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Homeobox regulator Wilms Tumour 1 is displaced by androgen receptor at cis-regulatory elements in the endometrium of PCOS patients

David W. James, Marcos Quintela Vazquez, Lisa Lucini, Noor K. Alkafri, Gareth Healey Orcid Logo, Kinza Younas, Adnan Bunkheila, Lavinia Margarit, Lewis Francis Orcid Logo, Deya Gonzalez Orcid Logo, Steve Conlan Orcid Logo

Frontiers in Endocrinology, Volume: 15

Swansea University Authors: Marcos Quintela Vazquez, Lisa Lucini, Gareth Healey Orcid Logo, Kinza Younas, Adnan Bunkheila, Lavinia Margarit, Lewis Francis Orcid Logo, Deya Gonzalez Orcid Logo, Steve Conlan Orcid Logo

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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...

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Published in: Frontiers in Endocrinology
ISSN: 1664-2392
Published: Frontiers Media SA 2024
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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. 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spelling v2 66500 2024-05-23 Homeobox regulator Wilms Tumour 1 is displaced by androgen receptor at cis-regulatory elements in the endometrium of PCOS patients 29d006fa16d293ca29762fce9c356f8e Marcos Quintela Vazquez Marcos Quintela Vazquez true false ebc4b2c67b34e2589ccd56a2a8fdb228 Lisa Lucini Lisa Lucini true false 5926519f89187489cfd5e1478aa188b1 0000-0001-9531-1220 Gareth Healey Gareth Healey true false 0b6acea714279ecb1edaec2e6a786be1 Kinza Younas Kinza Younas true false 77474a185486d196c0917f3500521662 Adnan Bunkheila Adnan Bunkheila true false 1cdeff800fa264ed1424b0d86c587c67 Lavinia Margarit Lavinia Margarit true false 10f61f9c1248951c1a33f6a89498f37d 0000-0002-7803-7714 Lewis Francis Lewis Francis true false bafdf635eb81280304eedf4b18e65d4e 0000-0002-1838-6752 Deya Gonzalez Deya Gonzalez true false 0bb6bd247e32fb4249de62c0013b51cb 0000-0002-2562-3461 Steve Conlan Steve Conlan true false 2024-05-23 ONDF 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. Journal Article Frontiers in Endocrinology 15 Frontiers Media SA 1664-2392 AR; WT1; decidualization; endometrium; epigenomics; polycystic ovary syndrome; transcription. 30 4 2024 2024-04-30 10.3389/fendo.2024.1368494 http://dx.doi.org/10.3389/fendo.2024.1368494 COLLEGE NANME Other/Subsidiary Companies - Not Defined COLLEGE CODE ONDF Swansea University SU College/Department paid the OA fee 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). 2024-05-23T12:26:20.2337538 2024-05-23T12:16:46.3198483 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine David W. James 1 Marcos Quintela Vazquez 2 Lisa Lucini 3 Noor K. Alkafri 4 Gareth Healey 0000-0001-9531-1220 5 Kinza Younas 6 Adnan Bunkheila 7 Lavinia Margarit 8 Lewis Francis 0000-0002-7803-7714 9 Deya Gonzalez 0000-0002-1838-6752 10 Steve Conlan 0000-0002-2562-3461 11 66500__30453__c625285b1e604b1680f27087d6ec5ed0.pdf 66500.VOR.pdf 2024-05-23T12:24:57.5145596 Output 2299953 application/pdf Version of Record true © 2024 James, Quintela, Lucini, Alkafri, Healey, 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). true eng http://creativecommons.org/licenses/by/4.0/ 248 R. Steven Conlan true https://www.ncbi.nlm.nih.gov/ false
title Homeobox regulator Wilms Tumour 1 is displaced by androgen receptor at cis-regulatory elements in the endometrium of PCOS patients
spellingShingle Homeobox regulator Wilms Tumour 1 is displaced by androgen receptor at cis-regulatory elements in the endometrium of PCOS patients
Marcos Quintela Vazquez
Lisa Lucini
Gareth Healey
Kinza Younas
Adnan Bunkheila
Lavinia Margarit
Lewis Francis
Deya Gonzalez
Steve Conlan
title_short Homeobox regulator Wilms Tumour 1 is displaced by androgen receptor at cis-regulatory elements in the endometrium of PCOS patients
title_full Homeobox regulator Wilms Tumour 1 is displaced by androgen receptor at cis-regulatory elements in the endometrium of PCOS patients
title_fullStr Homeobox regulator Wilms Tumour 1 is displaced by androgen receptor at cis-regulatory elements in the endometrium of PCOS patients
title_full_unstemmed Homeobox regulator Wilms Tumour 1 is displaced by androgen receptor at cis-regulatory elements in the endometrium of PCOS patients
title_sort Homeobox regulator Wilms Tumour 1 is displaced by androgen receptor at cis-regulatory elements in the endometrium of PCOS patients
author_id_str_mv 29d006fa16d293ca29762fce9c356f8e
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77474a185486d196c0917f3500521662
1cdeff800fa264ed1424b0d86c587c67
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0bb6bd247e32fb4249de62c0013b51cb
author_id_fullname_str_mv 29d006fa16d293ca29762fce9c356f8e_***_Marcos Quintela Vazquez
ebc4b2c67b34e2589ccd56a2a8fdb228_***_Lisa Lucini
5926519f89187489cfd5e1478aa188b1_***_Gareth Healey
0b6acea714279ecb1edaec2e6a786be1_***_Kinza Younas
77474a185486d196c0917f3500521662_***_Adnan Bunkheila
1cdeff800fa264ed1424b0d86c587c67_***_Lavinia Margarit
10f61f9c1248951c1a33f6a89498f37d_***_Lewis Francis
bafdf635eb81280304eedf4b18e65d4e_***_Deya Gonzalez
0bb6bd247e32fb4249de62c0013b51cb_***_Steve Conlan
author Marcos Quintela Vazquez
Lisa Lucini
Gareth Healey
Kinza Younas
Adnan Bunkheila
Lavinia Margarit
Lewis Francis
Deya Gonzalez
Steve Conlan
author2 David W. James
Marcos Quintela Vazquez
Lisa Lucini
Noor K. Alkafri
Gareth Healey
Kinza Younas
Adnan Bunkheila
Lavinia Margarit
Lewis Francis
Deya Gonzalez
Steve Conlan
format Journal article
container_title Frontiers in Endocrinology
container_volume 15
publishDate 2024
institution Swansea University
issn 1664-2392
doi_str_mv 10.3389/fendo.2024.1368494
publisher Frontiers Media SA
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
url http://dx.doi.org/10.3389/fendo.2024.1368494
document_store_str 1
active_str 0
description 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.
published_date 2024-04-30T12:26:20Z
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