Abstract PR004: Interplay between histone modifications and DNA methylation in cancer

Abstract During solid tumor development, gene-poor and lamina-associated genomic regions undergo progressive loss of DNA methylation, whereas promoter CpG islands become DNA hypermethylated. We report evidence suggesting that the recruitment of DNMT3A by histone modifications contributes to this cancer-associated DNA methylome reprogramming. The genomic targeting of DNMT3A is regulated by the competition between NSD1-mediated histone H3K36 methylation and polycomb-mediated H2AK119 ubiquitination, via DNMT3A's PWWP domain and N-terminal ubiquitin-interacting region, respectively. Mutations in NSD1, DNMT3A reader domains or polycomb complexes perturb DNMT3A recruitment and can recapitulate patterns of DNA methylation observed in patient tumors. Lastly, tumors exhibiting progressive hypomethylation, such as those harboring NSD1 mutations, are paradoxically immune-cold despite the increased expression of retrotransposons. These results suggest that DNA hypomethylation and aberrant retrotransposon activation are significant bottlenecks to tumor development and may represent promising therapeutic targets. Citation Format: Chao Lu. Interplay between histone modifications and DNA methylation in cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr PR004.