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

GSE253905 Homo sapiens Genome binding/occupancy profiling by high throughput sequencing 6 samples Submitted 2025/03/24 Platform GPL24676
Summary
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.
Published in
Endometrial tumorigenesis involves epigenetic plasticity demarcating non-coding somatic mutations and 3D-genome alterations
Gregoricchio S, Kojic A, Hoogstraat M et al. · Genome biology 2025 · PMID 40346709 · doi:10.1186/s13059-025-03596-5
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Direct links to NCBI, no account and no request form: the whole study as GSE253905_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 6 samples. Raw sequencing reads are also available from ENA.

Also filed as BioProject PRJNA1067642 and SRA study SRP485249. Searching any of these in the dataset finder brings you back here.

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