H2A.Z chaperones converge on E2F target genes for melanoma cell proliferation

作者：Sina Jostes, Chiara Vardabasso, Joanna Dong, Saul Carcamo, Rajendra Singh, Robert George Phelps, Austin Meadows, Elena Grossi, Dan Hasson, Emily Bernstein · 发表于：Genes & Development · 年份：2024 · DOI：10.1101/gad.351318.123 · 被引用次数：15 · 研究领域：Genomics and Chromatin Dynamics、Immunotherapy and Immune Responses、Epigenetics and DNA Methylation

High levels of H2A.Z promote melanoma cell proliferation and correlate with poor prognosis. However, the role of the two distinct H2A.Z histone chaperone complexes SRCAP and P400–TIP60 in melanoma remains unclear. Here, we show that individual subunit depletion ofSRCAP,P400, andVPS72(YL1) results in not only the loss of H2A.Z deposition into chromatin but also a reduction of H4 acetylation in melanoma cells. This loss of H4 acetylation is particularly found at the promoters of cell cycle genes directly bound by H2A.Z and its chaperones, suggesting a coordinated regulation between H2A.Z deposition and H4 acetylation to promote their expression. Knockdown of each of the three subunits downregulates E2F1 and its targets, resulting in a cell cycle arrest akin to H2A.Z depletion. However, unlike H2A.Z deficiency, loss of the shared H2A.Z chaperone subunit YL1 induces apoptosis. Furthermore, YL1 is overexpressed in melanoma tissues, and its upregulation is associated with poor patient outcome. Together, these findings provide a rationale for future targeting of H2A.Z chaperones as an epigenetic strategy for melanoma treatment.