Tissue-specific lncRNA GATA6-AS1 and its ortholog Moshe as essential regulators of aortic valve development.

Abstract

Long noncoding RNAs (lncRNAs) are integral to epigenetic regulation during cardiogenesis; however, their role in aortic valve disease is not well characterized. Investigating lncRNAs present in the human embryonic heart and pinpointing their specific isoforms presents notable challenges due to both technical and ethical limitations. In our research, we identified GATA6-AS1 as a lncRNA predominantly found in the heart by analyzing publicly accessible RNA sequencing data derived from human embryonic tissues. Employing in vitro models along with CS17 embryonic heart tissue, we determined that isoforms 202 and 208 of GATA6-AS1 are uniquely expressed in cardiac neural crest lineage cells throughout the development of the aortic valve. We also identified Moshe, the murine ortholog of GATA6-AS1, whose expression occurs during aortic valve formation in mice. Notably, depletion of Moshe results in the development of bicuspid aortic valves (BAV), accompanied by a significant downregulation of genes associated with BAV, particularly those related to the Notch and TGF-β signaling pathways. These findings highlight the critical role of GATA6-AS1 in aortic valve development through the study of its mouse ortholog Moshe. They also suggest that lncRNAs, still underexplored in congenital heart disease research, may hold significant implications for BAV pathogenesis and potential therapeutic strategies.