The H3.3 K36M oncohistone disrupts the establishment of epigenetic memory through loss of DNA methylation

Abstract

SummaryHistone H3.3 is frequently mutated in cancers, with the lysine 36 to methionine mutation (K36M) being a hallmark of chondroblastomas. While it is known that H3.3K36M changes the cellular epigenetic landscape, it remains unclear how it affects the dynamics of gene expression. Here, we use a synthetic reporter to measure the effect of H3.3K36M on silencing and epigenetic memory after recruitment of KRAB: a member of the largest class of human repressors, commonly used in synthetic biology, and associated with H3K9me3. We find that H3.3K36M, which decreases H3K36 methylation, leads to a decrease in epigenetic memory and promoter methylation weeks after KRAB release. We propose a new model for establishment and maintenance of epigenetic memory, where H3K36 methylation is necessary to convert H3K9me3 domains into DNA methylation for stable epigenetic memory. Our quantitative model can inform oncogenic mechanisms and guide development of epigenetic editing tools.

ISWI chromatin remodeling complexes recruit NSD2 and H3K36me2 in pericentromeric heterochromatin

“…H3K36me2 may also play a role in heterochromatin reorganization in embryogenesis mediated through the perinucleolar ring-shaped structures at the 2-cell stage to more typical chromocenters at the later stages. A very recent study has shown a model that H3K9me3 and H3K36 methylation tandemly promote DNA methylation (Sinha et al, 2023). DNA methylation in oocytes is also regulated by H3K36me2 and H3K36me3 (Yano et al, 2022).…”