A systems-based approach to uterine fibroids identifies differential splicing associated with abnormal uterine bleeding
Abstract Background Uterine fibroids (UFs), benign tumours prevalent in up to 80% of women of reproductive age, are associated with significant morbidity, including abnormal uterine bleeding, pain and infertility. Despite identification of key genomic alterations in MED12 and HMGA2, the pathogenic m...
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Nature Portfolio
2025-07-01
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| Series: | Communications Medicine |
| Online Access: | https://doi.org/10.1038/s43856-025-01051-x |
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| author | Chen-Yi Wang Martin Philpott Darragh P O’Brien Anne Ndungu Jessica Malzahn Marina Maritati Neelam Mehta Vicki Gamble Beatriz Martinez-Burgo Sarah Bonham Roman Fischer Kurtis Garbutt Christian M. Becker Sanjiv Manek Adrian L. Harris Frank Sacher Maik Obendorf Nicole Schmidt Jörg Müller Thomas M. Zollner Krina T. Zondervan Benedikt M. Kessler Udo Oppermann Adam P. Cribbs |
| author_facet | Chen-Yi Wang Martin Philpott Darragh P O’Brien Anne Ndungu Jessica Malzahn Marina Maritati Neelam Mehta Vicki Gamble Beatriz Martinez-Burgo Sarah Bonham Roman Fischer Kurtis Garbutt Christian M. Becker Sanjiv Manek Adrian L. Harris Frank Sacher Maik Obendorf Nicole Schmidt Jörg Müller Thomas M. Zollner Krina T. Zondervan Benedikt M. Kessler Udo Oppermann Adam P. Cribbs |
| author_sort | Chen-Yi Wang |
| collection | DOAJ |
| description | Abstract Background Uterine fibroids (UFs), benign tumours prevalent in up to 80% of women of reproductive age, are associated with significant morbidity, including abnormal uterine bleeding, pain and infertility. Despite identification of key genomic alterations in MED12 and HMGA2, the pathogenic mechanisms underlying UFs and heavy menstrual bleeding (HMB) remain poorly understood. Methods To correlate systematically genetic, transcriptional and proteomic phenotypes, we conducted an integrative multi-omic approach utilising targeted DNA sequencing, RNA sequencing and proteomic methodologies, encompassing fibroid, myometrium, and endometrium tissues from 91 patients. Results In addition to confirming the presence of MED12 mutations, we identify variants in AHR and COL4A6. Multi-omic analysis of endometrium identifies latent factors that correlate with HMB and fibroid presence with driver mutations of MED12, AHR, and COL4A6, which are associated with pathways involved in angiogenesis, extracellular matrix organisation and RNA splicing. We propose a model, supported by in vivo evidence, where altered signalling of MED12-mutated fibroids influences RNA transcript isoform expression in endometrium, potentially leading to abnormal uterine bleeding. Conclusions This study presents a comprehensive integrative approach, revealing that genetic alterations in UF may influence endometrial function via signalling impacts on the RNA splicing mechanism. Our findings advance the understanding of complex molecular pathways in UF pathogenesis and UF-associated endometrial dysfunction, offering insights for targeted therapeutic development. |
| format | Article |
| id | doaj-art-e9437efd468b482f8f302ec62eab89f8 |
| institution | Kabale University |
| issn | 2730-664X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Medicine |
| spelling | doaj-art-e9437efd468b482f8f302ec62eab89f82025-08-20T03:46:29ZengNature PortfolioCommunications Medicine2730-664X2025-07-015111610.1038/s43856-025-01051-xA systems-based approach to uterine fibroids identifies differential splicing associated with abnormal uterine bleedingChen-Yi Wang0Martin Philpott1Darragh P O’Brien2Anne Ndungu3Jessica Malzahn4Marina Maritati5Neelam Mehta6Vicki Gamble7Beatriz Martinez-Burgo8Sarah Bonham9Roman Fischer10Kurtis Garbutt11Christian M. Becker12Sanjiv Manek13Adrian L. Harris14Frank Sacher15Maik Obendorf16Nicole Schmidt17Jörg Müller18Thomas M. Zollner19Krina T. Zondervan20Benedikt M. Kessler21Udo Oppermann22Adam P. Cribbs23Botnar Research Centre, NIHR BRC, University of OxfordBotnar Research Centre, NIHR BRC, University of OxfordTarget Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of OxfordNuffield Department of Women’s & Reproductive Health, University of