RNA modifications are essential for the establishment of cellular identity. Although increasing evidence indicates that RNA modifications regulate the innate immune response, their role in monocyte-to-macrophage differentiation and polarisation is unclear. While mA has been widely studied, other RNA modifications, including 5 hmC, remain poorly characterised. We profiled mA and 5 hmC epitranscriptomes, transcriptomes, translatomes and proteomes of monocytes and macrophages at rest and pro- and anti-inflammatory states. Transcriptome-wide mapping of mA and 5 hmC reveals enrichment of mA and/or 5 hmC on specific categories of transcripts essential for macrophage differentiation. Our analyses indicate that mA and 5 hmC modifications are present in transcripts with critical functions in pro- and anti-inflammatory macrophages. Notably, we also discover the co-occurrence of mA and 5 hmC on alternatively-spliced isoforms and/or opposing ends of the untranslated regions (UTR) of mRNAs with key roles in macrophage biology. In specific examples, RNA 5 hmC controls the decay of transcripts independently of mA. This study provides (i) a comprehensive dataset to interrogate the role of RNA modifications in a plastic system (ii) a resource for exploring different layers of gene expression regulation in the context of human monocyte-to-macrophage differentiation and polarisation, (iii) new insights into RNA modifications as central regulators of effector cells in innate immunity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11116364 | PMC |
http://dx.doi.org/10.1007/s00018-024-05261-9 | DOI Listing |
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