TCL1A mediates DNA methylation defects in recurrent hydatidiform mole with NLRP7 pathogenic variants

Nat Commun. 2026 Mar 5;17(1):2160. doi: 10.1038/s41467-026-69744-y.

Zheng Gao ^# ¹ ², Qingting Liu ^# ³, Lei Li ^# ¹, Ting Hu ^# ⁴, Xukun Lu ⁵, Yu Wu ², Dandan Qin ², Xiaoxiao Wang ², Chen Gu ², Jinhong Li ³, Chengpeng Xu ², Dan Zhou ², Fan Zhou ⁴, YanLing Bai ¹, Xiangjin Kang ¹, Jianqiao Liu ⁶, Dong Deng ⁷, Lei Li ⁸

Affiliations

1 Department of Obstetrics and Gynecology, Center for Reproductive Medicine; Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; Key Laboratory for Reproductive Medicine of Guangdong Province; The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
2 The Key Laboratory of Organ Regeneration and Reconstruction, Beijing Institute of Stem Cell and Regenerative Medicine, Institute of Zoology; University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China.
3 Division of Obstetrics, Key Laboratory of Birth Defects and Related Disease of Women and Children of Ministry of Education, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Chengdu, China.
4 Department of Medical Genetics, Key Laboratory of Birth Defects and Related Disease of Women and Children of Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China.
5 Institute of Women, Children and Reproductive Health, State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, China.
6 Department of Obstetrics and Gynecology, Center for Reproductive Medicine; Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; Key Laboratory for Reproductive Medicine of Guangdong Province; The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China. [email protected].
7 Division of Obstetrics, Key Laboratory of Birth Defects and Related Disease of Women and Children of Ministry of Education, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Chengdu, China. [email protected].
8 The Key Laboratory of Organ Regeneration and Reconstruction, Beijing Institute of Stem Cell and Regenerative Medicine, Institute of Zoology; University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China. [email protected].
# Contributed equally.

PMID: 41786744 DOI: 10.1038/s41467-026-69744-y

Abstract

Pathogenic variants in NLRP7, implicated in 55% of recurrent hydatidiform mole characterized by hypomethylation at maternally methylated imprinted regions, are proposed to disrupt de novo DNA methylation in human oocytes. However, the precise mechanism remains unclear. Here, we identify TCL1A, a DNMT3A inhibitor, as an endogenous NLRP7-interacting partner. The cryo-EM structure of the NLRP7-TCL1A complex reveals its fundamental architecture. Comprehensive analysis demonstrates that the majority of recurrent hydatidiform mole-causing NLRP7 variants impair its interaction with TCL1A. Mechanistically, NLRP7 potentially safeguards oocyte methylome by sequestering TCL1A in the cytoplasm, thereby preventing its nuclear entry and subsequent suppression of DNMT3A-mediated de novo methylation. Combining in silico predictions and interaction analysis, we identify L766R as a pathogenic variant. These findings propose a cytoplasmic regulatory mechanism governing nuclear DNA methylation, explaining the hypomethylation pathogenesis in NLRP7 variant-associated recurrent hydatidiform mole.

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