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Loss of HDAC3 results in nonreceptive endometrium and female infertility.

Publication ,  Journal Article
Kim, TH; Yoo, J-Y; Choi, K-C; Shin, J-H; Leach, RE; Fazleabas, AT; Young, SL; Lessey, BA; Yoon, H-G; Jeong, J-W
Published in: Sci Transl Med
January 9, 2019

Endometriosis is a disease in which tissue that normally grows inside the uterus grows outside the uterus and causes chronic pelvic pain and infertility. However, the exact mechanisms of the pathogenesis of endometriosis-associated infertility are unknown. Epigenetic dysregulation has recently been implicated in infertility. Here, we report a reduction of histone deacetylase 3 (HDAC3) protein amounts in eutopic endometrium of infertile women with endometriosis compared to a control group. To investigate the effect of HDAC3 loss in the uterus, we generated mice with conditional ablation of Hdac3 in progesterone receptor (PGR)-positive cells (Pgrcre/+Hdac3f/f ; Hdac3d/d ). Loss of Hdac3 in the uterus of mice results in infertility due to implantation failure and decidualization defect. Expression microarray and ChIP-seq analyses identified COL1A1 and COL1A2 as direct targets of HDAC3 in both mice and humans. Reduction of HDAC3 abrogated decidualization in a primary culture of human endometrial stromal cells (hESCs) similar to that observed in infertile patients with endometriosis. Whereas attenuation of HDAC3 resulted in p300 recruitment to Col1a1 and Col1a2 genes in the uterus of mice as well as hESCs, inhibition of p300 permitted hESCs to undergo decidualization. Collectively, we found attenuation of HDAC3 and overexpression of collagen type I in the eutopic endometrium of infertile patients with endometriosis. HDAC3 loss caused a defect of decidualization through the aberrant transcriptional activation of Col1a1 and Col1a2 genes in mice and COL1A1 and COL1A2 genes in humans. Our results suggest that HDAC3 is critical for endometrial receptivity and decidualization.

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Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

January 9, 2019

Volume

11

Issue

474

Location

United States

Related Subject Headings

  • Young Adult
  • Stem Cells
  • Signal Transduction
  • Progesterone
  • Papio
  • Middle Aged
  • Mice, Inbred C57BL
  • Infertility, Female
  • Humans
  • Histone Deacetylases
 

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Kim, T. H., Yoo, J.-Y., Choi, K.-C., Shin, J.-H., Leach, R. E., Fazleabas, A. T., … Jeong, J.-W. (2019). Loss of HDAC3 results in nonreceptive endometrium and female infertility. Sci Transl Med, 11(474). https://doi.org/10.1126/scitranslmed.aaf7533
Kim, Tae Hoon, Jung-Yoon Yoo, Kyung-Chul Choi, Jung-Ho Shin, Richard E. Leach, Asgerally T. Fazleabas, Steven L. Young, Bruce A. Lessey, Ho-Geun Yoon, and Jae-Wook Jeong. “Loss of HDAC3 results in nonreceptive endometrium and female infertility.Sci Transl Med 11, no. 474 (January 9, 2019). https://doi.org/10.1126/scitranslmed.aaf7533.
Kim TH, Yoo J-Y, Choi K-C, Shin J-H, Leach RE, Fazleabas AT, et al. Loss of HDAC3 results in nonreceptive endometrium and female infertility. Sci Transl Med. 2019 Jan 9;11(474).
Kim, Tae Hoon, et al. “Loss of HDAC3 results in nonreceptive endometrium and female infertility.Sci Transl Med, vol. 11, no. 474, Jan. 2019. Pubmed, doi:10.1126/scitranslmed.aaf7533.
Kim TH, Yoo J-Y, Choi K-C, Shin J-H, Leach RE, Fazleabas AT, Young SL, Lessey BA, Yoon H-G, Jeong J-W. Loss of HDAC3 results in nonreceptive endometrium and female infertility. Sci Transl Med. 2019 Jan 9;11(474).

Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

January 9, 2019

Volume

11

Issue

474

Location

United States

Related Subject Headings

  • Young Adult
  • Stem Cells
  • Signal Transduction
  • Progesterone
  • Papio
  • Middle Aged
  • Mice, Inbred C57BL
  • Infertility, Female
  • Humans
  • Histone Deacetylases