Crosstalk between RNA m6A modification and epigenetic factors in plant gene regulation

Abstract

N⁶-methyladenosine (m⁶A) is the most abundant modification observed in eukaryotic mRNAs. Advances in transcriptome-wide m⁶A mapping and sequencing technologies have enabled the identification of several conserved motifs in plants, including the RRACH (R = A/G and H = A/C/U) and UGUAW (W = U or A) motifs. However, the mechanisms underlying deposition of m⁶A marks at specific positions in the conserved motifs of individual transcripts remain to be clarified. Evidence from plant and animal studies suggests that m⁶A writer or eraser components are recruited to specific genomic loci through interactions with particular transcription factors, 5-methylcytosine DNA methylation marks, and histone marks. In addition, recent studies in animal cells have shown that microRNAs play a role in depositing m⁶A marks at specific sites in transcripts through a base-pairing mechanism. m⁶A also affects the biogenesis and function of chromatin-associated regulatory RNAs and long noncoding RNAs. Although we have less of an understanding of the link between m⁶A modification and epigenetic factors in plants than in animals, recent progress in identifying the proteins that interact with m⁶A writer or eraser components has provided insights into the crosstalk between m⁶A modification and epigenetic factors, which plays a crucial role in transcript-specific methylation and regulation of m⁶A in plants.

Keywords: DNA methylation; RNA methylation; epigenetics; histone modification; long noncoding RNA; microRNA.

Figure 1

The interplay between mRNA m⁶A methylation and DNA methylation. In tomato, the m⁶A eraser SlALKBH2 removes m⁶A marks from mRNA of the DNA 5mC eraser SlDML2 to enhance its stability, leading to a higher protein level. In turn, increased SlDML2 causes DNA hypomethylation to activate SlALKBH2 expression via a positive feedback loop. The overall genome-wide DNA hypomethylation of fruit-ripening-related genes results in early fruit ripening.

Figure 2

Relationship between mRNA m⁶A methylation and histone modifications. (A) In Arabidopsis, the m⁶A writer complex preferentially installs m⁶A marks around the stop codons and in the 3′ untranslated regions (UTRs) of mRNAs. Given that H3K36me2 is enriched near the 3′ ends of genes, it is proposed that the H3K36me2 mark and an unidentified protein recruit m⁶A writers to an m⁶A site, leading to deposition of the m⁶A mark around the stop codon or in the 3′ UTR of the transcribing mRNA. (B) An unidentified m⁶A reader binds to m⁶A marks on transcribing mRNAs and recruits histone-modifying enzymes, leading to methylation or demethylation of histones at specific genomic loci.

Figure 3

The interplay between mRNA m⁶A methylation and miRNAs. (A) miRNA biogenesis. In Arabidopsis, the m⁶A writer installs m⁶A marks on primary miRNAs (pri-miRNAs), which are then processed to precursor miRNAs (pre-miRNAs) via the action of Dicer-like 1 (DCL1), HYPONASTIC LEAVES 1 (HYL1), and TOUGH (TGH). An unidentified m⁶A reader binds to m⁶A-modified pri-miRNAs, leading to either increased or decreased processing of pri-miRNAs to mature miRNAs. (B) miRNA-guided m⁶A modification. The m⁶A writer complex binds to an unidentified miRNA that guides the writer complex to the complementary m⁶A site via a base-pairing mechanism, leading to m⁶A modification at a specific site in a transcript.

Figure 4

Relationship between RNA m⁶A methylation and lncRNA processing and chromatin remodeling. (A) In Arabidopsis, the m⁶A writer installs m⁶A marks on COOLAIR, the long noncoding antisense RNA of FLOWERING LOCUS C (FLC), causing conformational changes in COOLAIR and enhancing its interaction with FLOWERING CONTROL LOCUS A (FCA) and the 3′-RNA processing factor FY. An unidentified m⁶A reader participates in chromatin silencing, leading to FLC repression and early flowering. (B) MTA is recruited to a transcribing chromatin-associated regulatory RNA (carRNA) by an unidentified factor and installs m⁶A marks on the nascent transcript. The m⁶A reader that recognizes and binds to the m⁶A mark recruits an unidentified histone-modifying enzyme, altering histone modification, thereby inducing changes from closed to open chromatin structure and enhancing chromatin accessibility.