title: Arginine methyltransferases mediate an epigenetic ovarian response to endometriosis.
abstract: Endometriosis is associated with infertility and debilitating chronic pain. Abnormal epigenetic modifications in the human endometrium have recently been implicated in the pathogenesis of this condition. However, whether an altered epigenetic landscape contributes to pathological changes in the ovary is unknown. Using an established baboon endometriosis model, early-, and late-stage epigenetic changes in the ovary were investigated. Transcript profiling of key chromatin-modifying enzymes using pathway-focused PCR arrays on ovarian tissue from healthy control animals and at 3 and 15 months of endometriosis revealed dramatic changes in gene expression in a disease duration-dependent manner. Ingenuity Pathway Analysis indicated that transcripts for chromatin-remodeling enzymes associated with reproductive system disease and cancer development were abnormally regulated, most prominently the arginine methyltransferases CARM1, PRMT2, and PRMT8. Downregulation of CARM1 protein expression was also detected in the ovary, fully-grown oocytes and eutopic endometrium following 15 months of endometriosis. Sodium bisulfite sequencing revealed DNA hypermethylation within the PRMT8 promoter, suggesting that deregulated CpG methylation may play a role in transcriptional repression of this gene. These results demonstrate that endometriosis is associated with changes of epigenetic profiles in the primate ovary and suggest that arginine methyltransferases play a prominent role in mediating the ovarian response to endometriosis. Owing to the critical role of CARM1 in nuclear receptor-mediated transcription and maintenance of pluripotency in the cleavage stage embryo, our results suggest that epigenetic alterations in the ovary may have functional consequences for oocyte quality and the etiology of infertility associated with endometriosis.
authors.affiliation: Department of Physiology and PharmacologyCollege of Veterinary Medicine, University of Georgia, 501 D.W. Brooks Drive, Athens, Georgia 30602, USADepartment of ObstetricsGynecology and Reproductive Biology, Michigan State University, Grand Rapids, Michigan 49534, USADepartment of Women's HealthSpectrum Health System, Grand Rapids, Michigan 49341, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Baumann
authors.affiliation: Department of Physiology and PharmacologyCollege of Veterinary Medicine, University of Georgia, 501 D.W. Brooks Drive, Athens, Georgia 30602, USADepartment of ObstetricsGynecology and Reproductive Biology, Michigan State University, Grand Rapids, Michigan 49534, USADepartment of Women's HealthSpectrum Health System, Grand Rapids, Michigan 49341, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Olson
authors.affiliation: Department of Physiology and PharmacologyCollege of Veterinary Medicine, University of Georgia, 501 D.W. Brooks Drive, Athens, Georgia 30602, USADepartment of ObstetricsGynecology and Reproductive Biology, Michigan State University, Grand Rapids, Michigan 49534, USADepartment of Women's HealthSpectrum Health System, Grand Rapids, Michigan 49341, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Physiology and PharmacologyCollege of Veterinary Medicine, University of Georgia, 501 D.W. Brooks Drive, Athens, Georgia 30602, USADepartment of ObstetricsGynecology and Reproductive Biology, Michigan State University, Grand Rapids, Michigan 49534, USADepartment of Women's HealthSpectrum Health System, Grand Rapids, Michigan 49341, USA Department of Physiology and PharmacologyCollege of Veterinary Medicine, University of Georgia, 501 D.W. Brooks Drive, Athens, Georgia 30602, USADepartment of ObstetricsGynecology and Reproductive Biology, Michigan State University, Grand Rapids, Michigan 49534, USADepartment of Women's HealthSpectrum Health System, Grand Rapids, Michigan 49341, USA rfuente@uga.edu asgi@hc.msu.edu.
authors.forename: Asgerally
authors.initials: A
authors.lastname: Fazleabas
authors.affiliation: Department of Physiology and PharmacologyCollege of Veterinary Medicine, University of Georgia, 501 D.W. Brooks Drive, Athens, Georgia 30602, USADepartment of ObstetricsGynecology and Reproductive Biology, Michigan State University, Grand Rapids, Michigan 49534, USADepartment of Women's HealthSpectrum Health System, Grand Rapids, Michigan 49341, USA rfuente@uga.edu asgi@hc.msu.edu.
authors.forename: Rabindranath
authors.initials: R
authors.lastname: De La Fuente
mesh_terms: D000818:Animals; D002843:Chromatin / Q000378:metabolism; D017124:Conserved Sequence; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation; D004715:Endometriosis / Q000235:genetics* / Q000503:physiopathology*; D004717:Endometrium / Q000201:enzymology; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D006570:Heterochromatin / Q000235:genetics; D006801:Humans; D007246:Infertility / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007527:Isoenzymes / Q000235:genetics; D009865:Oocytes / Q000201:enzymology; D010053:Ovary / Q000201:enzymology*; D010215:Papio; D011247:Pregnancy; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics*; D015533:Transcriptional Activation
chemical_list: D002843:Chromatin; D006570:Heterochromatin; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; C077013:PRMT2 protein, human; D011484:Protein-Arginine N-Methyltransferases; D004248:DNA (Cytosine-5-)-Methyltransferases