RNA Modifications in Gene Expression Regulation

Cellular RNAs are extensively decorated with chemical modifications that fine-tune gene expression at multiple levels. Among these, N6-methyladenosine (m6A) emerges as the most abundant internal mark on messenger RNA, dynamically installed by methyltransferase complexes and removed by demethylases. A cohort of specialised reader proteins interprets m6A signals to regulate RNA splicing, nuclear export, translation efficiency and decay. Beyond m6A, other modifications such as 5-methylcytosine (m5C) and pseudouridine modulate RNA secondary structure, interaction with protein factors and subcellular localisation. These modifications operate in concert to shape developmental programmes, stress responses and cellular differentiation, and their dysregulation underlies a spectrum of diseases, notably cancer. Technological advances in transcriptome-wide mapping have revealed that modification patterns vary between tissues and in response to environmental cues, highlighting their plasticity and broad significance for organismal physiology.

Research from Nature Portfolio

Recent studies have elucidated the molecular mechanisms by which reader proteins couple m6A recognition to transcript turnover. A foundational investigation revealed that the YTHDF2 reader binds m6A-marked RNAs and directly recruits the CCR4–NOT deadenylase complex, accelerating poly(A) tail shortening and promoting rapid degradation of target transcripts. This work defined a key pathway linking m6A deposition to control of mRNA stability and underscored the importance of reader–deadenylase interactions in sculpting gene expression programmes.

RNA Modifications in Gene Expression Regulation publication trend

The graph below shows the total number of articles in rna modifications in gene expression regulation across all publications each year (not limited to Nature Index journals).

Technical terms

N6-methyladenosine (m6A): The methylation of the nitrogen at position 6 of adenosine, a reversible modification affecting RNA metabolism and gene expression.

YTHDF2: A member of the YTH domain–containing family of m6A reader proteins that recognises m6A-modified RNAs and mediates their decay through recruitment of deadenylase complexes.

CCR4–NOT deadenylase complex: A multi-subunit enzyme complex responsible for removal of the poly(A) tail from transcripts, leading to RNA destabilisation and degradation.

O-GlcNAcylation: The enzymatic addition of N-acetylglucosamine to serine or threonine residues of proteins, modulating their stability and activity.

5-Methylcytosine (m5C): The methylation of cytosine at the 5-carbon position in RNA, influencing RNA structure, export and stability.

NSUN2: An RNA methyltransferase responsible for installing m5C marks on messenger RNAs, affecting their processing and export.

ALYREF: An mRNA export adaptor protein that recognises m5C modifications and facilitates the nuclear–cytoplasmic transport of mRNAs.

Writer, eraser and reader proteins: Writers are enzymes that deposit RNA modifications, erasers remove them, and readers recognise and bind modified residues to effect downstream processes.

References

1. O-GlcNAcylation of YTHDF2 promotes HBV-related hepatocellular carcinoma progression in an N6-methyladenosine-dependent manner. Signal Transduction and Targeted Therapy (2023).
2. YTHDF2 destabilizes m6A-containing RNA through direct recruitment of the CCR4–NOT deadenylase complex. Nature Communications (2016).
3. Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism. Cell Research (2018).
4. Transcriptome-wide Mapping Reveals Widespread Dynamic-Regulated Pseudouridylation of ncRNA and mRNA. Cell (2014).
5. m6A regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in gastric cancer. Molecular Cancer (2020).
6. 5-methylcytosine promotes mRNA export — NSUN2 as the methyltransferase and ALYREF as an m5C reader. Cell Research (2017).