Loss of HDAC3 results in nonreceptive endometrium and female infertility.

Abstract

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 <i>Hdac3</i> in progesterone receptor (PGR)-positive cells (<i>Pgr^cre/+Hdac3^f/f</i> ; <i>Hdac3^d/d</i> ). Loss of <i>Hdac3</i> in the uterus of mice results in infertility due to implantation failure and decidualization defect. Expression microarray and ChIP-seq analyses identified <i>COL1A1</i> and <i>COL1A2</i> as direct targets of HDAC3 in both mice and humans. Reduction of <i>HDAC3</i> abrogated decidualization in a primary culture of human endometrial stromal cells (hESCs) similar to that observed in infertile patients with endometriosis. Whereas attenuation of <i>HDAC3</i> resulted in p300 recruitment to <i>Col1a1</i> and <i>Col1a2</i> 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 <i>Col1a1</i> and <i>Col1a2</i> genes in mice and <i>COL1A1</i> and <i>COL1A2</i> genes in humans. Our results suggest that HDAC3 is critical for endometrial receptivity and decidualization.