Covalent modifications to both the DNA and the histone proteins allow chromatin to act as a dynamic information hub that integrates diverse biochemical stimuli to regulate genomic DNA access to the transcription machinery and ultimately establish and maintain cellular phenotypes. Moreover, there is increasing appreciation that chromatin alterations per se, including DNA and histone modifications, are involved in the pathogenesis of cancer. Nowhere is this better supported than with the groundbreaking discoveries of high-frequency, somatic mutations in histones that are drivers of oncogenesis. These mutations (collectively called "oncohistones") cause amino acid substitutions that localize to conserved residues in the N-terminal tail of histone H3 and all seem to be linked, either directly or indirectly, to disruption of normal levels and distribution of histone H3 methylation and thus genomic regulation. Specifically, oncohistones directly or indirectly promote aberrant genome-wide distribution of lysine 27 methylation on histone H3. H3K27 methylation, catalyzed by the Polycomb Repressive Complex 2 (PRC2), is mechanistically linked to establishment and maintenance of gene repression. We are currently using a combination of biochemical and genomic approaches to investigate how oncohistone-driven changes in histone H3 K27 methylation lead to altered chromatin states that profoundly influence gene expression patterns. I will discuss some of our recent mechanistic and functional work on various oncohistone mutations.

Citation Format: Peter W. Lewis. Polycomb dysregulation by oncohistones [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY05-02.