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

Natalia Pinello1,2,3, Renhua Song1,2, Quintin Lee1,2

  • 1Faculty of Medicine and Health, The University of Sydney, Camperdown, 2050, Australia.

Cellular and Molecular Life Sciences : CMLS
|May 23, 2024
PubMed

Insights

RNA modifications like N6-methyladenosine (m6A) and 5-hydroxymethylcytosine (5hmC) are crucial for innate immunity. This study reveals their roles in monocyte-to-macrophage differentiation and inflammatory responses.

Area of Science:

  • * Molecular Biology
  • * Immunology
  • * Epigenetics

Background:

  • * RNA modifications are vital for cellular identity and innate immune responses.
  • * The roles of N6-methyladenosine (m6A) and 5-hydroxymethylcytosine (5hmC) in monocyte-to-macrophage differentiation and polarization are not well understood.
  • * While m6A is extensively studied, 5hmC remains less characterized in this context.

Purpose of the Study:

  • * To comprehensively profile m6A and 5hmC epitranscriptomes, transcriptomes, translatomes, and proteomes during monocyte-to-macrophage differentiation and polarization.
  • * To investigate the enrichment and functional significance of m6A and 5hmC on specific transcripts involved in macrophage biology.
  • * To explore the interplay and distinct roles of m6A and 5hmC in regulating gene expression during innate immune cell plasticity.

Main Methods:

  • * Profiling of m6A and 5hmC epitranscriptomes, transcriptomes, translatomes, and proteomes.
  • * Transcriptome-wide mapping of m6A and 5hmC modifications.
  • * Analysis of alternatively-spliced isoforms and untranslated regions (UTRs) of mRNAs.
  • * Investigation of RNA 5hmC-mediated transcript decay.

Main Results:

  • * m6A and 5hmC modifications are enriched on transcripts critical for macrophage differentiation and function.
  • * These RNA modifications are present on transcripts involved in both pro- and anti-inflammatory macrophage states.
  • * Co-occurrence of m6A and 5hmC was observed on alternatively-spliced isoforms and UTRs of key macrophage-related mRNAs.
  • * RNA 5hmC was found to regulate transcript decay independently of m6A.

Conclusions:

  • * This study provides a comprehensive dataset and resource for understanding RNA modification roles in monocyte-to-macrophage differentiation and polarization.
  • * m6A and 5hmC are significant regulators of gene expression in plastic innate immune cells.
  • * New insights into RNA modifications as central regulators of effector cells in innate immunity are presented.
Keywords:
5 hmCEpitranscriptomicsM6AMacrophagesRNA modifications

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