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Thermal proteome profilng of BMAL1 ligand CCM in U2OS cell lysate

ABSTRACT: The master transcription factor BMAL1-CLOCK is crucial for orchestrating rhythmic gene expression and governing circadian rhythms. Pharmacological manipulation of this central circadian regulator requires accessible protein cavities and selective compounds. By targeting BMAL1 through a resident cavity in its PAS-B domain, we demonstrate that the small-molecule Core Circadian Modulator (CCM) penetrates and substantially expands this pocket. Biochemical and cellular analyses validate CCM's target engagement selectivity, enabling direct access to BMAL1's transcriptional activities. Thermal proteome profiling of CCM in U2OS cell lysate was performed at two concentrations (50 µM and 200 µM) and compared to DMSO. The proteome integral stability assay (PISA) setup was used.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Osteosarcoma

SUBMITTER: Ludwig Bauer

LAB HEAD: Kilian Huber

PROVIDER: PXD049298 | Pride | 2025-02-03

REPOSITORIES: pride

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Project description:Disruption of the Circadian Clock within the Cardiomyocyte Influences Myocardial Contractie Function, Metabolism, and Gene Expression Virtually every mammalian cell, including cardiomyocytes, possesses an intrinsic circadian clock. The role of this transcriptionally-based molecular mechanism in cardiovascular biology is poorly understood. We hypothesized that the circadian clock within the cardiomyocyte influences diurnal variations in myocardial biology. We therefore generated a cardiomyocyte-specific circadian clock mutant (CCM) mouse, in order to test this hypothesis. At 12 weeks of age, CCM mice exhibit normal myocardial contractile function in vivo, as assessed by echocardiography. Radiotelemetry studies reveal attenuation of heart rate diurnal variations and bradycardia in CCM mice (in the absence of conduction system abnormalities). Reduced heart rate persisted in CCM hearts perfused ex vivo in the working mode, highlighting the intrinsic nature of this phenotype. Wild-type, but not CCM, hearts exhibited a marked diurnal variation in responsiveness to an elevation in workload (80mmHg plus 1 microM epinephrine) ex vivo, with a greater increase in cardiac power and efficiency during the dark (active) phase versus the light (inactive) phase. Moreover, myocardial oxygen consumption and fatty acid oxidation rates were increased, while cardiac efficiency was decreased, in CCM hearts. These observations were associated with no alterations in mitochondrial content or structure, and modest mitochondrial dysfunction, in CCM hearts. Gene expression microarray analysis identified 548 and 176 genes in atria and ventricles, respectively, whose normal diurnal expression patterns were altered in CCM mice. These studies suggest that the cardiomyocyte circadian clock influences myocardial contractile function, metabolism, and gene expression. Keywords: Comparison of circadian oscillations in gene expression in hearts taken from wildtype and transgenic animals

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Thermal proteome profilng of BMAL1 ligand CCM in U2OS cell lysate

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