A feedforward regulatory loop between HuR and the long noncoding RNA linc-MD1 controls early phases of myogenesis.

Ivano Legnini (1, 2) , Mariangela Morlando (2) , Arianna Mangiavacchi (2) , Alessandro Fatica (2) , Irene Bozzoni (2, 3, 1)

1 Center for Life Nano Science@Sapienza
2 Department of Biology and Biotechnology "Charles Darwin"
3 Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti

The muscle-specific long noncoding RNA linc-MD1 was shown to be expressed during early phases of muscle differentiation and to trigger the switch to later stages by acting as a sponge for miR-133 and miR-135. Notably, linc-MD1 is also the host transcript of miR-133b, and their biogenesis is mutually exclusive. Here, we describe that this alternative synthesis is controlled by the HuR protein, which favors linc-MD1 accumulation through its ability to bind linc-MD1 and repress Drosha cleavage. We show that HuR is under the repressive control of miR-133 and that the sponging activity of linc-MD1 consolidates HuR expression in a feedforward positive loop. Finally, we show that HuR also acts in the cytoplasm, reinforcing linc-MD1 sponge activity by cooperating for miRNA recruitment. An increase in miR-133 synthesis, mainly from the two unrelated miR-133a coding genomic loci, is likely to trigger the exit from this circuitry and progression to later differentiation stages.

Domains: Biochemistry, Molecular Biology; Cellular Biology; Development Biology

Ivano Legnini, Mariangela Morlando, Arianna Mangiavacchi, Alessandro Fatica, Irene Bozzoni. A feedforward regulatory loop between HuR and the long noncoding RNA linc-MD1 controls early phases of myogenesis.. Molecular Cell, 2014, 53 (3), pp.506-14. ⟨10.1016/j.molcel.2013.12.012⟩. ⟨pasteur-01163642⟩