In recent years, the field of epigenetics has expanded significantly, revealing that RNA modifications play crucial roles in regulating various biological processes. A comprehensive review published in Signal Transduction and Targeted Therapy provides insights into the roles ofeight common RNA modifications in cellular metabolism, with implications for metabolism-targeted therapy and immunotherapy. Let's delve into the fascinating world of RNA modifications!

1. N6-methyladenosine (m6A)

m6A is one of the most prevalent RNA modifications, found in mRNA, rRNA, lncRNA, and other RNA types. It regulates RNA transcription, maturation, localization, function, and degradation. In mRNA, m6A affects translation efficiency and protein expression levels. For example, in rRNA, m6A modifications at specific positions are essential for translation. Additionally, m6A modulates the processing of snRNA and miRNA precursors.

2. 5-methylcytosine (m5C)

m5C occurs in DNA and RNA, with high abundance in tRNAs and rRNAs. It plays a key role in stabilizing RNA structures, ensuring translation fidelity, and regulating mRNA stability, nuclear export, and translation. Studies show that m5C methylation can influence processes like bladder cancer development and zebrafish embryogenesis.

3. N1-methyladenosine (m1A)

m1A modification affects RNA base pairing, altering RNA structure and function. Found in tRNAs, rRNAs, mRNAs, and lncRNAs, m1A influences translation initiation, mitochondrial ribosome structure, and tRNA stability. In mRNA, m1A near the start codon can regulate translation initiation.

4. N7-methylguanosine (m7G)

m7G is a well-known modification found in the 5' cap structure of mature mRNA, snRNA, and snoRNA. It regulates mRNA splicing, nuclear export, transcription elongation, translation, and degradation. In tRNAs, m7G maintains structural integrity and enhances translation ability.

5. N4-acetylcytidine (ac4C)

ac4C is the only known acetylation event in eukaryotic RNA, occurring in tRNAs, rRNAs, and mRNAs. It promotes RNA stability and translation efficiency. In 18S rRNA, ac4C is vital for pre-rRNA processing and ribosome synthesis. In mRNA, ac4C significantly enhances mRNA stability and protein translation.

6. Pseudouridine (Ψ)

Ψ is a C5-sugar glycosidic isomer of uridine, widespread in all types of RNA. It plays essential roles in RNA biosynthesis, structure, stability, and function. In tRNAs, Ψ modifications are crucial for maintaining stable structures and mediating codon-anticodon pairing. In snRNAs, Ψ affects RNA structure and interactions with RNA-binding proteins.

7. Adenosine-to-inosine Editing (A-to-I Editing)

A-to-I editing converts adenosine to inosine, a common post-transcriptional modification in mammals. It occurs in pre-mRNAs, mRNAs, non-coding RNAs, and even virus RNAs. A-to-I editing can alter RNA structure, affecting miRNA processing, mRNA stability, and translation efficiency.

8. N6,2′-O-dimethyladenosine (m6Am)

Itis a crucial RNA modification that occurs near the 5′ cap structure in mRNAs and snRNAs, playing a significant role in regulating mRNA stability and translation efficiency. This modification is catalyzed by enzymes like PCIF1 and METTL4, with the former being essential for immune evasion and the latter specific to U2 snRNA. The demethylation of m6Am is mediated by FTO, which has distinct substrate preferences based on its cellular localization. Despite its importance, the functional understanding of m6Am is hindered by methodological limitations in mapping techniques, leading to inconsistent findings on its impact on gene expression. Future research with more precise methods is needed to elucidate the regulatory roles of m6Am in cellular metabolism and therapeutic applications.

 The chemical structure, distribution, and molecular functions of eight RNA modifications. [1]

Implications for Cellular Metabolism and Therapy

These RNA modifications dynamically regulate gene expression, impacting various biological processes and disease progression. Understanding their roles in metabolism can lead to the development of novel therapeutic strategies. For instance, targeting m6A modification has shown promise in cancer therapy by regulating glycolytic pathways and enhancing immunotherapy responses.

Furthermore, RNA modifications are crucial in immunometabolism, the metabolic changes that occur in immune cells during differentiation and activation. Studies suggest that RNA modifications influence immune cell functions, making them potential targets for immunotherapy.

Synbio Technologies | RNA Synthesis

Synbio Technologies employs both chemical synthesis and IVT mRNA synthesis methodologies to offer a versatile range of services encompassing RNA oligo synthesis with varied modifications and tailored delivery solutions, as well as the synthesis of functional siRNA, miRNA, lncRNA, and in vitro transcription products.

Our company provides a diverse array of RNA modification options, including fluorescent labeling, to cater to the needs of our clients. These modifications not only bolster RNA's cellular delivery and stability but also improve its resistance to nuclease degradation through the use of modifications such as phosphorothioate, 2'-OMe, and 2'-F. Additionally, fluorescent labeling enables the visualization and precise localization of RNA through advanced imaging techniques like fluorescence and confocal laser microscopy, making it a pivotal tool in virus detection, disease diagnosis, and early tumor screening.

References

Liu WW, Zheng SQ, Li T, Fei YF, Wang C, Zhang S, Wang F, Jiang GM, Wang H. RNA modifications in cellular metabolism: implications for metabolism-targeted therapy and immunotherapy. Signal Transduction and Targeted Therapy. 2024 Mar 27;9(1):70.