A Study of Histone H2B Mutations in Cancer

Abstract

Cancer-associated histone mutations have drawn much attention in the cancer epigenetics field since 2012, when the missense mutations in histone H3 were characterized as drivers in brain and bone cancers. Mutations in other core histones have also been found recently, yet, their roles in cancers remain largely unknown. In this study, I focus on two of the most frequently mutated residues in H2B, namely H2BE113K and H2BG53D. The E113 residue of H2B is located on the acidic patch which is a chromatin-associated protein binding surface on the nucleosome. Significantly, physiological expression of H2BE113K mutant histone in MDA-MB-231 breast cancer cells increases the colony formation ability. Local presence of H2BE113K mutant histone appears to have fundamentally increased chromatin accessibility and increased H2BK120ub enrichment, which are related to significant gene expression changes. These results demonstrate that the mutation in the acidic patch gives rise to oncogenic properties due to deregulation of gene expression through affecting chromatin accessibility and histone modification. By contrast, the G53 residue is located in the global domain of H2B in close proximity to the double-stranded DNA near the DNA entry/exit site. We find that the H2BG53D mutation weakens the nucleosomal DNA–histones interaction and subsequently enhances transcription in vitro. The introduction of the H2BG53D mutation in S2VP10 pancreatic cancer cells results in gene transcription changes. Crucially, the G53D mutant H2B directly elevates target gene transcription and leads to enhanced oncogenic properties. Taken together, these findings indicate that histone H2B missense mutations affect gene expression and play critical roles in promoting tumorigenesis through distinct mechanisms.

Date of Award	26 Nov 2020
Original language	English
Awarding Institution	City University of Hong Kong
Supervisor	Kui Ming CHAN (Supervisor)