MAX deficiency impairs human endometrial decidualization through down-regulating OSR2 in women with recurrent spontaneous abortion.
MAX deficiency impairs human endometrial decidualization through down-regulating OSR2 in women with recurrent spontaneous abortion.
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MAX 缺乏通过下调反复自然流产女性的 OSR2 损害人类子宫内膜蜕膜化
DOI：
10.1007/s00441-022-03579-z
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发表时间：
2022-05
影响因子：
3.6
通讯作者：
中科院分区：
文献类型：
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作者：
人子宫基质细胞经历蜕膜形成和维持妊娠，这涉及到广泛的增殖和分化。越来越多的研究表明，复发性自然流产(RSA)可能是由于子宫内膜间质蜕膜化缺陷所致。然而，RSA中蜕膜化受损的关键分子机制仍不清楚。通过使用我们最近发表的单细胞RNA测序(scRNA-seq)图谱，我们发现MYC相关因子X(MAX)在RSA患者蜕膜组织来源的基质细胞中显著下调，随后通过免疫组织化学(IHC)和定量实时聚合酶链式反应(qRT-PCR)进行验证。MTS法和Ki67免疫组化检测结果显示，MAX基因敲除显著抑制人子宫内膜间质细胞(HESCs)的增殖，F-肌动蛋白和蜕膜化标记物检测其蜕膜化。应用RNA-SEQ、染色质免疫沉淀测序(CHIP-SEQ)和靶下裂解及核酸酶测序释放(CUT&RUN-SEQ)分析，探讨MAX调控蜕膜形成的分子机制，然后通过双荧光素酶报告基因分析，验证MAX直接靶向(奇数跳过的相关转录因子2)OSR2。免疫组织化学和定量逆转录聚合酶链式反应也证实OSR2在RSA患者蜕膜组织中表达降低。OSR2基因敲除也显著损害了hESCs的蜕膜化。OSR2的过表达至少可以部分挽救MAX基因敲除后下调的胰岛素样生长因子结合蛋白1(IGFBP1)的表达水平。总之，在RSA基质细胞中观察到的MAX缺乏不仅抑制hESCs的增殖，而且通过直接在转录水平下调OSR2的表达而损害hESCs的蜕膜形成。
Human uterine stromal cell undergoes decidualization for pregnancy establishment and maintenance, which involved extensive proliferation and differentiation. Increasing studies have suggested that recurrent spontaneous abortion (RSA) may result from defective endometrial stromal decidualization. However, the critical molecular mechanisms underlying impaired decidualization during RSA are still elusive. By using our recently published single-cell RNA sequencing (scRNA-seq) atlas, we found that MYC-associated factor X (MAX) was significantly downregulated in the stromal cells derived from decidual tissues of women with RSA, followed by verification with immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT-PCR). MAX knockdown significantly impairs human endometrial stromal cells (HESCs) proliferation as determined by MTS assay and Ki67 immunostaining, and decidualization determined by F-actin, and decidualization markers. RNA-seq together with chromatin immunoprecipitation sequencing (ChIP-seq) and cleavage under targets and release using nuclease sequencing (CUT&RUN-seq) analysis were applied to explore the molecular mechanisms of MAX in regulation of decidualization, followed by dual-luciferase reporter assay to verify that MAX targets to (odd-skipped related transcription factor 2) OSR2 directly. Reduced expression of OSR2 was also confirmed in decidual tissues in women with RSA by IHC and qRT-PCR. OSR2 knockdown also significantly impairs HESCs decidualization. OSR2-overexpression could at least partly rescue the downregulated insulin-like growth factor binding protein 1 (IGFBP1) expression level in response to MAX knockdown. Collectively, MAX deficiency observed in RSA stromal cells not only attenuates HESCs proliferation but also impairs HESCs decidualization by downregulating OSR2 expression at transcriptional level directly.
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