Epitranscriptomics: Decoding the RNA Modification Code

Gene expression control has traditionally focused on DNA sequences and their protein-coding potential. However, a new layer of complexity is emerging: epitranscriptomics. This field studies the chemical modifications made to RNA molecules after transcription, often referred to as the "RNA code." These modifications significantly impact gene regulation, adding a crucial dimension to understanding human health and disease.

RNA modifications and their links to human disease. The set of known RNA modifications classified by their reference nucleotide, highlighting those that have been associated to human diseases (red), as well as those for which a transcriptome-wide detection method has been established (circled in green).

RNA Modifications

Messenger RNA (mRNA) was previously considered a passive carrier of genetic information. Recent advancements have revealed a diverse array of RNA modifications, including N6-methyladenosine (m6A), acetylation, and pseudouridylation. These modifications can alter RNA structure, stability, and protein interactions, ultimately influencing translation, splicing, and localization.

m6A: A Well-Studied RNA Modification

One of the most studied RNA modifications is m6A. Found throughout the transcriptome, m6A is dynamically regulated by a dedicated enzymatic machinery consisting of "writer," "reader," and "eraser" proteins. Landmark studies have demonstrated that m6A can influence mRNA splicing, stability, and translation efficiency. For example, a 2017 study by Meyer et al. utilized m6A modification on specific mRNAs to demonstrate their role in stress granule assembly.


The dynamic and reversible process of m6A modification of RNA and its potential functions in the regulation of mRNA processing and metabolism. a m 6 A modification occurs primarily at sixth site of adenine in RRACH sequences (R indicates A or G; H indicates A, U, or C). Dynamic and reversible mRNA m 6 A modification: the m 6 A methyltransferase complex METTL3/METTL14/WTAP catalyzes the transformation of A to m 6 A, and the demethylases FTO and ALKBH5 catalyze its demethylation. The YTH family protein YTHDC1 binds to m 6 A modifications in the nucleus, and YTHDF2/1 binds to cytoplasmic m 6 A. MicroRNAs regulate m 6 A production by regulating METTL3 activity.

Non-Coding RNAs and Epitranscriptomics

Another exciting research area is the exploration of epitranscriptomic regulation in non-coding RNAs. Long non-coding RNAs (lncRNAs) are a diverse class of RNA molecules that lack protein-coding potential but play crucial roles in cellular processes. Recent studies suggest that lncRNAs can be decorated with RNA modifications, impacting their function and interaction with target molecules.

Gene expression regulation and examples of non-coding RNA in Down syndrome (DS) and Alzheimer's disease (AD). Gene regulation occurs through the genome, epigenome, and epitranscriptome. Beyond the DNA sequence, chromosomes are regulated by their locations or territories in the nucleus. The presence of an extra chromosome can alter the chromatin structure, ultimately affecting the transcription of the entire genome. At the epigenetic level, gene expression is regulated by reversible modifications of histones within nucleosomes that include methylation, acetylation, phosphorylation, ubiquitination, and sumoylation. Chemical modifications in RNA regulate the fate of transcription through a network of methyltransferases (writers), demethylases (drafts) and specific RNA reading proteins. The regulation of expression by ncRNAs can be affected at different levels. In red letters, the miRNAs and lncRNA encoded in Chr21 linked to DS and AD (miRNA-125b-a, miRNA-155, miR-99a, let-7c, and miRNA-802) and lncRNA (DSCR9) are highlighted.

Epitranscriptomics and Disease

Deciphering the epitranscriptomic code holds immense potential for comprehending complex diseases. Dysregulation of RNA modifications has been linked to various pathologies, including cancer, neurodegenerative diseases, and metabolic disorders. For instance, a 2021 study by Li et al. revealed that m6A modifications on specific mRNAs in cancer cells promote tumorigenesis and metastasis. These findings suggest that targeting epitranscriptomic regulators could offer novel therapeutic strategies.


Epitranscriptomics and Disease

Challenges and Future Directions

The field of epitranscriptomics is still nascent. Significant challenges remain, including the development of robust methods for comprehensive detection and quantification of RNA modifications across the transcriptome. Additionally, elucidating the functional consequences of specific modifications and their interplay with other regulatory mechanisms is crucial.

Despite these challenges, epitranscriptomics offers a burgeoning field of research with the potential to revolutionize our understanding of gene regulation and its role in human health and disease. As we continue to decipher the RNA modification code, we may unlock new avenues for diagnosis, treatment, and ultimately, improved patient outcomes.

learn more about Epitranscriptomics in this video.

 


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Epitranscriptomics: Decoding the RNA Modification Code
Gen store May 23, 2024
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