A feedforward regulatory loop between HuR and the long noncoding RNA linc-MD1 controls early phases of myogenesis.
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.
Department of Biology and Biotechnology "Charles Darwin" and IBPM, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Ivano
I
Legnini
Department of Biology and Biotechnology "Charles Darwin" and IBPM, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Mariangela
M
Morlando
Department of Biology and Biotechnology "Charles Darwin" and IBPM, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Arianna
A
Mangiavacchi
Department of Biology and Biotechnology "Charles Darwin" and IBPM, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Alessandro
A
Fatica
Department of Biology and Biotechnology "Charles Darwin" and IBPM, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy; Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy; Institute Pasteur Fondazione Cenci-Bolognetti, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy. Electronic address: irene.bozzoni@uniroma1.it.
Irene
I
Bozzoni
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D051959:ELAV Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D025461:Feedback, Physiological; D051379:Mice; D035683:MicroRNAs / Q000032:analysis / Q000378:metabolism; D024510:Muscle Development / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D051959:ELAV Proteins; D035683:MicroRNAs; C517732:Mirn133 microRNA, mouse; D062085:RNA, Long Noncoding; C568369:long noncoding RNA, linc-MD1, mouse