RT Journal
A1 Collins, Emily J.
A1 Cervantes-Silva, Mariana P.
A1 Timmons, George A.
A1 O'Siorain, James R.
A1 Curtis, Annie M.
A1 Hurley, Jennifer M.
T1 Post-transcriptional circadian regulation in macrophages organizes temporally distinct immunometabolic states
JF Genome Research 
JO Genome Research 
YR 2021 
FD February 01 
VO 31 
IS 2 
SP 171 
OP 185 
DO 10.1101/gr.263814.120 
UL http://genome.cshlp.org/content/31/2/171.abstract 
AB 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.