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

Area of Science:

• Epigenetics
• Reproductive Biology
• Molecular Genetics

Background:

• Pathogenic variants in NLRP7 gene are linked to 55% of recurrent hydatiform mole cases.
• Recurrent hydatiform mole is characterized by hypomethylation in maternally methylated imprinted regions.
• NLRP7 variants are proposed to disrupt de novo DNA methylation in human oocytes, but the mechanism is unclear.

Purpose of the Study:

• To elucidate the mechanism by which NLRP7 variants cause recurrent hydatiform mole.
• To identify NLRP7-interacting partners involved in de novo DNA methylation.
• To understand the role of NLRP7 in safeguarding the oocyte methylome.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine the structure of the NLRP7-TCL1A complex.
• Interaction analysis to assess the impact of NLRP7 variants on TCL1A binding.
• In silico predictions and interaction analysis to identify pathogenic variants.

Main Results:

• TCL1A, a DNMT3A inhibitor, was identified as an endogenous NLRP7-interacting partner.
• The cryo-EM structure of the NLRP7-TCL1A complex was resolved.
• Most recurrent hydatiform mole-associated NLRP7 variants impair interaction with TCL1A.
• NLRP7 sequesters TCL1A in the cytoplasm, preventing nuclear entry and DNMT3A inhibition.
• The pathogenic variant L766R was identified.

Conclusions:

• NLRP7 safeguards the oocyte methylome by regulating TCL1A localization.
• This cytoplasmic sequestration mechanism prevents the suppression of DNMT3A-mediated de novo methylation.
• The findings explain the hypomethylation pathogenesis in NLRP7 variant-associated recurrent hydatiform mole.
• A novel cytoplasmic regulatory mechanism for nuclear DNA methylation is proposed.