Elevated histone demethylase KDM5C increases recurrent miscarriage risk by preventing trophoblast proliferation and invasion

Min Xiao; Yan Zheng; Meng-Xi Wang; Yi-Hua Sun; Juan Chen; Kang-Yong Zhu; Fan Zhang; Yun-Hui Tang; Fan Yang; Ting Zhou; Yue-Ping Zhang; Cai-Xia Lei; Xiao-Xi Sun; Shan-He Yu; Fu-Ju Tian

doi:10.1038/s41420-022-01284-y

Elevated histone demethylase KDM5C increases recurrent miscarriage risk by preventing trophoblast proliferation and invasion

Cell Death Discov. 2022 Dec 22;8(1):495. doi: 10.1038/s41420-022-01284-y.

Authors

Min Xiao^#¹, Yan Zheng^#^{2

3}, Meng-Xi Wang^#⁴, Yi-Hua Sun⁵, Juan Chen⁴, Kang-Yong Zhu⁴, Fan Zhang⁴, Yun-Hui Tang⁶, Fan Yang⁵, Ting Zhou⁷, Yue-Ping Zhang¹, Cai-Xia Lei¹, Xiao-Xi Sun⁸, Shan-He Yu⁹, Fu-Ju Tian^{10

11}

Affiliations

¹ Shanghai Ji Ai Genetics and IVF Institute, the Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China.
² Department of Pancreatic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
³ Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
⁴ Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
⁵ Department of Pathology, the Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China.
⁶ Department of Family Planning, the Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China.
⁷ Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
⁸ Shanghai Ji Ai Genetics and IVF Institute, the Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China. steven3019@hotmail.com.
⁹ Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. yushanhe@shsmu.edu.cn.
¹⁰ The International Peace Maternity & Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China. fjtian@sibs.ac.cn.
¹¹ Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China. fjtian@sibs.ac.cn.

^# Contributed equally.

Abstract

KDM5C is a histone H3K4-specific demethylase, which has been shown to play a key role in biological disease and development. However, the role of KDM5C in trophoblasts at early pregnancy is currently unknown. Here, we showed that KDM5C was upregulated in placental trophoblasts from recurrent miscarriage (RM) patients compared with healthy controls (HCs). Trophoblast proliferation and invasion was inhibited by KDM5C overexpression and was promoted by KDM5C knockdown. Transcriptome sequencing revealed that elevated KDM5C exerted anti-proliferation and anti-invasion effects by repressing the expression of essential regulatory genes. The combination analysis of RNA-seq, ChIP-seq and CUT&Tag assay showed that KDM5C overexpression leads to the reduction of H3K4me3 on the promoters and the corresponding downregulation of expression of several regulatory genes in trophoblasts. Among these genes, TGFβ2 and RAGE are essential for the proliferation and invasion of trophoblasts. Importantly, overexpression of KDM5C by a systemically delivered KDM5C adenovirus vector (Ad-KDM5C) promoted embryo resorption rate in mouse. Our results support that KDM5C is an important regulator of the trophoblast function during early pregnancy, and suggesting that KDM5C activity could be responsible for epigenetic alterations seen RM disease.

Grants and funding

82071647/National Natural Science Foundation of China (National Science Foundation of China)