AbstractRigorous exploration and dissection of potential actions and effects of long noncoding RNA (lncRNA) in animals remain challenging. Here using multiple knockout mouse models and single- cell RNA sequencing, we demonstrate that the divergent lncRNAHand2ashas a key, complex modulatory effect on the expression of its neighboring geneHAND2and subsequently on heart development and function, largely independent ofHand2astranscription and transcripts. Full-length deletion ofHand2asin mouse causes moderate yet prevalent upregulation ofHAND2in hundreds of cardiac cells, resulting in profound biological consequences, including dysregulated cardiac gene programs, congenital heart defects and perinatal lethality. We propose acis-functional role for theHand2aslocus in dampeningHAND2expression to restrain cardiomyocyte proliferation, thereby orchestrating a balanced development of cardiac cell lineages. This study highlights the need for complementary genetic and single-cell approaches to delineate the function and primary molecular effects of an lncRNA in animals.Impact statementThe long noncoding RNAHand2ascritically controls the precise expression of its neighboring geneHAND2, thereby balancing cardiac lineages and expression programs that are essential for heart development and function.
Sirt1 Antisense Long Noncoding RNA Promotes Cardiomyocyte Proliferation by Enhancing the Stability of Sirt1
