m6A in mRNA coding regions promotes translation via the RNA helicase-containing YTHDC2

Abstract

Dynamic mRNA modification in the form of N6-methyladenosine (m6A) adds considerable richness and sophistication to gene regulation. The m6A mark is asymmetrically distributed along mature mRNAs, with approximately 35% of m6A residues located within the coding region (CDS). It has been suggested that methylation in CDS slows down translation elongation. However, neither the decoding feature of endogenous mRNAs nor the physiological significance of CDS m6A has been clearly defined. Here, we found that CDS m6A leads to ribosome pausing in a codon-specific manner. Unexpectedly, removing CDS m6A from these transcripts results in a further decrease of translation. A systemic analysis of RNA structural datasets revealed that CDS m6A positively regulates translation by resolving mRNA secondary structures. We further demonstrate that the elongation-promoting effect of CDS methylation requires the RNA helicase-containing m6A reader YTHDC2. Our findings established the physiological significance of CDS methylation and uncovered non-overlapping function of m6A reader proteins.

The emerging roles of N6-methyladenosine (m6A) deregulation in liver carcinogenesis

“…In addition, YTHDC1 also controls the nuclear export of its targets by interacting with SRSF3 and the RNA nuclear exporter NXF1 [45]. Recently, YTHDC2 was found to interact with RNA helicase to positively regulate translation elongation in an m6Adependent manner [46]. The class II m6A "readers" include three heterogeneous nuclear ribonucleoproteins (hnRNPs), hnRNPC, hnRNPG and hnRNPA2B1.…”

m6A-binding proteins: the emerging crucial performers in epigenetics

“…The YTH domain is found in 174 different proteins in eukaryotes [33], with a size from 100 to 150 amino acids. [8,9] METTL14 Nucleus Forming a heterodimer with METTL3 and strengthening its catalytic activity [8,9] WTAP Nucleus Promoting METTL3-METTL14 complex localization to nuclear speckles and modulating their recruitment to RNA targets [10] VIRMA Nucleus Preferentially mediating m 6 A modification in the 3'UTR and near stop codon, and affecting the selection of methylation sites [11] RBM15 [19,20] YTHDF3 Cytoplasm Not only promoting the translation of methylated RNA in cooperation with YTHDF1, but also strengthening RNA decay mediated by YTHDF2 [21,22] YTHDC1 Nucleus Mediating alternative splicing, facilitating m 6 A-methylated RNA nuclear export, and promoting X chromosome genes transcriptional silencing mediated by XIST [12,23,24] YTHDC2 Cytoplasm Increasing the translation efficiency of RNA [25,26] HNRNPA2B1 Nucleus Accelerating the processing of primary miRNA, regulating alternative splicing, and acting as a "m 6 A-switch" [27,28] HNRNPC Nucleus Participating in the pre-mRNA processing and functioning as a "m 6 A-switch" [29,30] HNRNPG Nucleus Modulating pre-mRNA alternative splicing and acting as a "m 6 A-switch" [31] IGF2BP1 Cytoplasm Fortifying RNA stability [32] IGF2BP2 Cytoplasm Increasing the stability of RNA [32] IGF2BP3 Cytoplasm Facilitating RNA stabilization [32] It is featured by 14 invariant and 19 highly conserved residues [34], and contains a structure of four α helices and six β strands [35]. Interestingly, the six β strands shape a β barrel and then stabilize the hydrophobic core through combining with α helices [35].…”

“…Furthermore, YTHDC1 plays a promoting role in the X chromosome genes transcriptional silencing mediated by XIST [12]. YTHDC2, a putative RNA helicase, contains YTH domain, helicase domain, R3H domain, and ankyrin repeats [37], which is of great significance to increase the translation efficiency of mRNAs [25,26].…”

Chemical probe-based Nanopore Sequencing to Selectively Assess the RNA modifications

“…Transcriptome-wide profiling of RNA modifications have shifted its focus from high abundant non-coding RNAs to mRNAs of minuscules fraction. RNA modifications exert unpreceded regulation over major aspects of mRNA life such as structure 1,2,3,4 ,stability 5 ,6 decay 7 , translation 8,9,10 microRNA binding 11,12 and altering codon potential 10 . To date, 172 modifications (Modomics) 13 are known to exist in biological systems based on mass spectrometry characterizations.…”