Globular domain histone H3R131C mutation remodels chromatin accessibility to promote oncogenic transcriptional programs

Histone mutations, characterized as oncohistones, have emerged as important oncogenic driver events by altering chromatin structure and/or chromatin modifications, thereby dysregulating gene expression. While H3 tail domain oncohistone mutations such as H3K27M and H3K36M are well characterized, it is currently unknown whether mutations within the H3 globular domain represent oncogenic driver events. Using publicly available cancer patient tumor data, here we identify H3R131C as a recurrent histone H3 globular domain mutation. H3R131C mutation is present in diverse human tumors including breast and bladder cancers. Phenotypic assays demonstrate that H3R131C expression does not augment cellular proliferation but enhances cellular migration and invasion. H3R131C frequently co-occurs with mutations in oncogenes including PIK3CA and ESR1, and tumor suppressors TP53 and CDKN2A with an allele frequency consistent with H3R131C representing a subclonal event that enhances tumor fitness rather than initiating transformation. Mechanistically, ATAC-seq reveals that H3R131C expression increases chromatin accessibility, with enrichment of AP-1/bZIP transcription factor motifs at gained accessible regions. Integration of chromatin accessibility and transcriptomic profiling identifies concordant upregulation of pro-oncogenic target genes including PGF, SOX5, and CCDC88C, supporting a model in which H3R131C destabilizes the nucleosome to remodel chromatin and activate transcriptional programs associated with cellular migration, angiogenesis, and epithelial plasticity. Collectively, these findings identify H3R131C as a functionally active globular domain oncohistone that reshapes the epigenome to promote oncogenic gene expression.