RESUMEN
Chromatin remodeling complexes have functions in transcriptional regulation and chromosome maintenance, but it is mostly unknown how the function of these normally ubiquitous complexes is specified in the cellular context. Here, we describe that the evolutionary conserved long non-coding RNA linc-MYH regulates the composition of the INO80 chromatin remodeler complex in muscle stem cells and prevents interaction with WDR5 and the transcription factor YY1. Linc-MYH acts as a selective molecular switch in trans that governs the pro-proliferative function of the ubiquitous INO80 complex but does not affect its role in maintaining genomic stability. The molecular switch is essential for restricting generation of quiescent MuSCs and proliferation of myoblasts in homeostasis and regeneration. Since linc-MYH is expressed in proliferating myoblasts but not in quiescent MuSCs, we reason that the extent of myoblast proliferation has decisive effects on the size of the quiescent MuSC pool.
Asunto(s)
ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Proteínas de Unión al ADN/metabolismo , Hipertrofia/metabolismo , Músculo Esquelético/metabolismo , Mioblastos/metabolismo , ARN Largo no Codificante/metabolismo , ATPasas Asociadas con Actividades Celulares Diversas/genética , Animales , Proliferación Celular , Cromatina , ADN Glicosilasas/genética , Proteínas de Unión al ADN/genética , Epigenómica , Regulación Enzimológica de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Noqueados , Músculo Esquelético/citología , Mioblastos/citología , ARN Largo no Codificante/genética , ARN no Traducido , Regeneración/fisiología , Transcriptoma , Factor de Transcripción YY1/genéticaRESUMEN
Dedifferentiation of cardiomyocytes is part of the survival program in the remodeling myocardium and may be essential for enabling cardiomyocyte proliferation. In addition to transcriptional processes, non-coding RNAs play important functions for the control of cell cycle regulation in cardiomyocytes and cardiac regeneration. Here, we demonstrate that suppression of FGFR1 and OSMR by miR-1/133a is instrumental to prevent cardiomyocyte dedifferentiation and cell cycle entry in the adult heart. Concomitant inactivation of both miR-1/133a clusters in adult cardiomyocytes activates expression of cell cycle regulators, induces a switch from fatty acid to glycolytic metabolism, and changes expression of extracellular matrix genes. Inhibition of FGFR and OSMR pathways prevents most effects of miR-1/133a inactivation. Short-term miR-1/133a depletion protects cardiomyocytes against ischemia, while extended loss of miR-1/133a causes heart failure. Our results demonstrate a crucial role of miR-1/133amediated suppression of Osmr and Ffgfr1 in maintaining the postmitotic differentiated state of cardiomyocytes.