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 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 ChlP-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.

Loss of CDYL Results in Suppression of CTNNB1 and Decreased Endometrial Receptivity

“…Epigenetic modifications mainly refer to the DNA methylation and histone modifications, of which histone methylation and acetylation are most studied (Zhou et al, 2011), that aberrant epigenetic modifications may be associated with the progress of endometriosis (Izawa et al, 2013;Forte et al, 2014;Zhang et al, 2017), recurrent miscarriage (Arias-Sosa et al, 2018;Yu et al, 2018), and implantation failure. For instance, HDAC3 is critical for endometrial receptivity, such that loss of HDAC3 caused an impaired decidualization through the abnormal activation of COL1A1/2 genes in humans (Kim and Yoo, 2019).…”

Does the Act of Copulation per se, without Considering Seminal Deposition, Change the Expression of Genes in the Porcine Female Genital Tract?

“…It is thus logical to suggest, based on the results of the present study, that uterine ACKR3 may be responsible of reducing chemokine activity in the pig endometrium towards the establishment of a state of maternal sperm tolerance [92]. By the same line of reasoning, a downregulation of collagen alpha-2 (I) chain (COL1A2) may contribute to prepare the endometrium to the presence of hemi-allogeneic embryos, as it occurs in other species [93,94]. The fact that copulation downregulated β-1,4-galactosyltransferase 1 (B4GALT1) during this period should not be surprising.…”

Histone acetylation and the role of histone deacetylases in normal cyclic endometrium

“…A recently published study on mice demonstrated that loss of HDAC 3 in the uterus of mice leads to implantation failures. Interestingly, HDAC 3 is usually the least frequently expressed HDAC in the endometrial tissue [7,10]. In the study, HDAC 3 was shown to be involved in transcription activation of COL1A1 and COL1A2 (collagenase) genes in humans and col1a1 and col1a2 genes in mice [7].…”

“…Interestingly, HDAC 3 is usually the least frequently expressed HDAC in the endometrial tissue [7,10]. In the study, HDAC 3 was shown to be involved in transcription activation of COL1A1 and COL1A2 (collagenase) genes in humans and col1a1 and col1a2 genes in mice [7]. Collagenases are involved in endometrial remodelling and trophoblast invasion during implantation [91].…”

“…HDACs also play a crucial role in implantation and decidualization. Loss of HDAC 3 is linked to decidualization defects and implantation failure in mice [7]. HDAC inhibitor TSA in endometrial stromal cells negatively regulates trophoblast invasion and facilitates decidualization, influencing embryo implantation [91,95] (Fig.…”