Enhancer plasticity in endometrial tumorigenesis demarcates non-coding driver mutations and 3D genome alterations to stimulate oncogene expression [Hi-C_ECa_patients]. Enhancer plasticity in endometrial tumorigenesis demarcates non-coding driver mutations and 3D genome alterations to stimulate oncogene expression [Hi-C_ECa_patients]

The 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 ERa 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 ERa 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 of ESR1 in 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. Overall design: For Hi-C libraries preparation we used 3x10 50um-thick slices of flash frozen tissue derived from 3 healthy and 3 tumor endometrial tissues of post-menopausal patients. *************************************************************** Raw data are available at EGA under restricted access: EGAS00001007240 ***************************************************************