The expanding landscape of ‘oncohistone’ mutations in human cancers

Abstract

Mutations in epigenetic pathways are common oncogenic drivers. Histones, the fundamental substrate for chromatin-modifying and remodeling enzymes, are mutated in tumors including in gliomas, sarcomas, head and neck cancers, and carcinosarcomas. Classical 'oncohistone' mutations occur in the N-terminal tail of histone H3 and impact the function of Polycomb Repressor Complexes 1 and 2. However, the prevalence and function of histone mutations in additional tumor contexts is unknown. Here we show that somatic histone mutations conservatively occur in ~ 4% of tumors of diverse types and in critical regions of histone proteins. Mutations occur in all four core histones, in both the N-terminal tails and globular histone fold domains, and at or near residues that harbor important post-translational modifications. Many globular domain mutations are either homologous to yeast mutants that abrogate the need for SWI/SNF function, occur in the key regulatory 'acidic patch' of histone H2A and H2B, or are predicted to disrupt the H2B-H4 interface. The histone mutation dataset (https://bit.ly/2GXH5Ve) and the hypotheses presented herein on the impact of the mutations on important chromatin functions should serve as a resource and starting point for the chromatin and cancer biology fields in exploring an expanding role of histone mutations in cancer.

Histone variants in archaea and the evolution of combinatorial chromatin complexity

“…The case of M. stadtmanae Msp_0383 illustrates that substitutions of individual amino acids can have strong effects on histone properties and, ultimately, chromatin state. This is also true in eukaryotes (Maze et al 2014;Henikoff and Smith 2015;Nacev et al 2019). H3.3 and H3.1, for example, differ in only four amino acids (three of which are located in the histone fold domain), but are recognized by different chaperones, deposited at defined locations along the genome, and make distinct, non-redundant contributions to genome function, notably during gametogenesis (Talbert and Henikoff 2010;Filipescu et al 2014;Wollmann et al 2017).…”

Histone variant H3.3 residue S31 is essential for Xenopus gastrulation regardless of the deposition pathway

“…Conversely, other modifications on the H3 tail could themselves impact H3.3 S31 modification and in this respect, the effects of mutations affecting neighboring residues will be interesting to explore. Notably, as H3.3 S31 is close to residues often mutated in aggressive cancers such as H3 K27M and G34R in pediatric glioblastoma [42][43][44]47,96 , it will be interesting to evaluate the impact of these onco-histone mutations on H3.3-specific phosphorylation as well. Altogether, we show that H3.3 S31 is the key residue that confers specific functions to H3.3 within chromatin, compared with its H3.2 counterpart.…”

Dynamics of transcription-dependent H3K36me3 marking by the SETD2:IWS1:SPT6 ternary complex

“…Many of the processes dependent on H3K36me3 are ubiquitous and highly conserved from yeast to humans. Additionally, H3K36 oncohistone mutations 72 and loss of the H3K36me3 methyltransferase SETD2 73 both play important roles during cancer development. In particular, lysine-tomethionine mutations of H3K36 (H3K36M) contribute to distinct subtypes of sarcomas and pediatric chondroblastoma 74,75 .…”