Functional mapping of epigenomic regulators uncovers coordinated tumor suppression by the HBO1 and MLL1 complexes [KP787]

Epigenomic dysregulation is widespread in cancer. However, the specific epigenomic 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 epigenomic regulators within autochthonous oncogenic KRAS-driven lung tumors. We identified many previously unappreciated epigenomic tumor-suppressor and tumor-dependency genes. We show that a specific HBO1 complex and MLL1 complex are robust tumor suppressors in lung cancer. Histone modifications generated by HBO1 complex are frequently diminshed in human lung adenocarcinomas and is associated with worse clinical features. HBO1 and MLL1 complexes co-occupy shared genomic regions, impacting chromatin accessibility, expression of canonical tumor suppressor genes and lineage fidelity. The HBO1 complex is epistatic with the MLL1 complex and other tumor suppressor genes in lung adenocarcinoma development. Collectively, these results uncover HBO1 and MLL1 complexes as critical functional modules restraining lung adenocarcinoma development and provide a in vivo phenotypic roadmap of epigenomic regulators in lung tumorigenesis.