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 classical modulators, epigenetic mechanisms regulate gene expression during development, in response to environmental factors, 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 and mid-secretory 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. Together, the data support 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 interplay between steroid hormone and methylome dynamics regulate normal endometrial functions and, if abnormal, may result in endometrial dysfunction and associated disorders.
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ABSTRACT: Implantation is an essential process during establishment of pregnancy in mammals. It is initiated with the attachment of the blastocyst to a receptive uterine epithelium followed by its invasion into the stromal tissue. These events are profoundly regulated by the steroid hormones 17β-estradiol (E) and progesterone (P). During the past several years, mouse models harboring conditional gene knockout mutations have become powerful tools for determining the functional roles of cellular factors involved in various aspects of implantation biology. Studies employing these genetic models as well as primary cultures of human endometrial cells have established that the estrogen receptor alpha (ESR1), the progesterone receptor (PGR), and their downstream target genes critically regulate uterine growth and differentiation, which in turn control embryo-endometrial interactions during early pregnancy. These studies have uncovered a diverse array of molecular cues, which are produced under the influence of ESR1 and PGR and exchanged between the epithelial and stromal compartments of the uterus during the progressive phases of implantation. These paracrine signals are critical for acquisition of uterine receptivity and functional interactions with the embryo. This review highlights recent work describing paracrine mechanisms that govern steroid-regulated uterine stromal-epithelial dialogue during implantation and their roles in fertility and disease.Molecular Endocrinology 07/2014; 28(9):me20141074. DOI:10.1210/me.2014-1074 · 4.20 Impact Factor