Post-transcriptional circadian regulation in macrophages organizes temporally distinct immunometabolic states
- Emily J. Collins1,
- Mariana P. Cervantes-Silva2,
- George A. Timmons2,
- James R. O'Siorain2,
- Annie M. Curtis2 and
- Jennifer M. Hurley1,3
- 1Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, New York 12180, USA;
- 2School of Pharmacy and Biomedical Sciences and Tissue Engineering Research Group, Royal College of Surgeons in Ireland, Dublin D02, Ireland;
- 3Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, New York 12180, USA
Abstract
Our core timekeeping mechanism, the circadian clock, plays a vital role in immunity. Although the mechanics of circadian control over the immune response is generally explained by transcriptional activation or repression derived from this clock's transcription-translation negative-feedback loop, research suggests that some regulation occurs beyond transcriptional activity. We comprehensively profiled the transcriptome and proteome of murine bone marrow-derived macrophages and found that only 15% of the circadian proteome had corresponding oscillating mRNA, suggesting post-transcriptional regulation influences macrophage clock regulatory output to a greater extent than any other tissue previously profiled. This regulation may be explained by the robust temporal enrichment we identified for proteins involved in degradation and translation. Extensive post-transcriptional temporal-gating of metabolic pathways was also observed and further corresponded with daily variations in ATP production, mitochondrial morphology, and phagocytosis. The disruption of this circadian post-transcriptional metabolic regulation impaired immune functionality. Our results demonstrate that cell-intrinsic post-transcriptional regulation is a primary driver of circadian output in macrophages and that this regulation, particularly of metabolic pathways, plays an important role in determining their response to immune stimuli.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.263814.120.
- Received March 20, 2020.
- Accepted November 20, 2020.
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