H2A.Z, a variant of H2A, is found at the promoters of inducible genes in both yeast and higher eukaryotes. However, its role in transcriptional regulation is complex since it has been reported to function both as a repressor and activator. We have previously found that mono-ubiquitylation of H2A.Z is linked to transcriptional silencing. Here, we provide new evidence linking H2A.Z deubiquitylation to transcription activation. We found that H2A.Z and ubiquitin-specific protease 10 (USP10) are each required for transcriptional activation of the androgen receptor (AR)-regulated PSA and KLK3 genes. USP10 directly deubiquitylates H2A.Z in vitro and in vivo, and reducing USP10 expression in prostate cancer cells results in elevated steady-state levels of mono-ubiquitylated H2A.Z (H2A.Zub1). Moreover, knockdown of USP10 ablates hormone-induced deubiquitylation of chromatin proteins at the AR-regulated genes. Finally, by sequential ChIP assays, we found that H2A.Zub1 is enriched at the PSA and KLK3 regulatory regions, and loss of H2A.Zub1 is associated with transcriptional activation of these genes. Together, these data provide novel insights into how H2A.Z ubiquitylation/deubiquitylation and USP10 function in AR-regulated gene expression
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