Steroid hormones regulate genome-wide epigenetic programming and gene transcription in human endometrial cells with marked aberrancies in endometriosis

English version

Autoři: Sahar Houshdaran ^aff001; Ashwini B. Oke ^aff001; Jennifer C. Fung ^aff001; Kim Chi Vo ^aff001; Camran Nezhat ^aff002; Linda C. Giudice ^aff001
Působiště autorů: University of California San Francisco, Dept. of Obstetrics, Gynecology and Reproductive Sciences, San Francisco, California, United States of America ^aff001; Camran Nezhat Institute, Palo Alto, California, United States of America ^aff002
Vyšlo v časopise: Steroid hormones regulate genome-wide epigenetic programming and gene transcription in human endometrial cells with marked aberrancies in endometriosis. PLoS Genet 16(6): e1008601. doi:10.1371/journal.pgen.1008601
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008601

Souhrn

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.

Klíčová slova:

DNA methylation – endometrium – Gene expression – Gene regulation – Genetic loci – Chromatin – Methylation – Steroid hormones

Zdroje

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