Loss of GLTSCR1 causes congenital heart defects by regulating NPPA transcription

Precise and specific spatiotemporal domains of gene expression regulation is critical for embryonic development. Recent studies have identified GLTSCR1 as a gene transcriptional elongation regulator in cancer research. However, the function of GLTSCR1, especially in embryonic development, remains poorly understood. Here, we found that GLTSCR1 is essential for cardiac development because Gltscr1 knockout (Gltscr1 −/− ) led to embryonic lethality in mice with severe congenital heart defects (CHDs). Ventricular septal defect (VSD) and double outflow right ventricular (DORV) were also observed in conditional deletion of Gltscr1 in neural crest cells, which was associated with neonatal lethality in mice. Mechanistically, GLTSCR1 deletion promoted NPPA expression by coordinating the CHD risk G allele of rs56153133 in the NPPA enhancer and releasing the transcription factor ZNF740 binding site on the NPPA promoter. These findings demonstrate that GLTSCR1 acts as a candidate CHD-related gene.