Aberrant Endometrial DNA Methylome and Associated Gene Expression in Women with Endometriosis

Abstract

Endometriosis is an estrogen-dependent, progesterone-resistant disorder largely derived from retrograde transplantation of menstrual tissue/cells into the pelvis, eliciting an inflammatory response, pelvic pain, and infertility. Eutopic endometrium (within the uterus), giving rise to pelvic disease, displays cycle-dependent transcriptomic, proteomic, and signaling abnormalities, and although its DNA methylation profiles dynamically change across the cycle in healthy women, studies in endometriosis are limited. Herein, we investigated the DNA methylome and associated gene expression in three phases of the cycle in eutopic endometrium of women with severe endometriosis versus controls, matched for ethnicity, medications, smoking, and no recent contraceptive steroid use. Genome-wide DNA methylation and gene expression were coassessed in each sample. Cycle phase was determined by histology, serum hormone levels, and unsupervised principal component and hierarchical cluster analyses of microarray data. Altered endometrial DNA methylation in endometriosis was most prominent in the midsecretory phase (peak progesterone), with disruption of the normal pattern of cycle-dependent DNA methylation changes, including a bias toward methylation of CpG islands, suggesting wide-range abnormalities of the chromatin remodeling machinery in endometriosis. DNA methylation changes were associated with altered gene expression relevant to endometrial function/dysfunction, including cell proliferation, inflammation/immune response, angiogenesis, and steroid hormone response. The data provide insight into epigenetic reprogramming and steroid hormone actions in endometrium contributing to the pathogenesis and pathophysiology of endometriosis.

Biological age of the endometrium using DNA methylation

“…This could be a consequence of the large changes in the endometrial DNA methylation profile across the menstrual cycle (Munro et al 2010, Houshdaran et al 2014, which could affect methylation levels at CpG sites used by Horvath's epigenetic clock. In addition, DNA methylation changes associated with gynecological diseases such as endometriosis (Guo 2009, Houshdaran et al 2016, Saare et al 2016 could also have an influence on the biological age in the endometrium. Further studies are needed to address this.…”

Variability of genome-wide DNA methylation and mRNA expression profiles in reproductive and endocrine disease related tissues

“…A recent study including 17 endometriosis cases (4 proliferative, 7 early secretory, 6 mid-secretory phases) and 16 controls (6 proliferative, 5 early secretory, 5 mid-secretory phases) suggested that DNA methylation changes across the menstrual cycle are associated with changes in gene expression for many loci associated with endometriosis, and that the greatest DNA methylation differences were observed in the mid-secretory phase. 38 It is therefore important to investigate: (1) expression and DNA methylation profiles of endometrium in cases vs. controls; (2) DNA methylation profiles of peritoneal lesion vs. other tissues, adjusted or matched for menstrual cycle phase.…”

Pathogenesis of endometriosis: the genetic/epigenetic theory

“…These changes are increasingly viewed as a consequence of genetic or epigenetic polymorphism (154,(188)(189)(190). Other epigenetic changes (191)(192)(193)(194)(195)(196) comprise methylation, demethylation of DNA and modifications in histone code (193,197,198).…”