bims-ciryme Biomed News
on Circadian rhythms and metabolism
Issue of 2023–10–08
two papers selected by
Gabriela Da Silva Xavier, University of Birmingham
  1. Impact of Bmal1 rescue and time-restricted feeding on liver and muscle proteomes during the active phase in mice.
  2. An intrinsically disordered region controlling condensation of a circadian clock component and rhythmic transcription in the liver.
  1. Mol Cell Proteomics. 2023 Oct 02. pii: S1535-9476(23)00166-4. [Epub ahead of print] 100655
    Impact of Bmal1 rescue and time-restricted feeding on liver and muscle proteomes during the active phase in mice.
    Jacob G Smith, Jeffrey Molendijk, Ronnie Blazev, Wan Hsi Chen, Qing Zhang, Christopher Litwin, Valentina M Zinna, Patrick-Simon Welz, Salvador Aznar Benitah, Carolina M Greco, Paolo Sassone-Corsi, Pura Muñoz-Cánoves, Benjamin L Parker, Kevin B Koronowski.
       OBJECTIVE: Molecular clocks and daily feeding cycles support metabolism in peripheral tissues. Although the roles of local clocks and feeding are well defined at the transcriptional level, their impact on governing protein abundance in peripheral tissues is unclear. Here, we determine the relative contributions of local molecular clocks and daily feeding cycles on liver and muscle proteomes during the active phase in mice.
    METHODS: LC-MS/MS was performed on liver and gastrocnemius muscle harvested four hours into the dark phase from wild-type (WT), Bmal1 knockout (KO), and dual liver- and muscle- Bmal1-rescued (LMRE) mice housed under 12-h light/12-h dark cycles with either ad libitum feeding or time-restricted feeding (TRF) in the dark phase. Additional molecular and metabolic analyses were performed on liver and cultured hepatocytes.
    RESULTS: Feeding-fasting cycles had only minimal effects on liver and few, if any, on muscle. In contrast, Bmal1 KO altered the abundance of 674 proteins in liver, and 80 in muscle. Rescue of liver and muscle Bmal1 restored ∼50% of proteins in liver and ∼25% in muscle. These included proteins involved in fatty acid oxidation in liver and carbohydrate metabolism in muscle. For liver, proteins involved in de novo lipogenesis were largely dependent on Bmal1 function in other tissues (i.e., the wider clock system). Proteins regulated by BMAL1 in liver and muscle were enriched for secreted proteins. We found that the abundance of FGF1, a liver secreted protein, requires BMAL1, and that autocrine FGF1 signaling modulates mitochondrial respiration in hepatocytes.
    CONCLUSIONS: In liver and muscle, BMAL1 is a more potent regulator of dark phase proteomes than daily feeding cycles, highlighting the need to assess protein levels in addition to mRNA when investigating clock mechanisms. The proteome is more extensively regulated by BMAL1 in liver than in muscle and many metabolic pathways in peripheral tissues are reliant on the function of the clock system as a whole.
    Keywords:  Bmal1; Circadian clock; FGF1; circadian rhythm; fibroblast growth factor; liver; muscle; time-restricted feeding
    DOI:  https://doi.org/10.1016/j.mcpro.2023.100655
  2. Mol Cell. 2023 Oct 05. pii: S1097-2765(23)00705-0. [Epub ahead of print]83(19): 3457-3469.e7
    An intrinsically disordered region controlling condensation of a circadian clock component and rhythmic transcription in the liver.
    Kun Zhu, Isaac J Celwyn, Dongyin Guan, Yang Xiao, Xiang Wang, Wenxiang Hu, Chunjie Jiang, Lan Cheng, Rafael Casellas, Mitchell A Lazar.
      Circadian gene transcription is fundamental to metabolic physiology. Here we report that the nuclear receptor REV-ERBα, a repressive component of the molecular clock, forms circadian condensates in the nuclei of mouse liver. These condensates are dictated by an intrinsically disordered region (IDR) located in the protein's hinge region which specifically concentrates nuclear receptor corepressor 1 (NCOR1) at the genome. IDR deletion diminishes the recruitment of NCOR1 and disrupts rhythmic gene transcription in vivo. REV-ERBα condensates are located at high-order transcriptional repressive hubs in the liver genome that are highly correlated with circadian gene repression. Deletion of the IDR disrupts transcriptional repressive hubs and diminishes silencing of target genes by REV-ERBα. This work demonstrates physiological circadian protein condensates containing REV-ERBα whose IDR is required for hub formation and the control of rhythmic gene expression.
    Keywords:  3D genome; REV-ERB; circadian; condensates; intrinsically disordered region; liver; repression; transcription
    DOI:  https://doi.org/10.1016/j.molcel.2023.09.010
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