Journal Article

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

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

2017

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adult / Antigens / Apoptosis / Azacitidine - analogs & derivatives / Azacitidine - pharmacology / Biology and life sciences / Bisulfite / Brain-derived neurotrophic factor / Brain-Derived Neurotrophic Factor - genetics / Brain-Derived Neurotrophic Factor - metabolism / Cancer / Cell activation / Cellular signal transduction / Chromatin / Chromatin - chemistry / Chromatin - metabolism / Chromosome translocations / CpG islands / Death-associated protein kinase / Death-Associated Protein Kinases - genetics / Death-Associated Protein Kinases - metabolism / Deoxyribonucleic acid / Development and progression / DNA / DNA Methylation / Endometriosis / Endometriosis - genetics / Endometriosis - metabolism / Endometriosis - pathology / Endometrium / Endometrium - drug effects / Endometrium - metabolism / Endometrium - pathology / Epigenesis, Genetic / Epigenetics / Estrogens / Female / Gene expression / Gene Ontology / Genes / Genetic aspects / Genetics / Genomes / Gynecology / Health aspects / Humans / Infertility / Kinases / Laboratory animals / Laparoscopy / Medicine and Health Sciences / Methylation / Middle Aged / Molecular Sequence Annotation / Neoplasm Proteins - genetics / Neoplasm Proteins - metabolism / Obstetrics / Oncology / Organic Anion Transporters - genetics / Organic Anion Transporters - metabolism / Pathogenesis / Pathology / Primary Cell Culture / Properties / Receptor Tyrosine Kinase-like Orphan Receptors - genetics / Receptor Tyrosine Kinase-like Orphan Receptors - metabolism / Ribonucleic acid / RNA / Sequence Analysis, RNA / Signal transduction / Signal Transduction - genetics / Signaling / Stromal cells / Stromal Cells - drug effects / Stromal Cells - metabolism / Stromal Cells - pathology / Studies / Transcription factors / Transcription Factors - genetics / Transcription Factors - metabolism / Tumors / Uterus / Wnt protein / Wnt-5a Protein - genetics / Wnt-5a Protein - metabolism / Womens health