The role of m6A modification in physiology and disease

Abstract

Similar to DNA epigenetic modifications, multiple reversible chemical modifications on RNAs have been uncovered in a new layer of epigenetic modification. N6-methyladenosine (m⁶A), a modification that occurs in ~30% transcripts, is dynamically regulated by writer complex (methylase) and eraser (RNA demethylase) proteins, and is recognized by reader (m⁶A-binding) proteins. The effects of m⁶A modification are reflected in the functional modulation of mRNA splicing, export, localization, translation, and stability by regulating RNA structure and interactions between RNA and RNA-binding proteins. This modulation is involved in a variety of physiological behaviors, including neurodevelopment, immunoregulation, and cellular differentiation. The disruption of m⁶A modulations impairs gene expression and cellular function and ultimately leads to diseases such as cancer, psychiatric disorders, and metabolic disease. This review focuses on the mechanisms and functions of m⁶A modification in a variety of physiological behaviors and diseases.

Fig. 1. The regulation of m6A modification.

M⁶A is added, removed and recognized by its writers, erasers and readers. METTL3-METTL14 is the core of the methyltransferase and functions in cellular m⁶A deposition on nuclear RNAs. WTAP is a subunit of the methyltransferase, which promotes the recruitment of the m6A methyltransferase complex to mRNA targets. KIAA1429 and RBM15 (RNA binding motif protein 15) are also required for the above process. FTO and ALKBH5 are two enzymes capable of removing m⁶A, exhibiting efficient oxidative demethylation activity of abundant m⁶A in RNA. YTH domain family, HNRNP protein family, IGF2BPs and eIF3 bind to m⁶A-modified RNA through conserved m6A-binding domains and play different roles in RNA metabolism.

Fig. 2. The role of m6A in different cancers.

M⁶A plays diverse roles in different cancer, and even plays the opposite roles in a type of cancer. On the on hand, m⁶A promotes tumor progression by increasing oncogene expression and decreasing tumor suppressor gene expression. On the other hand, m⁶A suppresses tumor progression in opposite ways. Specific functions of m6A in the main text.