The crosstalk between m6A RNA methylation and other epigenetic regulators: a novel perspective in epigenetic remodeling

Abstract

Epigenetic regulation involves a range of sophisticated processes which contribute to heritable alterations in gene expression without altering DNA sequence. Regulatory events predominantly include DNA methylation, chromatin remodeling, histone modifications, non-coding RNAs (ncRNAs), and RNA modification. As the most prevalent RNA modification in eukaryotic cells, N⁶-methyladenosine (m⁶A) RNA methylation actively participates in the modulation of RNA metabolism. Notably, accumulating evidence has revealed complicated interrelations occurring between m⁶A and other well-known epigenetic modifications. Their crosstalk conspicuously triggers epigenetic remodeling, further yielding profound impacts on a variety of physiological and pathological processes, especially tumorigenesis. Herein, we provide an up-to-date review of this emerging hot area of biological research, summarizing the interplay between m⁶A RNA methylation and other epigenetic regulators, and highlighting their underlying functions in epigenetic reprogramming.

Keywords: DNA methylation; N6-methyladenosine (m6A); RNA modification; chromatin remodeling; histone modification; non-coding RNA (ncRNA).

Figure 1

The dynamic and reversible processes of m⁶A modification. “Writers” deposit m⁶A methylation on RNAs, while “erasers” remove the m⁶A marks. Then “readers” are responsible for regulating the fate of targeted RNAs.

Figure 2

The complex interplay between m⁶A modification and other epigenetic regulators including DNA methylation, chromatin remodeling, histone modification and RNA modification. (A) The regulatory circuit of m⁶A modification and DNA methylation. (B) The loss of 5mC DNA methylation on METTL3 promotes its expression. (C) m⁶A methylation affects the chromatin state by regulating the expression of carRNAs. (D) m⁶A impacts histone modification through modulating the level of histone-associated enzymes. (E) JMJD6 mediates the demethylation of hnRNPA2B1, impelling its translocation to cytoplasm. (F) Histone acetylation facilitates METTL3 expression. (G) m⁶A methylation and m⁵C modification cooperatively promote the translation process. (H) Deficiency of m⁶A methylation leads to the enhanced level of A-to-I editing. (I) m⁶A methylation regulates the expression of pseudogene and impacts its sponge to miRNA.

Figure 3

The functions and mechanisms of m⁶A modification on ncRNAs. (A) m⁶A promotes the maturation of miRNA. (B) m⁶A modulates lncRNA level. (C) m⁶A facilitates lncRNA to combine with miRNA. (D) m⁶A interferes the binding of lncRNA to proteins. (E) m⁶A mediates the cytoplasmic export of circRNA. (F) m⁶A regulates circRNA translation. (G) m⁶A assists the innate immune system to recognize self circRNA.