Dynamic changes in RNA m6A and 5 hmC influence gene expression programs during macrophage differentiation and polarisation

• DOI: 10.1007/s00018-024-05261-9
• Publication Date: 2024-05-23T04:01:55Z
• Authors: Natalia Pinello; Renhua Song; Quintin Lee; Emilie Calonne; Kun-Long Duan; Emilie Wong; Jessica Tieng; Majid Mehravar; Bowen Rong; Fei Lan; Ben Roediger; Cheng-Jie Ma; Bi-Feng Yuan; John E. J. Rasko; Mark Larance; Dan Ye; François Fuks; Justin J.-L. Wong
• Keywords: 0301 basic medicine; Adenosine; 5 hmC; Macrophages; Biologie moléculaire; Cell Polarity; Cell Differentiation; Pharmacologie; M6A; Monocytes; 03 medical and health sciences; RNA modifications; Gene Expression Regulation; Humans; RNA; Biologie cellulaire; Original Article; RNA, Messenger; RNA Processing, Post-Transcriptional; Transcriptome; Sciences cognitives; Epitranscriptomics

AbstractRNA 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 m6A has been widely studied, other RNA modifications, including 5 hmC, remain poorly characterised. We profiled m6A and 5 hmC epitranscriptomes, transcriptomes, translatomes and proteomes of monocytes and macrophages at rest and pro- and anti-inflammatory states. Transcriptome-wide mapping of m6A and 5 hmC reveals enrichment of m6A and/or 5 hmC on specific categories of transcripts essential for macrophage differentiation. Our analyses indicate that m6A 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 m6A 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 m6A. 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.