BPA modulates the WDR5/TET2 complex to regulate ERβ expression in eutopic endometrium and drives the development of endometriosis

Wen Xue, Yao Xiong, Xiong Yao, Geng Ting, Jin Ling, Ling Jin, Huimin Liu, Liu Huimin, Yuan Qiao, Qiao Yuan, Zhou Chun, Chun Zhou, Zhang Ming, Ming Zhang, Yuanzhen Zhang, Zhang Yuanzhen
Environmental pollution (Barking, Essex : 1987) · 2020 · vol. 268(Pt B) , pp. 115748 · doi:10.1016/j.envpol.2020.115748 · PMID:33022573 · W3090679687
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This study found that BPA promotes endometriosis by increasing ERβ expression in eutopic endometrium via the WDR5/TET2 complex, which enhances H3K4me3 levels and reduces DNA methylation at the ERβ promoter.

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Abstract

Overexpression of estrogen receptor β (ERβ) in endometrium contributes to endometriosis (EM) pathogenesis. Trimethylation of the H3 lysine (K) 4 (H3K4me3) in promoters is strongly correlated with gene expression. This study aimed to explore the effects of bisphenol A (BPA) exposure on EM development from the perspective of the regulation of ERβ expression in eutopic endometrium via the H3K4me3-related epigenetic pathway. A mouse EM model was established to investigate the effects of BPA. Immortalized human normal endometrial stromal cells (iESCs) were cultured and treated with BPA to explore the underlying mechanism. Eutopic endometria from patients with or without EM were collected and analyzed. Results showed that BPA elevated ERβ expression in mouse eutopic endometrium and promoted lesion growth. BPA also promoted WD repeat domain 5 (WDR5) expression and upregulated H3K4me3 levels in the ERβ promoter and Exon 1. Further research indicated that WDR5 interacted with tet methylcytosine dioxygenase 2 (TET2), while BPA exposure enhanced the interaction between these two proteins, promoted the recruitment of the WDR5/TET2 complex to the ERβ promoter and Exon 1, and inhibited DNA methylation of CpG islands. The WDR5/TET2 interaction was essential for BPA-induced ERβ overexpression. Enhanced WDR5/TET2 interaction was also observed in eutopic endometria from EM patients. Further results showed that BPA upregulated WDR5 expression through the G protein-coupled estrogen receptor (GPER)-mediated PI3K/mTOR signaling pathway. In conclusion, our study suggests that BPA exposure promotes EM development by upregulating ERβ expression in eutopic endometrium via the WDR5/TET2-mediated epigenetic pathway.

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Condition tags

mesh:D004715endometriosis

MeSH descriptors

Endometriosis Endometriosis Endometriosis Estrogen Receptor beta Estrogen Receptor beta Animals Benzhydryl Compounds Benzhydryl Compounds Bisphenol A Compounds Dioxygenases DNA-Binding Proteins Endometrium Epigenomics Female Humans Intracellular Signaling Peptides and Proteins Mice Phenols Proto-Oncogene Proteins Proto-Oncogene Proteins

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