RT Journal Article SR Electronic T1 Transcriptional changes are regulated by metabolic pathway dynamics but decoupled from protein levels JF bioRxiv FD Cold Spring Harbor Laboratory SP 833921 DO 10.1101/833921 A1 Jack E. Feltham A1 Shidong Xi A1 Struan C. Murray A1 Meredith Wouters A1 Julian Urdiain-Arraiza A1 Raphael Heilig A1 Charlotte George A1 Anna F. Townley A1 Emile Roberts A1 Benedikt M. Kessler A1 Sabrina Liberatori A1 Philip D. Charles A1 Andrew Angel A1 Roman Fischer A1 Jane Mellor YR 2020 UL http://biorxiv.org/content/early/2020/06/10/833921.abstract AB Transcription is necessary for the synthesis of new proteins, often leading to the assumption that changes in transcript levels lead to changes in protein levels which directly impact a cell’s phenotype. Using a synchronized biological rhythm, we show that despite genome-wide partitioning of transcription, transcripts and translation levels into two phase-shifted expression clusters related to metabolism, detectable protein levels remain constant over time. This disconnect between cycling translation and constant protein levels can be explained by slow protein turnover rates, with overall protein levels maintained by low level pulses of new protein synthesis. Instead, rhythmic post-translational regulation of the activities of different proteins, influenced by the metabolic state of the cells, appears to be key to coordinating the physiology of the biological rhythm with cycling transcription. Thus, transcriptional and translational cycling reflects, rather than drives, metabolic and biosynthetic changes during biological rhythms. We propose that transcriptional changes are often the consequence, rather than the cause, of changes in cellular physiology and that caution is needed when inferring the activity of biological processes from transcript data. Changes in protein levels do not explain the changing states of a biological rhythmSlow protein turnover rates decouple proteins levels from a rhythmic transcriptomeMetabolites determine protein activity via rhythmic post-translational modificationsCycling protein activity explains rhythmic transcription and ribosome biogenesisA cycling transcriptome is a consequence, not a cause, of physiological changesCompeting Interest StatementJM holds stock in Oxford Biodynamcs plc, Chronos Therapeutics Ltd. and Sibelius Natural Products Ltd., and acts an as advisor to OBD and Sibelius.