TCL1A Mediates DNA Methylation Defects in NLRP7 Mutation-Associated Recurrent Hydatidiform Mole (PRJCA045356)
Pathogenic NLRP7 variants, implicated in 55% of recurrent hydatidiform moles (RHM) with hypomethylation at maternal imprinting are suggested to disrupt de novo DNA methylation in human oocytes. However, the precise molecular mechanism remains to be elucidated. Here, we identify TCL1A, an DNA methyltransferase 3A (DNMT3A) inhibitor, as an endogenous NLRP7-interacting partner. The cryo-EM structure of NLRP7-TCL1A complex provides crucial insights into their architecture. Comprehensive analysis reveals that the majority of RHM-associated missense and truncation mutations in NLRP7 impair the 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. In this project, we examined the DNA methylation levels in germinal vesicle (GV) stage oocytes from NLRP5 and FILIA knockout mouse models, as well as the effect of TCL1A overexpression on de novo DNA methylation during the conversion of mouse embryonic stem cells (ESCs) to formative pluripotent stem cells (fPSCs)