Trophoblast PR-SET7 dysfunction induces viral mimicry response and necroptosis associated with recurrent miscarriage.
Trophoblast PR-SET7 dysfunction induces viral mimicry response and necroptosis associated with recurrent miscarriage.
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DOI：
10.1073/pnas.2216206120
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发表时间：
2023-06-20
影响因子：
11.1
通讯作者：
Lu, Jinhua
中科院分区：
文献类型：
--
作者：
Zhou, Xiaobo;Xu, Yingchun;Ren, Shengnan;Yang, Ningjie;Sun, Yang;Yang, Qibing;Zhang, Yue;Cai, Han;Deng, Wenbo;Chen, Jingsi;Chen, Dunjin;Cao, Bin;Qi, Hongbo;Wang, Haibin;Lu, Jinhua
胎盘对妊娠期间胎儿的生存和发育至关重要。滋养层细胞是胎盘的主要细胞成分，任何对滋养层细胞的干扰都可能导致妊娠障碍。PR-SET 7是催化H4 K20（H4 K20 me 1）单甲基化的甲基转移酶，但它在滋养层中的功能尚不清楚。在目前的工作中，我们证明，PR-SET 7介导的H4 K20 me 1和H4 K20 me 3是必要的内源性逆转录病毒（ERVs）的转录抑制，防止双链RNA应力和随后压倒性的干扰素反应和坏死性凋亡的滋养层。重要的是，PR-SET 7表达和H4 K20 me 1的失调与复发性流产的发生有关。我们的研究结果揭示了一个表观遗传机制的重要性，滋养层细胞和胎盘的发展，潜在的发病机制，反复流产的妇女。复发性流产（RM）是一种令人痛苦的妊娠并发症。虽然RM的病因尚不清楚，但越来越多的证据表明滋养细胞损伤与RM的发病机制相关。PR-SET 7是催化H4 K20（H4 K20 me 1）的单甲基化的唯一酶，并且已经涉及许多病理生理过程。然而，PR-SET 7如何在滋养层细胞中发挥作用及其与RM的相关性仍然未知。在这里，我们发现小鼠中滋养层特异性Pr-set 7的丢失导致滋养层缺陷，导致早期胚胎丢失。机制分析显示，滋养层中的PR-SET 7缺陷使内源性逆转录病毒（ERVs）去抑制，导致双链RNA应激和随后的病毒模拟，这驱动了压倒性的干扰素应答和坏死性凋亡。进一步的研究发现H4 K20 me 1和H4 K20 me 3介导ERVs细胞内表达的抑制。重要的是，在RM的胎盘中观察到PR-SET 7表达的失调和相应的异常表观遗传修饰。总的来说，我们的研究结果表明，PR-SET 7作为一种表观遗传转录调节因子，对抑制滋养层细胞中的ERVs至关重要，确保正常妊娠和胎儿存活，这为RM的潜在表观遗传原因提供了新的线索。
The placenta is essential for fetal survival and development during pregnancy. Any disturbance to trophoblasts, the main cellular components of the placenta, could lead to pregnancy disorders. PR-SET7 is the methyltransferase catalyzing monomethylation of H4K20 (H4K20me1), but how it functions in trophoblasts is unclear. In the present work, we demonstrate that PR-SET7-mediated H4K20me1 and H4K20me3 are essential for repressing transcription of endogenous retroviruses (ERVs), preventing double-stranded RNA stress and subsequent overwhelming interferon response and necroptosis in trophoblasts. Importantly, dysregulation of PR-SET7 expression and H4K20me1 is associated with the occurrence of recurrent miscarriage. Our findings reveal an epigenetic mechanism important for the maintenance of trophoblast and placental development potentially underlying the pathogenesis of recurrent miscarriage in women. Recurrent miscarriage (RM) is a distressing pregnancy complication. While the etiology of RM remains unclear, growing evidence has indicated the relevance of trophoblast impairment to the pathogenesis of RM. PR-SET7 is the sole enzyme catalyzing monomethylation of H4K20 (H4K20me1) and has been implicated in many pathophysiological processes. However, how PR-SET7 functions in trophoblasts and its relevance to RM remain unknown. Here, we found that trophoblast-specific loss of Pr-set7 in mice led to defective trophoblasts, resulting in early embryonic loss. Mechanistic analysis revealed that PR-SET7 deficiency in trophoblasts derepressed endogenous retroviruses (ERVs), leading to double-stranded RNA stress and subsequent viral mimicry, which drove overwhelming interferon response and necroptosis. Further examination discovered that H4K20me1 and H4K20me3 mediated the inhibition of cell-intrinsic expression of ERVs. Importantly, dysregulation of PR-SET7 expression and the corresponding aberrant epigenetic modifications were observed in the placentas of RM. Collectively, our results demonstrate that PR-SET7 acts as an epigenetic transcriptional modulator essential for repressing ERVs in trophoblasts, ensuring normal pregnancy and fetal survival, which sheds new light on potential epigenetic causes contributing to RM.
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DOI：
10.1038/nri3665
发表时间：
2014-05
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
24.5
作者：
Južnić L;Peuker K;Strigli A;Brosch M;Herrmann A;Häsler R;Koch M;Matthiesen L;Zeissig Y;Löscher BS;Nuber A;Schotta G;Neumeister V;Chavakis T;Kurth T;Lesche M;Dahl A;von Mässenhausen A;Linkermann A;Schreiber S;Aden K;Rosenstiel PC;Franke A;Hampe J;Zeissig S
通讯作者：
Zeissig S
影响因子：
9.2
作者：
Fang, J;Feng, Q;Zhang, Y
通讯作者：
Zhang, Y
EZH2下调引起的滋养层侵袭减弱与人类复发性流产的发病机制有关。
影响因子：
8.8
作者：
Lv, Shijian;Wang, Na;Chen, Zi-Jiang
通讯作者：
Chen, Zi-Jiang
影响因子：
4.6
作者：
Kurup, Jiji T.;Han, Zhijun;Kidder, Benjamin L.
通讯作者：
Kidder, Benjamin L.