Long noncoding RNAs (lncRNAs) are emerging as important regulators of 
developmental pathways. However, their roles in human cardiac precursor cell 
(CPC) remain unexplored. To characterize the long noncoding transcriptome during 
human CPC cardiac differentiation, we profiled the lncRNA transcriptome in CPCs 
isolated from the human fetal heart and identified 570 lncRNAs that were 
modulated during cardiac differentiation. Many of these were associated with 
active cardiac enhancer and super enhancers (SE) with their expression being 
correlated with proximal cardiac genes. One of the most upregulated lncRNAs was 
a SE-associated lncRNA that was named CARMEN, (CAR)diac (M)esoderm 
(E)nhancer-associated (N)oncoding RNA. CARMEN exhibits RNA-dependent enhancing 
activity and is upstream of the cardiac mesoderm-specifying gene regulatory 
network. Interestingly, CARMEN interacts with SUZ12 and EZH2, two components of 
the polycomb repressive complex 2 (PRC2). We demonstrate that CARMEN knockdown 
inhibits cardiac specification and differentiation in cardiac precursor cells 
independently of MIR-143 and -145 expression, two microRNAs located proximal to 
the enhancer sequences. Importantly, CARMEN expression was activated during 
pathological remodeling in the mouse and human hearts, and was necessary for 
maintaining cardiac identity in differentiated cardiomyocytes. This study 
demonstrates therefore that CARMEN is a crucial regulator of cardiac cell 
differentiation and homeostasis.