H3K36me3-mediated mismatch repair preferentially protects actively transcribed genes from mutation

Abstract

Histone H3 trimethylation at lysine 36 (H3K36me3) is an important histone mark involved in both transcription elongation and DNA mismatch repair (MMR). It is known that H3K36me3 recruits the mismatch-recognition protein MutSα to replicating chromatin via its physical interaction with MutSα's PWWP domain, but the exact role of H3K36me3 in transcription is undefined. Using ChIP combined with whole-genome DNA sequencing analysis, we demonstrate here that H3K36me3, together with MutSα, is involved in protecting against mutation, preferentially in actively transcribed genomic regions. We found that H3K36me3 and MutSα are much more co-enriched in exons and actively transcribed regions than in introns and nontranscribed regions. The H3K36me3-MutSα co-enrichment correlated with a much lower mutation frequency in exons and actively transcribed regions than in introns and nontranscribed regions. Correspondingly, depleting H3K36me3 or disrupting the H3K36me3-MutSα interaction elevated the spontaneous mutation frequency in actively transcribed genes, but it had little influence on the mutation frequency in nontranscribed or transcriptionally inactive regions. Similarly, HO-induced mutations, which mainly cause base oxidations, preferentially occurred in actively transcribed genes in MMR-deficient cells. The data presented here suggest that H3K36me3-mediated MMR preferentially safeguards actively transcribed genes not only during replication by efficiently correcting mispairs in early replicating chromatin but also during transcription by directly or indirectly removing DNA lesions associated with a persistently open chromatin structure.

Single-cell whole-genome sequencing reveals mutational landscapes of DNA mismatch repair deficiency in mouse primary fibroblasts

“…Depletion of SNVs from exons was greater in wild-type cells than in Msh2 -/cells, which seems counterintuitive. However, this is likely a result of higher MMR efficiency in exons than in other genomic regions in the wild type, which is in agreement with previous findings of SNV distribution in human MMR-deficient tumors (24) and may be a result of H3K36me3mediated MMR protecting exonic regions preferentially (25,26). In contrast to SNVs, INDELs in wild-type cells showed significant depletion in the exome, and the depletion was more dramatic in the Msh2 -/-.…”

Mutation bias shapes gene evolution inArabidopsis thaliana

“…This provides an opportunity for mutation rates to evolve in beneficial directions (e.g., lower mutation rates in cytogenetic states characteristic of essential housekeeping genes where mutations are more likely to be deleterious). Indeed, processes facilitating reduced mutation rates in genic regions 22,29,33 and active genes 15,17,21,24,34 have already been documented in recent years. These discoveries are consistent with contemporary theoretical predictions from population genetics that beneficial mutation rates could readily evolve even in the face of genetic drift if mutation rates are linked to gene regulation or common sequence and epigenomic features 3,8 .…”

“…And while reports of non-random relationships between mutation rates and fitness consequences have been previously made, these have been questioned because they have largely relied on substitution rates in natural populations rather than direct measures of de novo mutations 3,9-12 .More recently though, discoveries in genome biology have inspired a reevaluation of classical theories of mutation rate evolution. It is now recognized that mutation rates across genomes are influenced by DNA sequence composition, epigenomic features, and bias in the targets of DNA repair mechanisms 5,6,[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] . It is also known that broad classes of genes (e.g., housekeeping genes) exist in distinct cytogenetic (DNA sequence + epigenomic) states.…”

Regulation of SETD2 stability is important for the fidelity of H3K36me3 deposition

“…Pol II independent deposition of H3K36me3 can result in the mistargeting of important epigenetic regulators. The PWWP domain-containing proteins DNMT3a, MutSα, and MORF depend on H3K36me3 for proper recruitment [4][5][36] [37]. It is important to note that besides histone H3, SETD2 also has non-histone targets like tubulin, the methylation of which is important for metaphase transition [38].…”

“…Besides affecting the transcriptome, the aberrant H3K36me3 deposition upon SETD2 overexpression can result in adverse consequences as the H3K36me3 mark is required for proper recruitment of important epigenetic regulators such as the PWWP domain-containing proteins DNMT3a, MutSα and MORF (Dhayalan et al, 2010) (Li et al, 2013) (Luco et al, 2010) (Huang et al, 2018). Aberrant H3K36me3 deposition might result in the mistargeting of such regulators.…”