Six homeoproteins and a Iinc-RNA at the fast MYH locus lock fast myofiber terminal phenotype.

Iori Sakakibara,Vincent Hakim,Marc Santolini,Pascal Maire,Arnaud Ferry,Cornelison Dawn

doi:10.1371/journal.pgen.1004386

Abstract

Thousands of long intergenic non-coding RNAs (lincRNAs) are encoded by the mammalian genome. However, the function of most of these lincRNAs has not been identified in vivo. Here, we demonstrate a role for a novel lincRNA, linc-MYH, in adult fast-type myofiber specialization. Fast myosin heavy chain (MYH) genes and linc-MYH share a common enhancer, located in the fast MYH gene locus and regulated by Six1 homeoproteins. linc-MYH in nuclei of fast-type myofibers prevents slow-type and enhances fast-type gene expression. Functional fast-sarcomeric unit formation is achieved by the coordinate expression of fast MYHs and linc-MYH, under the control of a common Six-bound enhancer.

Highlights

Adult skeletal muscles are composed of slow and fast myofiber subtypes which selectively express the genes required for their specific contraction activity and metabolic properties [1,2,3,4]
We identify in this manuscript a new mechanism controlling in vivo adult muscle fiber-type specification implicating a long intergenic non-coding RNA, linc-myosin heavy chain (MYH)
Our previous studies suggested that Six1 could be directly involved in the control of the expression of fast Myh genes, since higher levels of this transcription factor accumulate in the nuclei of adult fast myofibers than in slow myofibers [11]

Summary

Introduction

Adult skeletal muscles are composed of slow and fast myofiber subtypes which selectively express the genes required for their specific contraction activity and metabolic properties [1,2,3,4]. Distinct intramyofibrillary calcium transients, evoked by slow tonic motor neuron firing, induce a cascade of downstream signaling involving Calcineurin and CamK. This results in the activation of selective transcription activators and repressors in slow myofibres. The signaling pathways operating in distinct Myh, Myh and Myh myofiber subtypes, which coordinate the activation of the other fast-type genes and the repression of slow-type genes, is less well understood [1]. Better knowledge of the mechanisms controlling muscle specialization and plasticity is important to enable the understanding and modulation of muscle adaptations in pathophysiological conditions

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Conclusion