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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2025-05-01
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| Online Access: | https://doi.org/10.1186/s13059-025-03596-5 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Sebastian Gregoricchio |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b545d677e4464fa18aa71d22dc97fb39 |
| institution | OA Journals |
| issn | 1474-760X |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Biology |
| spelling | doaj-art-b545d677e4464fa18aa71d22dc97fb392025-08-20T02:32:03ZengBMCGenome Biology1474-760X2025-05-0126113110.1186/s13059-025-03596-5Endometrial tumorigenesis involves epigenetic plasticity demarcating non-coding somatic mutations and 3D-genome alterationsSebastian Gregoricchio0Aleksandar Kojic1Marlous Hoogstraat2Karianne Schuurman3Suzan Stelloo4Tesa M. Severson5Tracy A. O’Mara6Marjolein Droog7Abhishek A. Singh8Dylan M. Glubb9Lodewyk F. A. Wessels10Michiel Vermeulen11Flora E. van Leeuwen12Wilbert Zwart13Division of Oncogenomics, Oncode Institute, The Netherlands Cancer InstituteDivision of Oncogenomics, Oncode Institute, The Netherlands Cancer InstituteDivision of Oncogenomics, Oncode Institute, The Netherlands Cancer InstituteDivision of Oncogenomics, Oncode Institute, The Netherlands Cancer InstituteDepartment of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University NijmegenDivision of Oncogenomics, Oncode Institute, The Netherlands Cancer InstituteCancer Research Program, QIMR Berghofer Medical Research InstituteDivision of Oncogenomics, Oncode Institute, The Netherlands Cancer InstituteDivision of Oncogenomics, Oncode Institute, The Netherlands Cancer InstituteCancer Research Program, QIMR Berghofer Medical Research InstituteDivision of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer InstituteDepartment of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University NijmegenDepartment of Epidemiology, The Netherlands Cancer InstituteDivision of Oncogenomics, Oncode Institute, The Netherlands Cancer InstituteAbstract 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.https://doi.org/10.1186/s13059-025-03596-5Endometrial cancerEstrogen receptorEpigenetic plasticity in tumor developmentGene regulation3D genome organizationNon-coding somatic mutations |
| spellingShingle | 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 Endometrial tumorigenesis involves epigenetic plasticity demarcating non-coding somatic mutations and 3D-genome alterations Genome Biology Endometrial cancer Estrogen receptor Epigenetic plasticity in tumor development Gene regulation 3D genome organization Non-coding somatic mutations |
| title | Endometrial tumorigenesis involves epigenetic plasticity demarcating non-coding somatic mutations and 3D-genome alterations |
| title_full | Endometrial tumorigenesis involves epigenetic plasticity demarcating non-coding somatic mutations and 3D-genome alterations |
| title_fullStr | Endometrial tumorigenesis involves epigenetic plasticity demarcating non-coding somatic mutations and 3D-genome alterations |
| title_full_unstemmed | Endometrial tumorigenesis involves epigenetic plasticity demarcating non-coding somatic mutations and 3D-genome alterations |
| title_short | Endometrial tumorigenesis involves epigenetic plasticity demarcating non-coding somatic mutations and 3D-genome alterations |
| title_sort | endometrial tumorigenesis involves epigenetic plasticity demarcating non coding somatic mutations and 3d genome alterations |
| topic | Endometrial cancer Estrogen receptor Epigenetic plasticity in tumor development Gene regulation 3D genome organization Non-coding somatic mutations |
| url | https://doi.org/10.1186/s13059-025-03596-5 |
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