Introduction
RNA modifications are crucial for numerous biological processes, particularly in the development and regeneration of blood cells, which require rapid cell turnover. These modifications play a significant role in regulating stemness and cell fate decisions. A diverse array of RNA modifications has been identified, with roles extending from gene expression regulation to implications in various diseases. Understanding these modifications offers promising therapeutic potential.
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RNA Modifications
RNA modifications are chemical alterations introduced to RNA molecules either during transcription or post-transcriptionally. To date, nearly 150 unique RNA modifications have been identified. These include modifications such as N6-methyl adenosine (m6A), inosine (I), pseudouridine (Ψ), and 1-methyladenosine (m1A), among others. These modifications are prevalent across various RNA types including messenger RNA (mRNA), ribosomal RNA (rRNA), transfer RNA (tRNA), and long non-coding RNA (lncRNA).
RNA modifications affect gene activity by altering RNA stability, splicing, localization, and translation. They employ a set of molecular players often categorized into "writers", "erasers", and "readers". Writers are enzymes that add chemical marks to RNA, erasers remove these modifications, and readers recognize and bind to these modified RNAs to exert downstream effects. Hematopoietic stem cells (HSCs), which are critical for blood development, express a variety of these RNA-modifying enzymes, making this a fertile ground for research and potential therapeutic developments.
Fig. 1 Schematic depicting ribonucleic acid (RNA) species, RNA modification, and diverse blood cell types regulated by epitranscriptomic regulation. (Gunage R., Zon L. I. 2024)
Key RNA Modifications in Cell Fate Regulation
N6-methyl adenosine (m6A)
m6A is one of the most abundant and well-studied RNA modifications. It is found in mRNA, tRNA, and rRNA and affects RNA stability, splicing, localization, and translation. The m6A modification cap is recognized by multiple reader proteins like YTH domain family proteins (YTHDF1-3) and YTH domain-containing proteins (YTHDC1-2), which regulate RNA metabolism in various ways.
The enzymes involved in m6A modifications include METTL3 and METTL14, which form the catalytic core of the methyltransferase complex (MTC). This complex also includes auxiliary proteins like Wilms' tumor 1-associating protein (WTAP) and KIAA1429. Demethylation of m6A marks is carried out by RNA demethylases like FTO and ALKBH5. The coordinated action of these enzymes ensures that m6A modifications are dynamically regulated, allowing cells to quickly respond to signaling and environmental cues.
Inosine (I)
Inosine is formed by the deamination of adenosine and is involved in RNA editing. This modification is catalyzed by adenosine deaminases acting on RNA (ADAR) enzymes. Inosine can significantly alter RNA structure and function by changing hydrogen bonding properties. Mutations in ADAR enzymes, particularly ADAR1, have been associated with severe blood defects and other hematopoietic anomalies such as chronic myeloid leukemia (CML) and acute myeloid leukemia (AML).
Pseudouridine (Ψ)
Pseudouridine is another prevalent modification in RNA, affecting RNA stabilization and protein translation. The conversion of uridine to pseudouridine is catalyzed by pseudouridine synthase (PUS) enzymes. Ψ is essential for the proper function of tRNA and rRNA, impacting amino acid-tRNA coupling and ribosome recognition of correct tRNAs. Dysregulation of pseudouridine modifications has been linked to various cancers, including hematologic malignancies like leukemia.
RNA Modifications in Blood Diseases and Disorders
The emerging field of RNA modifications offers promising avenues for understanding and potentially treating blood diseases and disorders. For instance, aberrations in m6A regulatory machinery, specifically dysregulation in METTL3 or METTL14, have been associated with leukemia. METTL3-mediated m6A modification promotes the translation of oncogenes like MYC and BCL2, facilitating leukemogenesis. Conversely, inhibiting METTL3 activity has shown the potential to impede cancer progression, highlighting the therapeutic potential of targeting RNA modifications.
Inosine modification, mediated by ADAR enzymes, plays a significant role in hematopoietic stem cell function and immune response regulation. ADAR1 mutations are associated with severe autoimmune and inflammatory disorders, as the lack of ADAR1 leads to uncontrolled immune activation through the accumulation of double-stranded RNA, triggering innate immune responses. This has provided insights into novel therapeutic strategies aimed at modulating ADAR1 activity in inflammatory and autoimmune diseases.
Pseudouridine's role in RNA stabilization and translation further underscores its importance in hematopoiesis. The DKC1 gene, encoding for the pseudouridine synthase dyskerin, is mutated in X-linked dyskeratosis congenita (DC), a condition associated with bone marrow failure and increased leukemia risk. Understanding the regulation and function of pseudouridine modifications can reveal therapeutic targets for treating blood disorders associated with aberrant RNA modification.
RNA Modifications in Stemness and Regeneration
Regeneration requires the rapid supply of new cells from self-renewing stem cells. RNA modifications, particularly m6A, play a pivotal role in controlling stem cell fate and differentiation. METTL3 and METTL14 are essential for early developmental stages, with perturbations leading to developmental arrest and stem cell failure to commit to specific lineages. YTHDF3, an m6A reader, regulates hematopoietic stem cell fate by promoting the translation of key transcripts like cyclin D1 (CCND1). Loss of YTHDF3 impairs stem cell function, underscoring the importance of RNA modifications in stemness and regeneration.
Therapeutic Potential and Future Directions
The study of RNA modifications opens new avenues for therapeutic interventions in blood diseases and disorders. Targeting writers, erasers, and readers of RNA modifications offers promising strategies for treating leukemia and other hematologic malignancies. For instance, small molecule inhibitors of METTL3 have shown potential in preclinical studies for AML treatment.
Moreover, developing therapies that modulate RNA modification pathways can effectively treat autoimmune and inflammatory disorders associated with ADAR1 mutations. Investigating the role of pseudouridine modifications in cancer progression can reveal novel therapeutic targets for leukemia and other malignancies.
The discovery of GlycoRNAs, a novel class of glycosylated RNAs, further adds to the complexity of RNA biology. GlycoRNAs on the cell surface interact with immune receptors, playing a role in immune cell activation and cancer progression. Understanding the biogenesis and function of GlycoRNAs can pave the way for innovative therapeutic strategies targeting these unique RNA species.
Conclusion
RNA modifications significantly impact blood development, regeneration, and disease. The dynamic and reversible nature of these modifications allows for rapid cellular responses to environmental cues, making them crucial regulators of gene expression. Advances in the field of epitranscriptomics have provided insights into the roles of m6A, inosine, and pseudouridine modifications in hematopoiesis and cancer. Understanding these RNA modifications' regulatory mechanisms offers promising therapeutic targets for treating blood disorders and malignancies.
References
- Gunage R., Zon L. I. Role of RNA modifications in Blood development and Regeneration. Experimental Hematology. 2024: 104279.
- Dou X., et al. METTL14 is a chromatin regulator independent of its RNA N 6-methyladenosine methyltransferase activity. Protein & Cell. 2023, 14 (9): 683-697.
- Yankova E., et al. Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia. Nature. 2021, 593(7860): 597-601.
- Jiang X., et al. The role of m6A modification in the biological functions and diseases. Signal Transduction and Targeted Therapy. 2021, 6(1): 74.
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