OxfordBotnar Research Centre, NIHR BRC, University of OxfordBotnar Research Centre, NIHR BRC, University of OxfordBotnar Research Centre, NIHR BRC, University of OxfordBotnar Research Centre, NIHR BRC, University of OxfordNuffield Department of Women’s & Reproductive Health, University of OxfordTarget Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of OxfordTarget Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of OxfordNuffield Department of Women’s & Reproductive Health, University of OxfordNuffield Department of Women’s & Reproductive Health, University of OxfordNuffield Department of Women’s & Reproductive Health, University of OxfordDepartment of Oncology, University of OxfordResearch and Early Development, Bayer AGResearch and Early Development, Bayer AGResearch and Early Development, Bayer AGResearch and Early Development, Bayer AGResearch and Early Development, Bayer AGNuffield Department of Women’s & Reproductive Health, University of OxfordTarget Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of OxfordBotnar Research Centre, NIHR BRC, University of OxfordBotnar Research Centre, NIHR BRC, University of OxfordAbstract Background Uterine fibroids (UFs), benign tumours prevalent in up to 80% of women of reproductive age, are associated with significant morbidity, including abnormal uterine bleeding, pain and infertility. Despite identification of key genomic alterations in MED12 and HMGA2, the pathogenic mechanisms underlying UFs and heavy menstrual bleeding (HMB) remain poorly understood. Methods To correlate systematically genetic, transcriptional and proteomic phenotypes, we conducted an integrative multi-omic approach utilising targeted DNA sequencing, RNA sequencing and proteomic methodologies, encompassing fibroid, myometrium, and endometrium tissues from 91 patients. Results In addition to confirming the presence of MED12 mutations, we identify variants in AHR and COL4A6. Multi-omic analysis of endometrium identifies latent factors that correlate with HMB and fibroid presence with driver mutations of MED12, AHR, and COL4A6, which are associated with pathways involved in angiogenesis, extracellular matrix organisation and RNA splicing. We propose a model, supported by in vivo evidence, where altered signalling of MED12-mutated fibroids influences RNA transcript isoform expression in endometrium, potentially leading to abnormal uterine bleeding. Conclusions This study presents a comprehensive integrative approach, revealing that genetic alterations in UF may influence endometrial function via signalling impacts on the RNA splicing mechanism. Our findings advance the understanding of complex molecular pathways in UF pathogenesis and UF-associated endometrial dysfunction, offering insights for targeted therapeutic development.https://doi.org/10.1038/s43856-025-01051-x |
| spellingShingle | Chen-Yi Wang Martin Philpott Darragh P O’Brien Anne Ndungu Jessica Malzahn Marina Maritati Neelam Mehta Vicki Gamble Beatriz Martinez-Burgo Sarah Bonham Roman Fischer Kurtis Garbutt Christian M. Becker Sanjiv Manek Adrian L. Harris Frank Sacher Maik Obendorf Nicole Schmidt Jörg Müller Thomas M. Zollner Krina T. Zondervan Benedikt M. Kessler Udo Oppermann Adam P. Cribbs A systems-based approach to uterine fibroids identifies differential splicing associated with abnormal uterine bleeding Communications Medicine |
| title | A systems-based approach to uterine fibroids identifies differential splicing associated with abnormal uterine bleeding |
| title_full | A systems-based approach to uterine fibroids identifies differential splicing associated with abnormal uterine bleeding |
| title_fullStr | A systems-based approach to uterine fibroids identifies differential splicing associated with abnormal uterine bleeding |
| title_full_unstemmed | A systems-based approach to uterine fibroids identifies differential splicing associated with abnormal uterine bleeding |
| title_short | A systems-based approach to uterine fibroids identifies differential splicing associated with abnormal uterine bleeding |
| title_sort | systems based approach to uterine fibroids identifies differential splicing associated with abnormal uterine bleeding |
| url | https://doi.org/10.1038/s43856-025-01051-x |
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