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

ABSTRACT: 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

ORGANISM(S): Homo sapiens

PROVIDER: GSE253900 | GEO | 2025/03/24

REPOSITORIES: GEO

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