Abstract P2056: A Micropeptide Encoded By An Endogenous Retroviral-derived Lncrna Regulates Cardiomyocyte Multinucleation

Abstract

Endogenous retroelements (REs) are pervasive in mammalian genomes, and consist mostly of silenced mobile genetic sequences long considered to be ‘junk DNA.’ In a few known instances, mammalian genomes have captured and repurposed endogenous retroviral sequences to play important roles in regulating mammalian cell functions, notably cell fusion. Our previous work has shown that some mammalian transcripts misannotated as lncRNAs can be translated into small functional peptides, called micropeptides. Here we report the discovery of a cardiac-specific micropeptide encoded by a misannotated lncRNA transcribed from a murine endogenous retroviral element. We named this transcript CARDI, and the encoded micropeptide CARDI-B, since translation of the micropeptide occurs from the second ATG start codon. We show that CARDI-B shares homology with a singular domain of a retroviral protein and localizes to the nucleus. Genetic deletion of CARDI-B in mice from an isogenic background significantly increased the frequency of binucleated cardiomyocytes, at the expense of mononucleated cardiomyocytes. In line with previous reports that the frequency of mononucleated cardiomyocytes is correlated with cardiac regeneration, we show that CARDI-B-deficient hearts perform worse following myocardial infarction injury. These data reveal that functional micropeptides can be concealed within mammalian retroelements, and suggests that RE-derived micropeptides may contribute to the natural variation in heart development and regeneration observed across species.