Post-transcriptional circadian regulation in macrophages organizes temporally distinct immunometabolic states

Genome Research - Tập 31 Số 2 - Trang 171-185 - 2021
Emily Collins1, Mariana P. Cervantes‐Silva2, George A. Timmons2, James R. O’Siorain2, Annie M. Curtis2, Jennifer Hurley1,3
11Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, New York 12180, USA
22School of Pharmacy and Biomedical Sciences and Tissue Engineering Research Group, Royal College of Surgeons in Ireland, Dublin D02, Ireland
33Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, New York 12180, USA

Tóm tắt

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.

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Genome Research

Tập 31 Số 2

171-185

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