of H2A.Z downstream of the TSS. Therefore, the ability of H2A.Z to regulate EMT is dependent on its position, either upstream or downstream of the TSS.

A three layered histone epigenetics in breast cancer metastasis

“…Positive enhanced correlation between H2A.ZK101me2 with SMYD3 has been observed in human breast tissue biopsies [90]. However contradicting role of H2A.Z has also been reported recently by Domaschenz et al 2017 [87]. They confirmed that H2A.Z depletion imitates the EMT condition that is being produced by TGF-β pathway induction whereas overexpression induce the epithelial genes [87].This study could be further supported by the fact that loss in H2A.Z in MCF-10A cell line, EMT was induced ( Fig.…”

“…H2A.Z H2A.Z histone variant was for the first time reported by West and Bonner, 1980 [86]. It is encoded by two genes H2A.Z1 and H2A.Z2 [87]. Although H2A.Z accounts for only 5% of the total H2A canonical histones, it is expressed throughout the entire cell cycle [88].…”

“…3a). Thus, high H2A.Z is found to be associated with cell proliferation [87]. Another way, by which H2A.Z regulate cell cycle is via activation of oncoprotein C-MYC expression [93,94].…”

High Temporal-Resolution Transcriptome Landscape of Early Maize Seed Development

“…By contrast, for 5 expressed H2A.Z, only one H2A.Z (Zm00001d027760) was in module II, and the remaining 4 H2A.Z were distributed in four different modules (I-C,11,16, and 18; Supplemental Data Set 4). The high variation of expression patterns for different H2A.Z genes is in line with the diverse functions of H2A.Z variants, including DNA repair, apparently contradictory roles in gene activation and silencing, nucleosome turnover, heterochromatin, boundary element, and chromatin fiber formation (Zlatanova and Thakar, 2008;Altaf et al, 2009;Dai et al, 2017;Domaschenz et al, 2017).…”

Enhanced identification of significant regulators of gene expression

“…LMO4 (LIM domain only 4) has been shown to be an essential cofactor in EMT at least in neuroblastoma and neural crest cells [62]. ANP32E (Acidic nuclear phosphoprotein 32 family member E) is a histone chaperone that mediates removal of histone H2A.Z from the nucleosome [63], and it has been shown that H2A.Z is a master regulator of EMT [64]. TGFB1I1 (Transforming growth factor beta 1 induced transcript 1) is a coactivator of the androgen receptor, it is known to be associated with prostate cancer, and it can induce EMT, at least in astrocytomes.…”