Epigenetic Alterations Affecting Transcription Factors and Signaling Pathways in Stromal C...

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Epigenetic Alterations Affecting Transcription Factors and Signaling Pathways in Stromal Cells of Endometriosis

Plos One; 26 January 2017: /DOI:10.1371/journal.pone.0170859

Iveta Yotova, Emily Hsu, Catherine Do, Aulona Gaba, Matthias Sczabolcs, Sabine Dekan, Lukas Kenner, Rene Wenzl, Benjamin Tycko

Abstract

Endometriosis is characterized by growth of endometrial-like tissue outside the uterine cavity. Since its pathogenesis may involve epigenetic changes, we used Illumina 450K Methylation Beadchips to profile CpG methylation in endometriosis stromal cells compared to stromal cells from normal endometrium. We validated and extended the Beadchip data using bisulfite sequencing (bis-seq), and analyzed differential methylation (DM) at the CpG-level and by an element-level classification for groups of CpGs in chromatin domains. Genes found to have DM included examples encoding transporters (SLC22A23), signaling components (BDNF, DAPK1, ROR1, and WNT5A) and transcription factors (GATA family, HAND2, HOXA cluster, NR5A1, OSR2, TBX3). Intriguingly, among the TF genes with DM we also found JAZF1, a proto-oncogene affected by chromosomal translocations in endometrial stromal tumors. Using RNA-Seq we identified a subset of the DM genes showing differential expression (DE), with the likelihood of DE increasing with the extent of the DM and its location in enhancer elements. Supporting functional relevance, treatment of stromal cells with the hypomethylating drug 5aza-dC led to activation of DAPK1 and SLC22A23 and repression of HAND2, JAZF1, OSR2, and ROR1 mRNA expression. We found that global 5hmC is decreased in endometriotic versus normal epithelial but not stroma cells, and for JAZF1 and BDNF examined by oxidative bis-seq, found that when 5hmC is detected, patterns of 5hmC paralleled those of 5mC. Together with prior studies, these results define a consistent epigenetic signature in endometriosis stromal cells and nominate specific transcriptional and signaling pathways as therapeutic targets.

Introduction

Endometriosis is characterized by growth of endometrial-like tissue outside the uterine cavity. As a hormone-driven disorder it affects women of reproductive age, and it is associated with chronic pelvic pain, pelvic inflammatory reactions and infertility. Although it is not a malignant condition, it shares its metastasizing-like biological behavior and certain aspects of gene expression with cancers. In healthy individuals, the development and the maintenance of the decidua is dependent on progesterone, and a hormonal withdrawal in the absence of pregnancy provokes apoptosis and shedding of the endometrium and differentiated decidual cells during menstruation; this physiological response is altered in women with endometriosis partly due to progesterone-resistance of the ectopic endometrial tissue

Multiple predisposing factors of genetic, epigenetic and environmental origin, combined with an altered immune response, are thought to contribute to survival of endometrial cells outside the uterine cavity in the endometriotic lesions. Since there are important but to date only partly characterized interactions between epithelial cells, inflammatory cells with their associated cytokines, and mesenchymal stromal cells in these lesions, a full elucidation of the pathogenic mechanisms will require testing multiple biological hypotheses. Among these possibilities, epigenetic changes in endometriosis have come under scrutiny. Initial reports focused on DNA methylation changes in candidate genes associated with sex-steroid hormone signaling and the dysregulation of endometrial decidualization: losses of methylation in gene promoters for aromatase, steroidogenic factor-1 and estrogen receptor beta were associated with local estrogen production and enhanced estrogen signaling in ectopic whole endometriotic tissue compared to control uterine endometrium. Hypermethylation of promoter regions of genes involved in implantation including those encoding the progesterone receptor, homeobox A10, and e-cadherin were reported in endometrium of patients with endometriosis and several other genes have also been reported to show abnormal CpG methylation in endometriotic lesions. Recently, altered promoter methylation in eutopic endometrial cells was suggested as a possible mechanism in women who will develop endometriosis later in life.

Empire Genomic's IDetectâ„¢ Super Stain System - HRP 500 Slide Kit was used in this publication.

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