Genome-Wide DNA Methylation Analysis Predicts an Epigenetic Switch for GATA Factor Expression in Endometriosis

Matthew T Dyson, Damian Roqueiro, Diana Monsivais, Cihangir Mutlu Ercan, C Mutlu Ercan, Mary Ellen Pavone, David C Brooks, Toshiyuki Kakinuma, Masanori Ono, Nadereh Jafari, Yang Dai, Serdar E Bulun
PLoS genetics · 2014 · vol. 10(3) , pp. e1004158 · doi:10.1371/journal.pgen.1004158 · PMID:24603652 · PMC3945170 · W2048280620
article OA: gold CC0 ⤵ 133 in-corpus citations
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⚙ AI-generated summary by claude@2026-06, 2026-06-07 ⓘ

This study mapped genome-wide DNA methylation differences in endometriosis cells, revealing an epigenetic switch in GATA factor expression that drives progesterone resistance and disease progression.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-07 ⓘ

Dyson et al. studied genome-wide DNA methylation differences between healthy human endometrial stromal cells and ovarian endometriotic stromal cells, integrating methylation array data with gene expression profiling and analyzing patterns with and without in vitro decidualization stimuli. They identified 42,248 differentially methylated CpGs in endometriosis, with methylation changes concentrated intragenically and at distal sites, and mapped these to 403 genes enriched for transcription factors; a key finding was that GATA2 was hypermethylated and repressed in endometriotic cells, while GATA6 was hypomethylated and abundant. Functional experiments showed that expressing GATA6 in healthy endometrial cells blocked hormone sensitivity, repressed GATA2, and induced endometriosis markers, leading the authors to propose an epigenetic switch related to progesterone resistance, though the analyses are limited by the in vitro and cell-type-specific experimental design. This paper is centrally about endometriosis — identifying a DNA methylation–driven GATA2-to-GATA6 epigenetic switch that regulates hormone responsiveness in endometriotic stromal cells.

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Abstract

Endometriosis is a gynecological disease defined by the extrauterine growth of endometrial-like cells that cause chronic pain and infertility. The disease is limited to primates that exhibit spontaneous decidualization, and diseased cells are characterized by significant defects in the steroid-dependent genetic pathways that typify this process. Altered DNA methylation may underlie these defects, but few regions with differential methylation have been implicated in the disease. We mapped genome-wide differences in DNA methylation between healthy human endometrial and endometriotic stromal cells and correlated this with gene expression using an interaction analysis strategy. We identified 42,248 differentially methylated CpGs in endometriosis compared to healthy cells. These extensive differences were not unidirectional, but were focused intragenically and at sites distal to classic CpG islands where methylation status was typically negatively correlated with gene expression. Significant differences in methylation were mapped to 403 genes, which included a disproportionally large number of transcription factors. Furthermore, many of these genes are implicated in the pathology of endometriosis and decidualization. Our results tremendously improve the scope and resolution of differential methylation affecting the HOX gene clusters, nuclear receptor genes, and intriguingly the GATA family of transcription factors. Functional analysis of the GATA family revealed that GATA2 regulates key genes necessary for the hormone-driven differentiation of healthy stromal cells, but is hypermethylated and repressed in endometriotic cells. GATA6, which is hypomethylated and abundant in endometriotic cells, potently blocked hormone sensitivity, repressed GATA2, and induced markers of endometriosis when expressed in healthy endometrial cells. The unique epigenetic fingerprint in endometriosis suggests DNA methylation is an integral component of the disease, and identifies a novel role for the GATA family as key regulators of uterine physiology-aberrant DNA methylation in endometriotic cells correlates with a shift in GATA isoform expression that facilitates progesterone resistance and disease progression.

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Condition tags

endometriosisinfertility

MeSH descriptors

DNA Methylation Endometriosis Epigenesis, Genetic GATA2 Transcription Factor CpG Islands CpG Islands Disease Progression DNA Methylation Endometriosis Endometrium Endometrium Female GATA2 Transcription Factor Gene Expression Regulation Genome, Human Humans Stromal Cells Uterine Diseases Uterine Diseases

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