MyoD-induced circular RNA CDR1as promotes myogenic differentiation of skeletal muscle satellite cells

Abstract

Many protein coding and non-coding genes interplay in governing skeletal muscle formation. Nevertheless, comparing with the linear transcripts, functions of covalently closed circular RNAs (circRNAs), the new frontier of regulatory non-coding RNA (ncRNAs) molecules, remain largely unknown. Here, we identify CDR1as (antisense to the cerebellar degeneration-related protein 1 transcript, also termed as ciRS-7), a well-known cancer and neuron circRNA, plays a significant role in virtually controlling muscle differentiation. CDR1as is highly expressed in muscles of the mid-embryonic goat foetus, and activated at the initiation of myogenic differentiation in vitro. MyoD (myogenic differentiation protein 1), a driven transcription factor for myogenesis, promotes CDR1as by binding on its 5′ flank region (−646 to −634 bp, neighbouring the predicted transcription start site at −580 bp). Overexpression or knockdown of CDR1as dramatically induces or impedes muscle differentiation program, respectively. By competitively binding to miR-7 (microRNA 7), CDR1as relieves the downregulation of IGF1R (insulin like growth factor 1 receptor) caused by miR-7 and consequently activates muscle differentiation. These results unveil that CDR1as plays critical roles in myogenic differentiation, which extends the versatile functions of CDR1as in mammal development and disease.