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Homeobox regulator Wilms Tumour 1 is displaced by androgen receptor at cis-regulatory elements in the endometrium of PCOS patients
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Nick Jones ,
Kinza Younas,
Adnan Bunkheila,
Lavinia Margarit,
Lewis Francis ,
Deya Gonzalez ,
Steve Conlan
Frontiers in Endocrinology, Volume: 15
Swansea University Authors:
Marcos Quintela Vazquez, Lisa Lucini, Nour Al Kafri, Gareth Healey , Nick Jones , Kinza Younas, Adnan Bunkheila, Lavinia Margarit, Lewis Francis , Deya Gonzalez , Steve Conlan
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© 2024 James, Quintela, Lucini, Al Kafri, Healey, Jones, Younas, Bunkheila, Margarit, Francis, Gonzalez and Conlan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).
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DOI (Published version): 10.3389/fendo.2024.1368494
Abstract
Decidualisation, the process whereby endometrial stromal cells undergo morphological and functional transformation in preparation for trophoblast invasion, is often disrupted in women with polycystic ovary syndrome (PCOS) resulting in complications with pregnancy and/or infertility. The transcriptio...
| Published in: | Frontiers in Endocrinology |
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| ISSN: | 1664-2392 |
| Published: |
Frontiers Media SA
2024
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa66500 |
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| Abstract: |
Decidualisation, the process whereby endometrial stromal cells undergo morphological and functional transformation in preparation for trophoblast invasion, is often disrupted in women with polycystic ovary syndrome (PCOS) resulting in complications with pregnancy and/or infertility. The transcription factor Wilms tumour suppressor 1 (WT1) is a key regulator of the decidualization process, which is reduced in patients with PCOS, a complex condition characterized by increased expression of androgen receptor in endometrial cells and high presence of circulating androgens. Using genome-wide chromatin immunoprecipitation approaches on primary human endometrial stromal cells, we identify key genes regulated by WT1 during decidualization, including homeobox transcription factors which are important for regulating cell differentiation. Furthermore, we found that AR in PCOS patients binds to the same DNA regions as WT1 in samples from healthy endometrium, suggesting dysregulation of genes important to decidualisation pathways in PCOS endometrium due to competitive binding between WT1 and AR. Integrating RNA-seq and H3K4me3 and H3K27ac ChIP-seq metadata with our WT1/AR data, we identified a number of key genes involved in immune response and angiogenesis pathways that are dysregulated in PCOS patients. This is likely due to epigenetic alterations at distal enhancer regions allowing AR to recruit cofactors such as MAGEA11, and demonstrates the consequences of AR disruption of WT1 in PCOS endometrium. |
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| Keywords: |
AR; WT1; decidualization; endometrium; epigenomics; polycystic ovary syndrome; transcription. |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The research conducted herein was funded by SMART Expertise programmes CEAT and RISE via the Welsh Government and the European Regional Development Fund (2017/COL/004; 2017/COL/001). |