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Epigenetic Alterations Affecting Transcription Factors and Signaling Pathways in Stromal Cells of Endometriosis.
Yotova, Iveta; Hsu, Emily; Do, Catherine; Gaba, Aulona; Sczabolcs, Matthias; Dekan, Sabine; Kenner, Lukas; Wenzl, Rene; Tycko, Benjamin.
Afiliação
  • Yotova I; Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, United States of America.
  • Hsu E; Department of Gynecology and Gynecological Oncology, University Clinic of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria.
  • Do C; Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, United States of America.
  • Gaba A; Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, United States of America.
  • Sczabolcs M; Department of Gynecology and Gynecological Oncology, University Clinic of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria.
  • Dekan S; Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, United States of America.
  • Kenner L; Department of Experimental Pathology, Clinical Institute of Pathology, University Clinic of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria.
  • Wenzl R; Department of Experimental Pathology, Clinical Institute of Pathology, University Clinic of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria.
  • Tycko B; Pathology Laboratory Animal Pathology University of Veterinary Medicine Vienna, Vienna, Austria.
PLoS One ; 12(1): e0170859, 2017.
Article em En | MEDLINE | ID: mdl-28125717
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Células Estromais / Epigênese Genética / Endometriose / Endométrio / Proteínas de Neoplasias Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Células Estromais / Epigênese Genética / Endometriose / Endométrio / Proteínas de Neoplasias Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2017 Tipo de documento: Article