Long noncoding RNAs, emerging players in muscle differentiation and disease

Abstract

The vast majority of the mammalian genome is transcribed giving rise to many different types of noncoding RNAs. Among them, long noncoding RNAs are the most numerous and functionally versatile class. Indeed, the lncRNA repertoire might be as rich as the proteome. LncRNAs have emerged as key regulators of gene expression at multiple levels. They play important roles in the regulation of development, differentiation and maintenance of cell identity and they also contribute to disease. In this review, we present recent advances in the biology of lncRNAs in muscle development and differentiation. We will also discuss the contribution of lncRNAs to muscle disease with a particular focus on Duchenne and facioscapulohumeral muscular dystrophies.

Figure 1

Mechanisms for long noncoding RNA (lncRNA) function. (A) LncRNAs (in red) are able to recruit chromatin modifiers mediating the deposition of activatory (green dots) or repressive (red dots) histone marks. (B) LncRNAs control the recruitment of transcription factors and core components of the transcriptional machinery. (C) LncRNAs can directly bind mRNAs and modulate splicing events. (D-E) LncRNAs participate in the higher order organization of the nucleus by mediating chromatin looping (D) and as structural components for the formation and function of nuclear bodies (E). (F) LncRNAs control translation rates favoring or inhibiting polysome loading to mRNAs. (G) LncRNAs modulate mRNA decay protecting mRNA from degradation or, alternatively, mediating the recruitment of degradation machinery. (H) LncRNAs can act as miRNA sponges, thus favoring the expression of the mRNAs targeted by the sequestered miRNA.

Figure 2

Distinct roles of long noncoding RNAs (lncRNAs) in muscle differentiation. (A) Enhancer RNAs (eRNAs) ^{CE and DRR}RNAs can induce expression of myogenic regulators MyoD and MyoG acting in cis or in trans, respectively. (B) LncRNA SRA acts as a scaffold molecule for MyoD, p68 and p72 at the promoter region of myogenic genes to activate their expression. (C) LncRNAs Malat1, H19 and Gtl-Meg3 interact with PRC1/2 complex to modulate their target genes. (D) As a molecular sponge H19 inhibits let-7 mediated mRNA degradation of myogenic negative regulators Hmga2 and Igfbp2.(E) Short interspersed element (SINE) containing lncRNAs can bind to UTR region of Cdc6 and Traf6 mRNAs and promote their decay at different stages of muscle differentiation.

Figure 3

Proposed roles for long noncoding RNAs (lncRNAs) in Duchenne muscular dystrophy. (A) In the nucleus, sense and antisense transcription from intronic sequences of the dystrophin (DMD) gene gives rise to lncRNAs that play a repressive effect at specific DMD promoters. (B) In the cytoplasm, the muscle specific lncRNA linc-MD1 acts as a competitive endogenous RNA (ceRNA) by sequestering miRNAs away from their target mRNAs. Linc-MD1 contributes to muscle differentiation by sponging miRNA-135 and -133, and thus promoting the expression of MEF2C and MAML1. Linc-MD1 is strongly reduced in muscle cells from DMD patients.

Figure 4

Role of DBE-T long noncoding RNA (lncRNA) in facioscapulohumeral muscular dystrophy (FSHD). In healthy individuals, the D4Z4 array displays from 11 to more than 100 units and is extensively bound by Polycomb group proteins (PcG), leading to the repression of the locus. In FSHD patients, the reduction of D4Z4 copy number to below 11 units causes decreased PcG binding and hence reduced silencing. This allows the transcription of the lncRNA DBE-T that remains associated to the FSHD locus and recruits the TrxG protein ASHL1 leading to activation of FSHD candidate genes.