Reading the m6A-encoded epitranscriptomic information in development and diseases

Abstract

N⁶-methyladenosine (m⁶A) represents the most prevalent internal and reversible modification on RNAs. Different cell types display their unique m⁶A profiles, which are determined by the functions of m⁶A writers and erasers. M⁶A modifications lead to different outcomes such as decay, stabilization, or transport of the RNAs. The m⁶A-encoded epigenetic information is interpreted by m⁶A readers and their interacting proteins. M⁶A readers are essential for different biological processes, and the defects in m⁶A readers have been discovered in diverse diseases. Here, we review the latest advances in the roles of m⁶A readers in development and diseases. These recent studies not only highlight the importance of m⁶A readers in regulating cell fate transitions, but also point to the potential application of drugs targeting m⁶A readers in diseases.

Keywords: Cancers; Development; Diseases; m6A; m6A readers.

Fig. 1

Dynamic m⁶A modification in the nucleus and cytoplasm. The m⁶A modification exhibits dynamic processes in cellular compartments, with distinct mechanisms operating in the nucleus and cytoplasm. In the nucleus, the methyltransferase complex (WTAP, METTL3/METTL14) catalyzes m⁶A addition to RNAs, while nuclear demethylases (FTO or ALKBH5) facilitate m⁶A removal. Nuclear reader proteins, such as YTHDC1 and HNRNPs, recognize m⁶A sites and influence RNA splicing. Subsequently, m⁶A-modified RNAs are transported to the cytoplasm, where cytoplasmic reader proteins (e.g., YTHDF1/2/3, YTHDC2) further bind to regulate it. Additional proteins, such as IGF2BP1/2/3, are also involved in RNA recognition and regulation

Fig. 2

Structural Insights into m⁶A Reader Proteins and Their Functions in RNA Regulation. The illustration comprehensively describes the 3D structures and functions of distinct families of m⁶A reader proteins. A. YTHDF family, comprising YTHDF1, YTHDF2, and YTHDF3, serves as pivotal readers for m⁶A-modified RNAs. YTHDF1 facilitates RNA translation by recognizing m⁶A modification and engaging with eIF3. Meanwhile, YTHDF2 promotes the degradation of target RNAs by recognizing m⁶A modification and interacting with the carbon catabolite repressor 4-negative on TATA (CCR4-NOT) complex. YTHDF3 collaborates with YTHDF1 to enhance mRNA translation as well as mediates mRNA decay through interaction with YTHDF2. It can also enhance circRNA translation, by interacting with eIF4G2. B. YTHDC family consists of YTHDC1 and YTHDC2. YTHDC1 is involved in mRNA splicing, m⁶A mRNA nuclear export, and silencing of transposons, while YTHDC2 exerts influence over the stability and translation of specific target genes. C. hnRNPA2B1 recognizes and binds to m⁶A sites, exerting regulatory effects on RNA processing and metabolism through interacting with TBK1 and IRF3. D. IGF2BP family includes IGF2BP1, IGF2BP2, and IGF2BP3. IGF2BP1 prevents degradation of target RNAs by interacting with ELAVL2, while IGF2BP2 enhances translation efficiency by modulating ribosome binding to target mRNAs. IGF2BP3 stabilizes m⁶A-enriched target RNAs, safeguarding them from degradation

Fig. 3

The relationship between different m⁶A reader families and associated cancers. Dysregulation of m⁶A readers is associated with cancers in various human systems, including the central nervous system, digestive system, respiratory system, urogenital system, and hematopoietic system. The expression levels of reader proteins in cancer conditions and the potential targets recognized by different m⁶A readers are indicated. The circARHGAP12, marked with an asterisk (*) in the figure, is a circRNA