3 years ago

[Research Articles] Loss of HDAC3 results in nonreceptive endometrium and female infertility

Tae Hoon Kim, Jung-Yoon Yoo, Kyung-Chul Choi, Jung-Ho Shin, Richard E. Leach, Asgerally T. Fazleabas, Steven L. Young, Bruce A. Lessey, Ho-Geun Yoon, Jae-Wook Jeong

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.

Publisher URL: http://stm.sciencemag.org/cgi/content/short/11/474/eaaf7533

DOI: 10.1126/scitranslmed.aaf7533

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