NLRP7 maintains the genomic stability during early human embryogenesis via mediating alternative splicing

Genomic instability is the main cause of abnormal embryo development and abortion. NLRP7 dysfunctions affect embryonic development and lead to recurrent pregnancy loss (RPL) or hydatidiform moles (HM), but the underlying mechanisms remain largely elusive. In this study, we found that NLRP7 knockout affected the genetic stability, resulting in increased DNA damage in both human embryonic stem cells (hESCs) and blastoids, making embryonic cells in blastoids more susceptible to apoptosis. Mechanistically, NLRP7 could interact with factors related to alternative splicing (AS) and DNA damage response (DDR), including DDX39B, PRPF8, THRAP3 and PARP1, and its dysfunction led to abnormal AS of genes involved in Homologous recombination (HR) in hESCs, indicating that NLRP7-mediated AS is required for the maintenance of genome integrity during early human embryogenesis. Together, this study first uncovers that NLRP7 plays an essential role in the maintenance of genetic stability during early human embryonic development by regulating AS of HR-related genes. To investigate the involvement of NLRP7 in maintaining the genetic stability in early human embryonic cells, we established a NLRP7 knockout cell line using CRISPR/Cas9 gene-editing technology