Key result
CRISPR/Cas9 knockdown of STX18-AS1 cuts human embryonic stem cell differentiation into beating cardiomyocytes by ~78%.
Why the study?
Previous GWAS identified a chromosome 4p16 region associated with ASD risk, but the responsible gene and disease mechanisms were unclear.
Absolute Event Rate: 20% vs 90%
p-value: p=<0.001
The long noncoding RNA STX18-AS1 predisposes to Atrial Septal Defect by downregulating NKX2-5 and impairing cardiomyocyte differentiation.
STX18-AS1 may contribute to ASD pathogenesis; leaves open its therapeutic relevance pending in vivo confirmation.
Previous genome-wide association studies (GWAS) have identified a region of chromosome 4p16 associated with the risk of Atrial Septal Defect (ASD), which is among the commonest Congenital Heart Disease (CHD) phenotypes. Here, we identify the responsible gene in the region and elucidate disease mechanisms. Linkage disequilibrium in the region, eQTL analyses in human atrial tissues, and spatio-temporal gene expression studies in human embryonic hearts concordantly suggested the long noncoding RNA (lncRNA) STX18-AS1 as the causative gene in the region. Using CRISPR/Cas9 knockdown in HepG2 cells, STX18-AS1 was shown to regulate the expression of the key cardiac transcription factor NKX2-5 via a trans- acting effect on promoter histone methylation. Furthermore, STX18-AS1 knockdown depleted the potential of human embryonic stem cells (H9) to differentiate into cardiomyocytes, without affecting their viability and pluripotency, providing a mechanistic explanation for the clinical association.
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Liu et al. (2020) studied Atrial Septal Defect (n=108). STX18-AS1 CRISPR knockdown vs. Control CRISPR was evaluated on Proportion of wells with beating cardiomyocytes at Day 8 (p=<0.001). CRISPR/Cas9 knockdown of the long noncoding RNA STX18-AS1 significantly reduced the differentiation of human embryonic stem cells into beating cardiomyocytes from 90% to 20%.
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