Loss of HDAC3 results in nonreceptive endometrium and female infertility
Loss of HDAC3 results in nonreceptive endometrium and female infertility
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DOI：
10.1126/scitranslmed.aaf7533
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发表时间：
2019-01-09
影响因子：
17.1
通讯作者：
Jeong, Jae-Wook
中科院分区：
文献类型：
--
作者：
Kim, Tae Hoon;Yoo, Jung-Yoon;Jeong, Jae-Wook
子宫内膜异位症是一种正常生长在子宫内的组织生长到子宫外的疾病，导致慢性盆腔疼痛和不孕症。然而，子宫内膜异位症相关不孕症的确切发病机制尚不清楚。表观遗传失调最近被认为与不孕症有关。在这里，我们报告了与对照组相比，患有子宫内膜异位症的不孕妇女的异位子宫内膜中组蛋白去乙酰化酶3 （HDAC3）蛋白量的减少。为了研究HDAC3在子宫内丢失的影响，我们在孕激素受体（PGR）阳性细胞(PGR （cre/+) HDAC3 (f/f)）中条件消融HDAC3的小鼠；Hdac3 (d / d))。小鼠子宫中Hdac3缺失会导致着床失败和脱胎化缺陷导致不孕。表达芯片和ChIP-seq分析发现COL1A1和COL1A2在小鼠和人类中都是HDAC3的直接靶点。在原代培养的人子宫内膜基质细胞（hESCs）中，HDAC3的减少可以消除去个体化，这与在患有子宫内膜异位症的不育症患者中观察到的情况相似。尽管HDAC3的衰减导致p300在小鼠子宫和hESCs中募集到Col1a1和Col1a2基因，但抑制p300允许hESCs经历去个体化。总的来说，我们发现HDAC3的衰减和I型胶原蛋白在子宫内膜异位症不孕患者的异位子宫内膜中过表达。HDAC3缺失通过小鼠Col1a1和Col1a2基因以及人类Col1a1和Col1a2基因的异常转录激活导致去个体化缺陷。我们的研究结果表明，HDAC3对子宫内膜容受性和去个体化至关重要。
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 (Pgr(cre/+)Hdac3(f/f); Hdac3(d/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.