The role of m6A modification in the biological functions and diseases

Abstract

N⁶-methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher eukaryotic cells. m6A modification is modified by the m6A methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, and KIAA1429, and, removed by the demethylases, or erasers, including FTO and ALKBH5. It is recognized by m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 and HNRNPA2B1, also known as "readers". Recent studies have shown that m6A RNA modification plays essential role in both physiological and pathological conditions, especially in the initiation and progression of different types of human cancers. In this review, we discuss how m6A RNA methylation influences both the physiological and pathological progressions of hematopoietic, central nervous and reproductive systems. We will mainly focus on recent progress in identifying the biological functions and the underlying molecular mechanisms of m6A RNA methylation, its regulators and downstream target genes, during cancer progression in above systems. We propose that m6A RNA methylation process offer potential targets for cancer therapy in the future.

Fig. 1

Introduction of m6A RNA modification complex. m6A methylation is catalyzed by the writer complex including METTL3, METTL14, METTL16, WTAP, VIRMA, RBM15/15B, CBLL1, KIAA1429, and ZC3H13. The m6A modification is erased by demethylases including FTO and ALKBH5. The m6A-modified RNA reader proteins include YTHDF1/2/3, YTHDC1/2, IGF2BP1/2/3, and HNRNPC/A2B1. m6A modification modulates miRNA biogenesis, XIST-dependent X chromosome inactivation, m6A switch, RNA translocation, pre-mRNA splicing, RNA translation, RNA decay and RNA stability

Fig. 2

m6A RNA modification regulates hematopoietic system development. In the hematopoietic system, m6A methylation is essential for the proliferation and differentiation of hematopoietic stem/progenitor cells. Depletion of METTL3 promotes the formation of endogenous double-stranded RNAs (dsRNAs), which activates MDA5-RIG-I, PKR-eIF2α, and OAS-RNase L signaling pathways in hematopoietic stem/progenitor cells, resulting in hematopoietic development failure. YTHDF2 inhibits the Wnt signaling pathway by degrading the mRNA of ccnd1, c-Myc and Axin2, leading to reduced the proliferation and differentiation of hematopoietic stem/progenitor cells. METTL3 promotes the translation of c-Myc, PTEN, and BCL2 by increasing the methylation levels of reciprocal mRNAs, and promotes the proliferation of stem cells. METTL3 and YTHDF2 cooperate to inhibit the Notch signaling pathway in hematopoietic system

Fig. 3

m6A RNA methylation regulates central nervous system development. Neural stem/progenitor cells have the potential to self-renewal, which can differentiate to produce various types of nervous cells, including neurons, astrocytes, and oligodendrocytes. YTHDF2 and FTO promote the self-renewal and proliferation of NSCs by regulating the JAK/STAT and PI3K/AKT signaling pathways. METTL14 and METTL3 promote cortical biogenesis by accelerating the cell cycle of radial glial cells. PRRC2A and METTL14 promote the proliferation and differentiation of oligodendrocyte precursor cells and the myelination process by promoting the expression of Olig2 and NF155, respectively. YTHDF1 regulates learning and memory by promoting synaptic transmission and transcription of LTP-related target genes in neurons

Fig. 4

m6A RNA methylation regulates the reproductive system development. Primordial germ cells proliferate and differentiate into spermatocytes and oogonium in embryonic testes and ovaries, respectively. Spermatocytes and oogonium then undergo meiosis to become mature sperms and ovum, respectively. METTL3 and ALKBH5 regulate the levels of overall m6A mRNA methylation to promote the proliferation and motility of sperm cells. YTHDC1 and YTHDF1 regulate the maturation and translation of CPSF6 and Trcp5 transcripts, respectively, to promote the proliferation and maturation of oocytes

Fig. 5

The functional role of m6A modification in human acute myelocytic leukemia (AML). During the development of AML, aberrant methylation or demethylation of the corresponding cancer-related genes contribute differentially during AML progression, including the cell proliferation, cell differentiation, cancer stem cell self-renewal and cellular apoptosis. HSC hematopoietic stem cells, LSC leukemia stem cells

Fig. 6

The functional role of m6A modification in gliomas. In gliomas, m6A modifiers regulate the cell proliferation, cell invasion, cell migration and cancers stem cell maintenance by targeting to multiple critical cancer-related genes. CSCs Cancer stem cells

Fig. 7

The functional role of m6A mRNA modification in reproductive system related cancers. Aberrant m6A methylation or demethylation of the corresponding cancer-related genes plays different roles in bladder cancer and ovarian cancer. The cell proliferation, cell metastasis, cancer stem cell maintenance, cellular apoptosis, and cell invasion were regulated by different m6A modifiers. BC bladder cancer, OVC ovarian cancer