Gene dysregulation by histone variant H2A.Z in bladder cancer

Abstract

BackgroundThe incorporation of histone variants into nucleosomes is one of the main strategies that the cell uses to regulate the structure and function of chromatin. Histone H2A.Z is an evolutionarily conserved histone H2A variant that is preferentially localized within nucleosomes at the transcriptional start site (TSS). H2A.Z reorganizes the local chromatin structure and recruits the transcriptional machinery for gene activation. High expression of H2A.Z has been reported in several types of cancers and is causally linked to genomic instability and tumorigenesis. However, it is not entirely clear how H2A.Z overexpression in cancer cells establishes aberrant chromatin states and promotes gene expression.ResultsThrough integration of genome-wide H2A.Z ChIP-seq data with microarray data, we demonstrate that H2A.Z is enriched around the TSS of cell cycle regulatory genes in bladder cancer cells, and this enrichment is correlated with the elevated expression of cancer-promoting genes. RNAi-mediated knockdown of H2A.Z in the cancer cells causes transcriptional suppression of multiple cell cycle regulatory genes with a distinct decrease in cell proliferation. H2A.Z nucleosomes around the TSS have higher levels of H3K4me2/me3, which coincides with the recruitment of two chromatin factors, WDR5 and BPTF. The observed recruitment is functional, as the active states of H2A.Z target genes are largely erased by suppressing the expression of WDR5 or BPTF, effects resembling H2A.Z knockdown.ConclusionsWe conclude that H2A.Z is overexpressed in bladder cancer cells and contributes to cancer-related transcription pathways. We also provide evidence in support of the engagement of H3K4me2/me3 and WDR5/BPTF in H2A.Z-induced cancer pathogenesis. Further studies are warranted to understand how H2A.Z overexpression contributes to the recruitment of the full repertoire of transcription machinery to target genes in bladder cancer cells.

Genetic complementation analysis showed distinct contributions of the N‐terminal tail of H2A.Z to epigenetic regulations

“…H2A.Z is also reported to play important roles in various biological phenomena. For example, H2A.Z is required for ES cell pluripotency and differentiation (Creyghton et al, 2008;Wang et al, 2015), and over-expression of H2A.Z has been observed in several types of cancer cells, including breast cancer, bladder cancer, and malignant melanoma cells (Hua et al, 2008;Kim et al, 2013;Vardabasso et al, 2015).…”

“…All rights reserved tumorgenesis (Hua et al, 2008;Valdés-Mora et al, 2012;Kim et al, 2013), and cognate memory (Zovkic et al, 2014). H2A.Z is essential for the development of Drosophila and mice (Clarkson et al, 1999;Faast et al, 2001).…”

“…H2A.Z is also reported to play important roles in various biological phenomena. For example, H2A.Z is required for ES cell pluripotency and differentiation (Creyghton et al, 2008;Wang et al, 2015), and over-expression of H2A.Z has been observed in several types of cancer cells, including breast cancer, bladder cancer, and malignant melanoma cells (Hua et al, 2008;Kim et al, 2013;Vardabasso et al, 2015).Although certain features of H2A.Z, which are distinct from those of the canonical H2A, are thought to contribute to various functions orchestrated by H2A.Z, their identities remained unknown so far.non-allelic histone variants (Talbert et al, 2010; Talbert et al, 2012). Although the canonical histones are mainly expressed and incorporated into the chromatin during the S-phase of the cell cycle (Marzluff et al, 2008), the expression and incorporation of the histone variants are not restricted to S-phase (Talbert et al, 2012).…”

Chemical “Diversity” of Chromatin Through Histone Variants and Histone Modifications

“…H2A.Z has been shown to be upregulated in different cancer types, whereas the knockdown of H2A.Z expression results in a decrease in proliferation of cancer cells [72,75]. These discoveries underscore the importance of H2A.Z in transcriptional regulation and other chromatin-regulated processes, and that dysregulation of H2A.Z expression could lead to disease-causing consequences.…”

“…In addition to the mechanistic studies that connect H2A.Z to transcriptional regulation, other recent studies have implicated H2A.Z in cancer biology, in part through its role in regulating expression of cell cycle-related genes [72][73][74]. H2A.Z has been shown to be upregulated in different cancer types, whereas the knockdown of H2A.Z expression results in a decrease in proliferation of cancer cells [72,75].…”