Malat1 regulates myogenic differentiation and muscle regeneration through modulating MyoD transcriptional activity

Abstract

Malat1 is one of the most abundant long non-coding RNAs in various cell types; its exact cellular function is still a matter of intense investigation. In this study we characterized the function of Malat1 in skeletal muscle cells and muscle regeneration. Utilizing both in vitro and in vivo assays, we demonstrate that Malat1 has a role in regulating gene expression during myogenic differentiation of myoblast cells. Specifically, we found that knockdown of Malat1 accelerates the myogenic differentiation in cultured cells. Consistently, Malat1 knockout mice display enhanced muscle regeneration after injury and deletion of Malat1 in dystrophic mdx mice also improves the muscle regeneration. Mechanistically, in the proliferating myoblasts, Malat1 recruits Suv39h1 to MyoD-binding loci, causing trimethylation of histone 3 lysine 9 (H3K9me3), which suppresses the target gene expression. Upon differentiation, the pro-myogenic miR-181a is increased and targets the nuclear Malat1 transcripts for degradation through Ago2-dependent nuclear RNA-induced silencing complex machinery; the Malat1 decrease subsequently leads to the destabilization of Suv39h1/HP1β/HDAC1-repressive complex and displacement by a Set7-containing activating complex, which allows MyoD trans-activation to occur. Together, our findings identify a regulatory axis of miR-181a-Malat1-MyoD/Suv39h1 in myogenesis and uncover a previously unknown molecular mechanism of Malat1 action in gene regulation.

YY 1 regulates skeletal muscle regeneration through controlling metabolic reprogramming of satellite cells

“…Next, to study the role for YY1 in muscle regeneration, we employed a commonly used cardiotoxin (CTX)‐induced muscle injury‐regeneration model (Chen et al , ). Tibialis anterior (TA) muscles of Ctrl or YY1 iKO animals were subjected to a single CTX injury and then allowed to recover for 3–60 days before analysis of the regenerated tissue (Fig G).…”

Long noncoding RNAs and their roles in skeletal muscle fate determination

“…Through interaction with miR-125b, lnc-mg promotes myoblast differentiation (20). Malat1 is important for the transition between the proliferation and differentiation stages of myogenesis (21). Linc-RAM also acts during the differentiation stage of myogenesis, enhancing transcriptional initiation of miR-206 and MyoG (22).…”

Roles of lncRNAs and circRNAs in regulating skeletal muscle development

“…69 H19 modulates let-7 availability by acting as a molecular sponge. 73 The nuclear-retained non-coding RNA Malat1 also regulates alternative splicing by modulating serine/arginine splicing factor phosphorylation. 70 In addition, a direct interaction of the mesodermal enhancer with the H19 promoter can lead to increased H19 expression in the presence of MyoD; in turn, H19 represses IGF2 expression in a trans manner, and IGF2 also negatively regulates MyoD expression, possibly by reducing the expression of the serum response factor (SRF) transcription factor, a known MyoD activator.…”

“…Its knockdown accelerates myogenic differentiation in cultured cells. 73 The nuclear-retained non-coding RNA Malat1 also regulates alternative splicing by modulating serine/arginine splicing factor phosphorylation. 87 Malat1 also plays a role in tumour growth.…”