Enhancer plasticity in endometrial tumorigenesis demarcates non-coding driver mutations and alterations in 3D genome organization to stimulate oncogene expression

Abstract

AbstractThe incidence and mortality of Endometrial Cancer (EC) is on the rise. 85% of ECs depend on Estrogen Receptor alpha (ERα) for proliferation, but little is known about its transcriptional regulation in these tumors.We generated epigenomics and Hi-C data streams in healthy and tumor endometrial tissues, identifying robust ERα reprogramming and profound alterations in 3D genome organization that lead to a gain of tumor-specific enhancer activity during EC development. Integration with WGS data from metastatic samples revealed a striking enrichment of non-coding somatic mutations at tumor-enriched ERα sites. Through machine learning-based predictions and interaction proteomics analyses, we identified an enhancer mutation which alters 3D genome organization, impairing recruitment of the transcriptional repressor EHMT2/G9a/KMT1C, thereby alleviating transcriptional repression ofESR1in EC.In summary, we identified a complex genomic-epigenomic interplay in EC development and progression, altering 3D genome organization to enhance expression of the critical driver ERα.