Enhancer plasticity in endometrial tumorigenesis demarcates non-coding driver mutations and 3D genome alterations to stimulate oncogene expression [ChIP-seq_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. Keywords: Genome binding/occupancy profiling by high throughput sequencing 4 healthy and 5 tumor endometrial tissues derived from Endometrial Cancer patients. Antibodies against ERα (SantaCruz #sc-543, 5µg/IP) and H3K27ac (ActiveMotif #39133, 5µg/IP) Raw data are available with restricted access at the EGA under accession number EGAS00001007240.