An endogenous retrovirus-derived long non-coding RNA promotes fetal cardiomyocyte migration in primates

The protein-coding gene networks regulating heart development are well known. Less understood are the roles of long non-coding RNAs (lncRNAs), many of which are poorly conserved due to their origins from transposable elements (TEs) such as endogenous retroviruses (ERVs). Here, we report hundreds of ERV elements from the primate-specific MER41 family are expressed in pluripotent cell-derived cardiomyocytes and fetal heart, some of which are regulated by the cardiogenic transcription factor TBX5. The most significant of these are located within BANCR, an lncRNA exclusively expressed in primate fetal cardiomyocytes in normal physiology. Surprisingly, BANCR promotes cellular movement in fetal cardiomyocytes, which is due in part to Rho GTPase and ephrin receptor signaling. We postulate that ERV-derived BANCR is a recent evolutionary mechanism for enabling larger heart sizes in primates, and underscores the remarkable retroviral origins of humans. Overall design: We performed RNA-seq of human fetal tissues, and iPSCs and cardiomyocytes derived from iPSCs (iPSC-CMs) in both human and non-human primate cell lines (chimpanzee, gorilla, rhesus macaque). We also performed both RNA- and ATAC-seq of hESC-CMs with constitutive BANCR shRNA knockdown (BKD), lentiviral constitutive over-expression (BOE), as well as H3K27ac HiChIP in human iPSC-CMs. RNA-seq was also performed on E16 transgenic mouse embryo hearts with human BANCR expression, and compared with littermate control hearts. YAP1 ChIP-seq was performed with anti-YAP1 antibody (Novus; NB110).