No abstract

Enzymes catalyzing CpG methylation in DNA, including DNMT1 and DNMT3A/B, are indispensable for mammalian tissue development and homeostasis 1-4. They are also implicated in human developmental disorders and cancers 5-8 , supporting a critical role of DNA methylation during cell fate specification and maintenance. Recent studies suggest that histone posttranslational modifications (PTMs) are involved in specifying patterns of DNMT localization and DNA methylation at promoters and actively transcribed gene bodies 9-11. However, mechanisms governing the establishment and maintenance of intergenic DNA methylation remain poorly understood. Germline mutations in DNMT3A define Tatton-Brown-Rahman syndrome (TBRS), a

Lys-27-Met mutations in histone 3 genes (H3K27M) characterize a subgroup of deadly gliomas and decrease genome-wide H3K27 trimethylation. Here we use primary H3K27M tumor lines and isogenic CRISPR-edited controls to assess H3K27M effects in vitro and in vivo. We find that whereas H3K27me3 and H3K27me2 are normally deposited by PRC2 across broad regions, their deposition is severely reduced in H3.3K27M cells. H3K27me3 is unable to spread from large unmethylated CpG islands, while H3K27me2 can be deposited outside these PRC2 high-affinity sites but to levels corresponding to H3K27me3 deposition in wild-type cells. Our findings indicate that PRC2 recruitment and propagation on chromatin are seemingly unaffected by K27M, which mostly impairs spread of the repressive marks it catalyzes, especially H3K27me3. Genome-wide loss of H3K27me3 and me2 deposition has limited transcriptomic consequences, preferentially affecting lowly-expressed genes regulating neurogenesis. Removal of H3K27M restores H3K27me2/me3 spread, impairs cell proliferation, and completely abolishes their capacity to form tumors in mice.

Human papillomavirus negative (HPV-) head and neck squamous cell carcinomas (HNSCC) are deadly and common cancers. Recent genomic studies implicate multiple genetic pathways including cell-signalling, cell-cycle and/or immune evasion in their development. Here, we analyze public datasets and uncover a previously unappreciated role of epigenome deregulation in the genesis of 13% HPV-HNSCCs. Specifically, we identify novel recurrent p.K36M mutations occurring in multiple histone H3 genes. We further validate their presence in multiple independent HNSCC datasets and show that along with previously described NSD1 mutations, they correspond to a specific DNA methylation cluster. H3K36M and NSD1 defects converge on altering H3K36 methylation, subsequently blocking cellular differentiation and promoting oncogenesis. Our data further indicate surprisingly limited redundancy for NSD family members in HPV-HNSCCs and suggest a potential role of impaired H3K36 methylation in their development. Further investigation of drugs targeting chromatin regulators is warranted in HPV-HNSCCs driven by aberrant H3K36 methylation.