Human Endometrial DNA Methylome Is Cycle-Dependent and Is Associated With Gene Expression Regulation

Abstract

Human endometrium undergoes major gene expression changes, resulting in altered cellular functions in response to cyclic variations in circulating estradiol and progesterone, largely mediated by transcription factors and nuclear receptors. In addition to classic modulators, epigenetic mechanisms regulate gene expression during development in response to environmental factors and in some diseases and have roles in steroid hormone action. Herein, we tested the hypothesis that DNA methylation plays a role in gene expression regulation in human endometrium in different hormonal milieux. High throughput, genome-wide DNA methylation profiling of endometrial samples in proliferative, early secretory, and midsecretory phases revealed dynamic DNA methylation patterns with segregation of proliferative from secretory phase samples by unsupervised cluster analysis of differentially methylated genes. Changes involved different frequencies of gain and loss of methylation within or outside CpG islands. Comparison of changes in transcriptomes and corresponding DNA methylomes from the same samples revealed association of DNA methylation and gene expression in a number of loci, some important in endometrial biology. Human endometrial stromal fibroblasts treated in vitro with estradiol and progesterone exhibited DNA methylation changes in several genes observed in proliferative and secretory phase tissues, respectively. Taken together, the data support the observation that epigenetic mechanisms are involved in gene expression regulation in human endometrium in different hormonal milieux, adding endometrium to a small number of normal adult tissues exhibiting dynamic DNA methylation. The data also raise the possibility that the interplay between steroid hormone and methylome dynamics regulates normal endometrial functions and, if abnormal, may result in endometrial dysfunction and associated disorders.

Decidualization and Epigenetic Regulation

“…In addition, estrogen and progesterone treatment in human endometrial stromal cell cultures decreased DNMT3a and DNMT3b mRNA expression [12]. The DNA methylation status of many genes in the endometrium changes between the proliferative and mid-secretory phases [13]. These findings suggest that histone modifications and DNA methylation are involved in the regulation of gene expression of human endometrial stromal cells undergoing decidualization.…”

“…This suggests that decidualization did not remarkably change the DNA methylation status in human endometrial stromal cells. Recently, Houshdaran et al [13] compared DNA methylation status of the endometrial tissues between proliferative and mid-secretory phases using an Illumina Infinium HumanMethylation 27 BeadChip that covers DNA methylation in 27,000 CpG sites of the promoter region around the TSS. In that study, the cut-off value of the difference of DNA methylation rate between the two groups was set at 13.5 %, and only 67 differentially methylated CpG sites were identified.…”

Comparative systems genetics view of endometriosis and uterine leiomyoma: Two sides of the same coin?

“…[Houshdaran et al 2014]. Shift in methylation of two isoforms of transcription factor GATA (GATA2 and GATA6) results in impairment of hormonal sensitivity and aberrant expression of many candidate EM genes [Dyson et al 2014].…”

Functional single nucleotide polymorphisms of matrix metalloproteinase 7 and 12 genes in idiopathic recurrent spontaneous abortion

“…During the secretory phase, including the implantation window and decidual transformation, the expression profiles of endometrial genes are changed considerably compared to proliferative phase [5][6][7][8]. It has been suggested that abnormalities in gene expression during the secretory phase may lead to inappropriate endometrial development and, consequently, various reproductive disorders, including recurrent spontaneous abortion [9][10][11][12].…”