ARID1A Is Essential for Endometrial Function during Early Pregnancy

Tae Hoon Kim, Jung Yoon Yoo, Zhong Wang, John P. Lydon, Shikha Khatri, Shannon Hawkins, Richard E. Leach, Asgerally T. Fazleabas, Steven L. Young, Bruce A. Lessey, Bon Jeong Ku, Jae Wook Jeong

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1005537
JournalPLoS Genetics
Volume11
Issue number9
DOIs
StatePublished - 2015
Externally publishedYes

Fingerprint

Essential Genes
Endometriosis
pregnancy
Pregnancy
uterus
Uterus
gene
mice
genes
Genes
reproductive disorder
embryo implantation
reproductive disorders
endometrium
steroid hormones
DNA replication
reproductive biology
Microarray Analysis
steroid
Endometrium

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Kim, T. H., Yoo, J. Y., Wang, Z., Lydon, J. P., Khatri, S., Hawkins, S., ... Jeong, J. W. (2015). ARID1A Is Essential for Endometrial Function during Early Pregnancy. PLoS Genetics, 11(9), [e1005537]. https://doi.org/10.1371/journal.pgen.1005537

ARID1A Is Essential for Endometrial Function during Early Pregnancy. / Kim, Tae Hoon; Yoo, Jung Yoon; Wang, Zhong; Lydon, John P.; Khatri, Shikha; Hawkins, Shannon; Leach, Richard E.; Fazleabas, Asgerally T.; Young, Steven L.; Lessey, Bruce A.; Ku, Bon Jeong; Jeong, Jae Wook.

In: PLoS Genetics, Vol. 11, No. 9, e1005537, 2015.

Research output: Contribution to journalArticle

Kim, TH, Yoo, JY, Wang, Z, Lydon, JP, Khatri, S, Hawkins, S, Leach, RE, Fazleabas, AT, Young, SL, Lessey, BA, Ku, BJ & Jeong, JW 2015, 'ARID1A Is Essential for Endometrial Function during Early Pregnancy', PLoS Genetics, vol. 11, no. 9, e1005537. https://doi.org/10.1371/journal.pgen.1005537
Kim, Tae Hoon ; Yoo, Jung Yoon ; Wang, Zhong ; Lydon, John P. ; Khatri, Shikha ; Hawkins, Shannon ; Leach, Richard E. ; Fazleabas, Asgerally T. ; Young, Steven L. ; Lessey, Bruce A. ; Ku, Bon Jeong ; Jeong, Jae Wook. / ARID1A Is Essential for Endometrial Function during Early Pregnancy. In: PLoS Genetics. 2015 ; Vol. 11, No. 9.
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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.",
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