Regulation of RNA N6-methyladenosine modification and its emerging roles in skeletal muscle development

Abstract

N⁶-methyladenosine (m⁶A) is one of the most widespread and highly conserved chemical modifications in cellular RNAs of eukaryotic genomes. Owing to the development of high-throughput m⁶A sequencing, the functions and mechanisms of m⁶A modification in development and diseases have been revealed. Recent studies have shown that RNA m⁶A methylation plays a critical role in skeletal muscle development, which regulates myoblast proliferation and differentiation, and muscle regeneration. Exploration of the functions of m⁶A modification and its regulators provides a deeper understanding of the regulatory mechanisms underlying skeletal muscle development. In the present review, we aim to summarize recent breakthroughs concerning the global landscape of m⁶A modification in mammals and examine the biological functions and mechanisms of enzymes regulating m⁶A RNA methylation. We describe the interplay between m⁶A and other epigenetic modifications and highlight the regulatory roles of m⁶A in development, especially that of skeletal muscle. m⁶A and its regulators are expected to be targets for the treatment of human muscle-related diseases and novel epigenetic markers for animal breeding in meat production.

Keywords: RNA N6-methyladenosine; development; myogenesis; skeletal muscle.

Figure 1

Schematic representation of the regulation and functions of m⁶A RNA modification. The reversible m⁶A RNA modification is dynamically regulated by m⁶A methyltransferases (writers) and demethylases (erasers), and recognized binding proteins (readers). Depending on the cellular context and their position in RNAs, m⁶A is involved in a number of RNA processes including alternative splicing, RNA stability, pri-miRNA processing, RNA nuclear export, RNA decay, and translation.

Figure 2

The epigenetics regulation of skeletal muscle development. The development of skeletal muscle is tightly controlled by multiple epigenetic modifications at both the DNA (e.g., histone modification and DNA methylation) and the RNA (e.g., m⁶A methylation, non-coding RNAs, and RNA editing) levels. The interplay between m⁶A and other epigenetic modifications orchestrate the expression of myogenic genes during commitment, proliferation, differentiation, and fusion of skeletal muscle.

Figure 3

A diagram showing the functions and regulation of m⁶A and its regulators in myogenesis and skeletal muscle development.