The role of SMC3 in heart development by regulating super-enhancer associated genes

Abnormal cardiac development has been observed in individuals with Cornelia de Lange Syndrome (CdLS) due to mutations in genes encoding members of the cohesin complex. But the precise role of cohesin in heart development remains elusive. In this study, we aimed to elucidate the indispensable role of SMC3, a component of the cohesin complex, in cardiac development and its underlying mechanism. Our investigation revealed an association between SMC3 mutations and congenital heart disease (CHD) in CdLS patients. To further explore this relationship, we utilized heart-specific Smc3-knockout (SMC3-cKO) mice, which displayed varying degrees of outflow tract (OFT) abnormalities. Additionally, we identified 16 rare SMC3 variants with potential pathogenicity in individuals with isolated CHD. Employing single nucleus RNA sequencing and 3C-high-throughput genome-wide translocation sequencing, we unveiled that Smc3 deletion downregulates the expression of key genes, including Ets2, in OFT cardiac muscle cells by specifically decreasing interactions between super-enhancers (SE) and promoters. Notable, Ets2-SE-null mice also exhibit delayed OFT development in the heart. Our research uncovers a novel role for SMC3 in heart development by regulating SE-associated genes, suggesting its potential relevance as one of the CHD-related genes and providing crucial insights into the molecular basis of cardiac development. Transcriptome profiles and pair-wise chromatin interactions of diverse cell types were examined from different viewpoints respectively before or/and after SMC3 knock down (duplicates), respectively.