Functional mapping of epigenomic regulators uncovers coordinated tumor suppression by the HBO1 and MLL1 complexes [bullk ATAC-seq]

Epigenetic dysregulation is widespread in cancer. However, the specific epigenetic regulators and the processes they control to drive cancer phenotypes are poorly understood. We employed a novel, scalable and high-throughput in vivo method to perform iterative functional screens of >250 epigenetic regulators within autochthonous oncogenic KRAS-driven lung tumors. We identified many previously unappreciated epigenetic tumor-suppressor and tumor-dependency genes. We show that a specific HBO1 complex and MLL1 complex are the most impactful tumor suppressive epigenetic regulators in lung cancer. Histone modifications generated by HBO1 complex are frequently reduced in human lung adenocarcinomas. HBO1 and MLL1 complexes regulate chromatin accessibility at shared genomic regions, lineage fidelity and expression of canonical tumor suppressor genes. The HBO1 and MLL1 complexes are epistatic during lung tumorigenesis, and their functional correlation is conserved in human cancer cell lines. Together, these results provide a phenotypic roadmap of epigenetic regulators in lung tumorigenesis in vivo.