Tissue-specific lncRNA GATA6-AS1 and its ortholog Moshe as essential regulators of aortic valve development
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Long noncoding RNAs (lncRNAs) are integral to epigeneticregulation during cardiogenesis; however, their role in aorticvalve disease is not well characterized. Investigating lncRNAspresent in the human embryonic heart and pinpointing theirspecific isoforms presents notable challenges due to both technicaland ethical limitations. In our research, we identified GATA6-AS1 as a lncRNA predominantly found in the heart by analyzingpublicly accessible RNA sequencing data derived fromhuman embryonic tissues. Employing in vitro models along withCS17 embryonic heart tissue, we determined that isoforms 202and 208 of GATA6-AS1 are uniquely expressed in cardiacneural crest lineage cells throughout the development of the aorticvalve. We also identified Moshe, the murine ortholog ofGATA6-AS1, whose expression occurs during aortic valve formationin mice. Notably, depletion of Moshe results in the developmentof bicuspid aortic valves (BAV), accompanied by a significantdownregulation of genes associated with BAV, particularlythose related to the Notch and TGF- signaling pathways. These findings highlight the critical role of GATA6-AS1 in aorticvalve development through the study of its mouse orthologMoshe. They also suggest that lncRNAs, still underexplored in congenitalheart disease research, may hold significant implications forBAV pathogenesis and potential therapeutic strategies.
Abstract
Long noncoding RNAs (lncRNAs) are integral to epigeneticregulation during cardiogenesis; however, their role in aorticvalve disease is not well characterized. Investigating lncRNAspresent in the human embryonic heart and pinpointing theirspecific isoforms presents notable challenges due to both technicaland ethical limitations. In our research, we identified GATA6-AS1 as a lncRNA predominantly found in the heart by analyzingpublicly accessible RNA sequencing data derived fromhuman embryonic tissues. Employing in vitro models along withCS17 embryonic heart tissue, we determined that isoforms 202and 208 of GATA6-AS1 are uniquely expressed in cardiacneural crest lineage cells throughout the development of the aorticvalve. We also identified Moshe, the murine ortholog ofGATA6-AS1, whose expression occurs during aortic valve formationin mice. Notably, depletion of Moshe results in the developmentof bicuspid aortic valves (BAV), accompanied by a significantdownregulation of genes associated with BAV, particularlythose related to the Notch and TGF- signaling pathways. These findings highlight the critical role of GATA6-AS1 in aorticvalve development through the study of its mouse orthologMoshe. They also suggest that lncRNAs, still underexplored in congenitalheart disease research, may hold significant implications forBAV pathogenesis and potential therapeutic strategies.