The incorporation loci of H3.3K36M determine its preferential prevalence in chondroblastomas

Yanjun Zhang,Dong Fang

doi:10.1038/s41419-021-03597-9

Abstract

The histone H3.3K36M mutation, identified in over 90% of chondroblastoma cases, reprograms the H3K36 methylation landscape and gene expression to promote tumorigenesis. However, it’s still unclear how the H3K36M mutation preferentially occurs in the histone H3 variant H3.3 in chondroblastomas. Here, we report that H3.3K36M-, but not H3.1K36M-, mutant cells showed increased colony formation ability and differentiation defects. H3K36 methylations and enhancers were reprogrammed to different status in H3.3K36M- and H3.1K36M-mutant cells. The reprogramming of H3K36 methylation and enhancers was depended on the specific loci at which H3.3K36M and H3.1K36M were incorporated. Moreover, targeting H3K36M-mutant proteins to the chromatin inhibited the H3K36 methylation locally. Taken together, these results highlight the roles of the chromatic localization of H3.3K36M-mutant protein in the reprogramming of the epigenome and the subsequent induction of tumorigenesis, and shed light on the molecular mechanisms by which the H3K36M mutation mainly occurs in histone H3.3 in chondroblastomas.

Highlights

The epigenetic landscape is often altered and dysregulated to drive carcinogenesis
Given our previous observation that H3.3K36M-mutant cells exhibit several hallmarks of cancer phenotypes[13], we examined whether the H3.1K36M mutation could induce the cancer-related phenotypes
The H3K36 methylations at BMP2, SOX5, and SOX9 remained unchanged in H3.3K36M-mutant cells, but increased in wild-type and H3.1K36M-mutant cells during differentiation (Fig. 1E, F)

Summary

Introduction

Heterozygous mutations in histone H3 have been identified in pediatric bone tumors[1]. >95% of chondroblastoma cases carry a somatic mutation in the H3F3B gene (which encodes the histone H3 variant H3.3) that substitutes lysine 36 (K36) with a methionine (H3.3K36M)[1]. Additional histone mutations are being identified and characterized in tumors[2]. H3K36 can be mono-, di-, and tri-methylated (H3K36me1/H3K36me2/H3K36me3) to regulate RNA splicing[3], DNA methylation[4,5], DNA repair[6], gene transcription[7], imprinting[8], as well as m6A RNA modification[9]. There are 13 genes encoding canonical histone H3 (H3.1/H3.2), which are assembled into nucleosomes during S phase of the cell cycle[10]. Two genes encode histone H3 variant H3.3, which is assembled into nucleosomes in a replication-independent manner[11]

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Conclusion