title: 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.
authors.affiliation: Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, California 94143.
authors.forename: Sahar
authors.initials: S
authors.lastname: Houshdaran
authors.forename: Zara
authors.initials: Z
authors.lastname: Zelenko
authors.forename: Juan C
authors.initials: JC
authors.lastname: Irwin
authors.forename: Linda C
authors.initials: LC
authors.lastname: Giudice
mesh_terms: D000328:Adult; D049109:Cell Proliferation; D016000:Cluster Analysis; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D004247:DNA / Q000378:metabolism*; D019175:DNA Methylation; D000070819:Discoidin Domain Receptor 1; D004717:Endometrium / Q000166:cytology / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000235:genetics*; D004958:Estradiol / Q000097:blood / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D053505:Matrix Metalloproteinases, Secreted / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D008597:Menstrual Cycle / Q000235:genetics; D008875:Middle Aged; D018396:Mucin-1 / Q000235:genetics; D011374:Progesterone / Q000097:blood / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D017154:Stromal Cells / Q000166:cytology; D059467:Transcriptome / Q000235:genetics
chemical_list: D050677:Core Binding Factor Alpha 3 Subunit; C482290:MPP7 protein, human; C060192:MUC1 protein, human; D008565:Membrane Proteins; D018396:Mucin-1; C493729:Runx3 protein, human; D011374:Progesterone; D004958:Estradiol; D004247:DNA; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases; C410599:MMP26 protein, human; D053505:Matrix Metalloproteinases, Secreted