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

Green, Immanuel D., Pinello, Natalia, Song, Renhua, Lee, Quitin, Halsted, James M., Kwok, Chau-To, Wong, Alex C. H., Nair, Shalima S., Clark, Susan J., Roediger, Ben, Schmitz, Ulf, Larance, Mark, Hayashi, Rippei, Rasko, John E. J., and Wong, Justin J.-L. (2020) Macrophage development and activation involve coordinated intron retention in key inflammatory regulators. Nucleic Acids Research, 48 (12). pp. 6513-6529.

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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.

Item ID: 68815
Item Type: Article (Research - C1)
ISSN: 1362-4962
Copyright Information: C The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
Funders: Cancer Council NSW (CC)
Projects and Grants: (RG20-12)
Date Deposited: 03 Aug 2021 00:20
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320407 Innate immunity @ 50%
31 BIOLOGICAL SCIENCES > 3105 Genetics > 310505 Gene expression (incl. microarray and other genome-wide approaches) @ 50%
SEO Codes: 28 EXPANDING KNOWLEDGE > 2801 Expanding knowledge > 280102 Expanding knowledge in the biological sciences @ 100%
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