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Type of publication: Journal Article
Type of document: Full Paper

Year: 2017

Authors: Yotova, I; Hsu, E; Do, C; Gaba, A; Sczabolcs, M; Dekan, S; Kenner, L; Wenzl, R; Tycko, B

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

Source: PLoS One. 2017; 12(1):e0170859

Authors Vetmeduni Vienna:

Kenner Lukas

Vetmed Research Units
Institute of Pathology, Pathology of Laboratory Animals

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.

Keywords Pubmed: Adult
Azacitidineanalogs & derivativespharmacology
Brain-Derived Neurotrophic Factorgeneticsmetabolism
DNA Methylation
Death-Associated Protein Kinasesgeneticsmetabolism
Endometriumdrug effectsmetabolismpathology
Epigenesis, Genetic
Gene Ontology
Middle Aged
Molecular Sequence Annotation
Neoplasm Proteinsgeneticsmetabolism
Organic Anion Transportersgeneticsmetabolism
Primary Cell Culture
Receptor Tyrosine Kinase-like Orphan Receptorsgeneticsmetabolism
Sequence Analysis, RNA
Signal Transductiongenetics
Stromal Cellsdrug effectsmetabolismpathology
Transcription Factorsgeneticsmetabolism
Wnt-5a Proteingeneticsmetabolism

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