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

James, David W., Quintela, Marcos, Lucini, Lisa, Alkafri, Noor K., Healey, Gareth D., Younas, Kinza, Bunkheila, Adnan, Margarit, Lavinia, Francis, Lewis W., Gonzalez, Deyarina and Conlan, R. Steven 2024. Homeobox regulator Wilms Tumour 1 is displaced by androgen receptor at cis-regulatory elements in the endometrium of PCOS patients. Frontiers in Endocrinology 15 , 1368494. 10.3389/fendo.2024.1368494

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Additional Information:	A correction has been applied to this article in: Corrigendum: Homeobox regulator Wilms Tumour 1 is displaced by androgen receptor at cis-regulatory elements in the endometrium of PCOS patients. Front. Endocrinol., 27 September 2024 Sec. Reproduction Volume 15 - 2024 | https://doi.org/10.3389/fendo.2024.1450375
Publisher:	Frontiers Media
ISSN:	1664-2392
Related URLs:	https://doi.org/10.3389/fendo.2024.14503...
Date of First Compliant Deposit:	15 October 2024
Date of Acceptance:	8 April 2024
Last Modified:	15 Oct 2024 09:00
URI:	https://orca.cardiff.ac.uk/id/eprint/172370

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