FHL1抑制HOXA10蛋白乙酰化修饰促进胚胎着床的机制研究

Transcription factor HOXA10 is essential for embryo implantation, but the underlying mechanism of HOXA10 post-translational modification on embryo implantation needs to be uncovered. Our previous results demonstrate that enhanced HOXA10 acetylation impairs endometrial receptivity and embryo adhesion. Recently, we found that FHL1 expression was significantly lower in the endometrium of infertile women compared with the fertile controls, which impaired the endometrial stromal cells decidualization and embryo implantation, but the mechanisms are unclear. Our preliminary results demonstrate that FHL1 specifically interacts with and suppresses HOXA10 acetylation to promote its protein stability and transcriptional activity. We hypothesized that the aberrantly decreased expression of FHL1 in the endometrium might lead to endometrial development retardation and impair embryo implantation by promoting acetylation of HOXA10, which may be a novel mechanism underlying embryo implantation failure. This study will delineate the molecular mechanisms of embryo implantation through FHL1-regulated HOXA10 acetylation in vitro and in a uterine-specific Fhl1 knockout mouse model, to clarify why some infertile women after trearment with assistant reproductive technology develop impaired endometrial receptivity and embryo implantation.

转录因子HOXA10是胚胎着床最为关键的调控分子之一，其蛋白翻译后修饰改变与不孕患者胚胎种植失败密切相关，而且其调控分子或因素仍未明确。我们前期研究证实，HOXA10蛋白乙酰化修饰降低胚胎着床；进一步发现胚胎着床失败患者子宫内膜组织中FHL1表达显著下降，并影响子宫内膜间质细胞蜕膜化与胚胎着床，但机制不清。初步研究显示FHL1与HOXA10结合，抑制HOXA10蛋白乙酰化修饰，增加其稳定性与转录活性。推测这类患者子宫内膜组织中FHL1异常低表达，导致HOXA10蛋白乙酰化修饰增多，影响HOXA10功能，使子宫内膜容受性发生缺陷，可能是胚胎着床失败的一种新机制。本研究将重点从HOXA10乙酰化修饰角度探讨FHL1如何对胚胎着床产生影响；并利用Fhl1子宫特异性敲除小鼠整体实验研究FHL1调控胚胎着床的分子新机制，以期阐明部分不孕患者行辅助生殖治疗时子宫内膜容受性缺陷和胚胎着床率低下的原因。

辅助生殖技术临床实践中，反复种植失败患者胚胎植入失败的确切机制尚不清楚。本研究发现反复种植失败患者子宫内膜中FHL1的表达显著降低，并抑制囊胚-上皮细胞黏附导致胚胎种植失败。围绕FHL1抑制胚胎着床关键调控分子HOXA10蛋白乙酰化修饰促进胚胎着床的机制研究，我们明确FHL1在正常分泌期妇女子宫内膜上皮细胞中显著高表达，而在反复种植失败患者子宫内膜上皮细胞中表达降低。FHL1过表达促进囊胚-上皮粘附，干扰小鼠子宫中的FHL1表达显着抑制胚胎着床。机制研究表明，FHL1不调节HOXA10 mRNA表达，但增加HOXA10蛋白稳定性并促进其对下游靶基因的表达和整合素β3/FAK通路的调节。同时，筛选发现SIRT2特异性抑制剂参与调节FHL1对胚胎种植的调控，并证实FHL1通过促进HOXA10和SIRT2的结合调节HOXA10蛋白的乙酰化修饰。最后，我们也证实反复种植失败患者的子宫内膜上皮细胞中，FHL1和HOXA10与其下游靶基因表达的相关性。同时，初步发现敲除子宫中母源性FHL1的表达，导致小鼠子宫容受性建立失败，小鼠胚胎种植延迟。本项目的研究有望为寻求改善反复种植失败患者内膜容受状态，提供新的潜在治疗靶点。