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Macrophage development and activation involve coordinated intron retention in key inflammatory regulators

Abstract

Monocytes and macrophages are essential components of the innate immune system. Herein, we report that intron retention (IR) plays an important role in the development and function of these cells. Using Illumina mRNA sequencing, Nanopore direct cDNA sequencing and proteomics analysis, we identify IR events that affect the expression of key genes/proteins involved in macrophage development and function. We demonstrate that decreased IR in nuclear-detained mRNA is coupled with increased expression of genes encoding regulators of macrophage transcription, phagocytosis and inflammatory signalling, including ID2, IRF7, ENG and LAT. We further show that this dynamic IR program persists during the polarisation of resting macrophages into activated macrophages. In the presence of proinflammatory stimuli, intron-retaining CXCL2 and NFKBIZ transcripts are rapidly spliced, enabling timely expression of these key inflammatory regulators by macrophages. Our study provides novel insights into the molecular factors controlling vital regulators of the innate immune response.

Type Journal
ISBN 1362-4962 (Electronic) 0305-1048 (Linking)
Authors Green, I. D.; Pinello, N.; Song, R.; Lee, Q.; Halstead, J. M.; Kwok, C. T.; Wong, A. C. H.; Nair, S. S.; Clark, S. J.; Roediger, B.; Schmitz, U.; Larance, M.; Hayashi, R.; Rasko, J. E. J.; Wong, J. J.
Responsible Garvan Author Prof Susan Clark
Publisher Name NUCLEIC ACIDS RESEARCH
Published Date 2020-07-09
Published Volume 48
Published Issue 12
Published Pages 6513-6529
Status Published in-print
DOI 10.1093/nar/gkaa435
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/32449925