부산대학교 도서관

Programmed cellular responses to cycling ovarian-derived steroid hormones are central to normal endometrial function. Abnormalities therein, as in the estrogen-dependent, progesterone-"resistant" disorder, endometriosis, predispose to infertility and poor pregnancy outcomes. The endometrial stromal fibroblast (eSF) is a master regulator of pregnancy success. However, the complex hormone-epigenome-transcriptome interplay in eSF by each individual steroid hormone, estradiol (E2) and/or progesterone (P4), under physiologic and pathophysiologic conditions, is poorly understood and was investigated herein. Genome-wide analysis in normal, early and late stage eutopic eSF revealed: i) In contrast to P4, E2 extensively affected the eSF DNA methylome and transcriptome. Importantly, E2 resulted in a more open versus closed chromatin, confirmed by histone modification analysis. Combined E2 with P4 affected a totally different landscape than E2 or P4 alone. ii) P4 responses were aberrant in early and late stage endometriosis, and mapping differentially methylated CpG sites with progesterone receptor targets from the literature revealed different but not decreased P4-targets, leading to question the P4-"resistant" phenotype in endometriosis. Interestingly, an aberrant E2-response was noted in eSF from endometriosis women; iii) Steroid hormones affected specific genomic contexts and locations, significantly enriching enhancers and intergenic regions and minimally involving proximal promoters and CpG islands, regardless of hormone type and eSF disease state. iv) In eSF from women with endometriosis, aberrant hormone-induced methylation signatures were mainly due to existing DNA methylation marks prior to hormone treatments and involved known endometriosis genes and pathways. v) Distinct DNA methylation and transcriptomic signatures revealed early and late stage endometriosis comprise unique disease subtypes. Taken together, the data herein, for the first time, provide significant insight into the hormone-epigenome-transcriptome interplay of each steroid hormone in normal eSF, and aberrant E2 response, distinct disease subtypes, and pre-existing epigenetic aberrancies in the setting of endometriosis, provide mechanistic insights into how endometriosis affects endometrial function/dysfunction. Author summary: Steroid hormones regulate genes in select tissues, including the lining of the uterus ("endometrium"). If the hormone response in the endometrium is abnormal, infertility and poor pregnancy outcomes can result. Interaction of steroid hormones with the second genome ("epigenome") to regulate gene expression is poorly understood. Thus, we studied the response to estrogen (E2), progesterone (P4) and their combination of the endometrial stromal fibroblast (eSF), a cell that is pivotal in pregnancy. The cells were derived from normal woman and those with endometriosis, an E2-responsive, P4-resistant, inflammatory disorder with implantation-based infertility and poor pregnancy outcomes. Hormone-regulated genome-wide DNA methylation (a key epigenetic mechanism) and gene expression patterns and profiles were distinct for each hormone and in normal versus disease. Advanced stage disease had the most blunted response, and novel, not previously reported E2 responses were observed in eSF from women with endometriosis. Intergenic regions and enhancers were significantly enriched, with minimal involvement of gene proximal promoters, indicating a broad, genome-wide hormone effect. Unexpectedly, pre-existing aberrant DNA methylation signatures in eSF from women with endometriosis were found and revealed distinct disease sub-types. These data advance our understanding of genome-wide hormone-epigenome dynamics critical in hormone-responsive tissues with downstream impact on physiologic processes. [ABSTRACT FROM AUTHOR]