Trophoblast PR-SET7 dysfunction induces viral mimicry response and necroptosis associated with recurrent miscarriage

作者全名："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"

作者地址："[Zhou, Xiaobo; Xu, Yingchun; Ren, Shengnan; Yang, Ningjie; Sun, Yang; Yang, Qibing; Zhang, Yue; Cai, Han; Deng, Wenbo; Cao, Bin; Wang, Haibin; Lu, Jinhua] Xiamen Univ, Affiliated Hosp 1, Sch Med, Dept Obstet & Gynecol, Xiamen 361102, Fujian, Peoples R China; [Zhou, Xiaobo] Chongqing Med Univ, Dept Obstet & Gynecol, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Chen, Jingsi; Chen, Dunjin] Guangzhou Med Univ, Dept Obstet & Gynecol, Key Lab Major Obstet Dis Guangdong Prov, Affiliated Hosp 3, Guangzhou 510150, Peoples R China; [Qi, Hongbo] Chongqing Med Univ, Dept Obstet & Gynecol, Women & Childrens Hosp, Chongqing 400016, Peoples R China"

通信作者："Cao, B; Wang, HB; Lu, JH (通讯作者)，Xiamen Univ, Affiliated Hosp 1, Sch Med, Dept Obstet & Gynecol, Xiamen 361102, Fujian, Peoples R China.; Qi, HB (通讯作者)，Chongqing Med Univ, Dept Obstet & Gynecol, Women & Childrens Hosp, Chongqing 400016, Peoples R China."

来源：PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

ESI学科分类：Multidisciplinary

WOS号：WOS:001039509300001

JCR分区：Q1

影响因子：9.4

年份：2023

卷号：120

期号：25

开始页：　

结束页：　

文献类型：Article

关键词：PR-SET7; 3; ERVs; viral mimicry; recurrent miscarriage

摘要："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 mon-omethylation of H4K20 (H4K20me1) and has been implicated in many pathophysio-logical processes. However, how PR- SET7 functions in trophoblasts and its relevance to RM remain unknown. Here, we found that trophoblast-specific loss of Pr-set7in 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."

基金机构："National Key Ramp;D Program of China [2022YFC2702400, 2022YFC2704700, 2022YFC2702500, 2021YFC2700302]; National Natural Science Foundation of China [82288102, 81830045, 31971071, 82171660, 82201887, 32000807]; Fujian Natural Science Foundation [2020J05006]; Science and Technology Program of Guangzhou, China [202102010006]"

基金资助正文："We thank S. B. Kong and X. W. Lv for their scientific advice. This work was supported in parts by the National Key R & amp;D Program of China (2022YFC2702400 and 2022YFC2704700 to J.L., 2022YFC2702500 and 2021YFC2700302 to H.W.) , National Natural Science Foundation of China (82288102 to H.W., 81830045 to D.C., 31971071 and 82171660 to J.L., 82201887 to X.Z., 32000807 to H.C.) , Fujian Natural Science Foundation (2020J05006 to H.C.) , and Science and Technology Program of Guangzhou, China (202102010006 to D.C.) ."