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

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.

Molecular-genetic background of endometriosis: diagnostic potential of heritable and expressed factors

“…За последние годы в англоязычной литературе появились десятки публикаций, описывающих разницу в экспрессии факторов регуляции иммунного статуса [17], апоптотической активности [18], метастатического потенциала [19], наблюдае-мую между эктопическим и эутопическим эпи-телием. Ряд публикаций посвящен исследова-нию разницы эпигенетических особенностей: метилированию [20,21], экспрессии регуля-торных молекул РНк [22] и др. Результаты этих исследований носят описательный характер и плохо сопоставимы.…”

“…1. Supervised hierarchical clustering analysis of 72 differentially expressed genes between the 13 eutopic endometrium samples from eight endometriosis patients (EU 11,19,6,1,21,7,18,5) and five healthy control subjects (n 16,8,12,2,19). The expression levels are indicated using colors.…”

Aberrant endometrial DNA methylome of homeobox A10 and catechol-O-methyltransferase in endometriosis

“…Aberrant DNA methylation has been identified as a vital mechanism in tumorigenesis and multiple other diseases [8,9]. A recent study analyzed the genome-wide DNA methylation in patients with endometriosis and identified 42,248 differentially methylated CpGs in the endometriosis cells as compared to the healthy cells [10]. The homeobox gene (HOX) clusters were some of the maximum differentially methylated families of genes [10].…”

“…A recent study analyzed the genome-wide DNA methylation in patients with endometriosis and identified 42,248 differentially methylated CpGs in the endometriosis cells as compared to the healthy cells [10]. The homeobox gene (HOX) clusters were some of the maximum differentially methylated families of genes [10]. HOX genes are dynamically expressed in the endometrium, where they are necessary for endometrial growth, differentiation, and implantation.…”

Aberrant expression and localization of deoxyribonucleic acid methyltransferase 3B in endometriotic stromal cells

“…Full differentiation and maintenance of the decidua is contingent upon pregnancy, since the absence of a conceptus provokes shedding of the pre-decidualized endometrial layer and menstruation, and it has been suggested that the evolution of spontaneous decidualization necessitated menstruation (3). This intriguing observation led us to propose that the gene regulatory pathways that coordinate spontaneous decidualization in menstruating primates are the key pathways dysregulated in endometriosis (4). …”