Endometrial tumorigenesis involves epigenetic plasticity demarcating non-coding somatic mutations and 3D-genome alterations

Endometrial tumorigenesis involves epigenetic plasticity demarcating non-coding somatic mutations and 3D-genome alterations

Abstract Background The incidence and mortality of endometrial cancer (EC) is on the rise. Eighty-five percent of ECs depend on estrogen receptor alpha (ERα) for proliferation, but little is known about its transcriptional regulation in these tumors. Results We generate epigenomics, transcriptomics,...

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Main Authors: Sebastian Gregoricchio, Aleksandar Kojic, Marlous Hoogstraat, Karianne Schuurman, Suzan Stelloo, Tesa M. Severson, Tracy A. O’Mara, Marjolein Droog, Abhishek A. Singh, Dylan M. Glubb, Lodewyk F. A. Wessels, Michiel Vermeulen, Flora E. van Leeuwen, Wilbert Zwart
Format: Article
Language:English
Published: BMC 2025-05-01
Series:Genome Biology
Subjects:
Endometrial cancer
Estrogen receptor
Epigenetic plasticity in tumor development
Gene regulation
3D genome organization
Non-coding somatic mutations
Online Access:https://doi.org/10.1186/s13059-025-03596-5
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Summary:Abstract Background The incidence and mortality of endometrial cancer (EC) is on the rise. Eighty-five percent of ECs depend on estrogen receptor alpha (ERα) for proliferation, but little is known about its transcriptional regulation in these tumors. Results We generate epigenomics, transcriptomics, and Hi-C datastreams 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 endometrial cancer risk single-nucleotide polymorphisms and whole-genome sequencing data from primary tumors and metastatic samples reveals a striking enrichment of risk variants and non-coding somatic mutations at tumor-enriched ERα sites. Through machine learning-based predictions and interaction proteomics analyses, we identify an enhancer mutation which alters 3D genome conformation, impairing recruitment of the transcriptional repressor EHMT2/G9a/KMT1C, thereby alleviating transcriptional repression of ESR1 in EC. Conclusions In summary, we identify a complex genomic-epigenomic interplay in EC development and progression, altering 3D genome organization to enhance expression of the critical driver ERα.
ISSN:1474-760X

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