title: ARID1A Is Essential for Endometrial Function during Early Pregnancy.
abstract: AT-rich interactive domain 1A gene (ARID1A) loss is a frequent event in endometriosis-associated ovarian carcinomas. Endometriosis is a disease in which tissue that normally grows inside the uterus grows outside the uterus, and 50% of women with endometriosis are infertile. ARID1A protein levels were significantly lower in the eutopic endometrium of women with endometriosis compared to women without endometriosis. However, an understanding of the physiological effects of ARID1A loss remains quite poor, and the function of Arid1a in the female reproductive tract has remained elusive. In order to understand the role of Arid1a in the uterus, we have generated mice with conditional ablation of Arid1a in the PGR positive cells (Pgrcre/+Arid1af/f; Arid1ad/d). Ovarian function and uterine development of Arid1ad/d mice were normal. However, Arid1ad/d mice were sterile due to defective embryo implantation and decidualization. The epithelial proliferation was significantly increased in Arid1ad/d mice compared to control mice. Enhanced epithelial estrogen activity and reduced epithelial PGR expression, which impedes maturation of the receptive uterus, was observed in Arid1ad/d mice at the peri-implantation period. The microarray analysis revealed that ARID1A represses the genes related to cell cycle and DNA replication. We showed that ARID1A positively regulates Klf15 expression with PGR to inhibit epithelial proliferation at peri-implantation. Our results suggest that Arid1a has a critical role in modulating epithelial proliferation which is a critical requisite for fertility. This finding provides a new signaling pathway for steroid hormone regulation in female reproductive biology and furthers our understanding of the molecular mechanisms that underlie dysregulation of hormonal signaling in human reproductive disorders such as endometriosis.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University College of Human Medicine, Grand Rapids, Michigan, United States of America.
authors.forename: Tae Hoon
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University College of Human Medicine, Grand Rapids, Michigan, United States of America.
authors.forename: Jung-Yoon
authors.initials: JY
authors.lastname: Yoo
authors.affiliation: Department of Cardiac Surgery, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: John P
authors.initials: JP
authors.lastname: Lydon
authors.affiliation: Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Shikha
authors.initials: S
authors.lastname: Khatri
authors.affiliation: Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Hawkins
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University College of Human Medicine, Grand Rapids, Michigan, United States of America; Department of Women's Health, Spectrum Health System, Grand Rapids, Michigan, United States of America.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Leach
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University College of Human Medicine, Grand Rapids, Michigan, United States of America; Department of Women's Health, Spectrum Health System, Grand Rapids, Michigan, United States of America.
authors.forename: Asgerally T
authors.initials: AT
authors.lastname: Fazleabas
authors.affiliation: Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Young
authors.affiliation: Department of Obstetrics and Gynecology, University Medical Group, Greenville Health System, Greenville, South Carolina, United States of America.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Lessey
authors.affiliation: Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, South Korea.
authors.forename: Bon Jeong
authors.initials: BJ
authors.lastname: Ku
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University College of Human Medicine, Grand Rapids, Michigan, United States of America; Department of Women's Health, Spectrum Health System, Grand Rapids, Michigan, United States of America.
authors.forename: Jae-Wook
authors.initials: JW
authors.lastname: Jeong
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004715:Endometriosis / Q000235:genetics; D005260:Female; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D011247:Pregnancy; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
chemical_list: C112476:ARID1A protein, human; C511511:Arid1a protein, mouse; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors