Multilayer Timing of Cardiac Circadian Regulation Informs Prevention and Treatment of Cardiovascular Disease

Mar 3, 2026Vascular health and risk management

Multiple Daily Patterns of Heart Clock Timing May Help Prevent and Treat Heart Disease

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

A total of 2552 rhythmic transcripts and 139 rhythmic proteins were identified in the mouse heart.

Only 31 genes were rhythmic at both the transcript and protein levels, indicating significant phase decoupling.
The stability of translation efficiency was positively correlated with the amplitude of rhythmic proteins.
Rhythmic proteins showed enrichment of specific phosphorylation motifs influenced by proline-directed kinases.
BMAL1 binding enhanced transcriptional amplitude, while REV-ERBα binding caused delayed expression of target genes.
These findings suggest that cardiac circadian regulation involves complex interactions between transcriptional activation, translation, and post-translational modifications.

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BACKGROUND: Cardiovascular diseases remain the leading cause of death and economic burden worldwide. Increasing evidence indicates that sleep disturbance and circadian rhythm disruption are major risk drivers for hypertension, coronary artery disease, heart failure, and arrhythmia. Although the classical transcription-translation feedback loop (TTFL) model explains the basic mechanism of rhythm generation, increasing evidence suggests that the heart-an organ with high metabolic demand-maintains circadian stability through coordinated transcriptional, translational, and post-translational regulation.

METHODS: We developed an integrative, time-resolved, multilayer in silico framework to systematically analyze cardiac circadian regulation by combining mouse heart time-series RNA-seq (GSE54650), proteomics (PXD002870), phosphoproteomics (PXD036824), BMAL1 and Rev-erbα ChIP-seq, and enhancer RNA (eRNA) datasets. Rhythmicity was assessed using MetaCycle, with cross-layer comparisons evaluating concordance and divergence between transcriptomic and proteomic rhythms, and translation efficiency (TE) estimated from protein-to-mRNA ratios. Enhancer-gene coupling, transcription factor binding, and phosphorylation motif analyses were integrated to investigate multilayer regulatory coordination.

RESULTS: We identified 2552 rhythmic transcripts and 139 rhythmic proteins, with only 31 genes rhythmic at both layers, indicating substantial RNA-protein phase decoupling in the heart. Temporal stability of TE correlated positively with protein amplitude, suggesting that stable translation supports robust protein rhythmicity. Phosphoproteomic analyses revealed enrichment of SP motifs mediated by proline-directed kinases in rhythmic proteins. BMAL1 binding was associated with enhanced transcriptional amplitude, whereas REV-ERBα binding was associated with delayed target gene expression, forming complementary enhancer-level regulatory dynamics.

CONCLUSION: This study supports a multilayered integrative model of cardiac circadian regulation in which rhythmic gene expression is jointly shaped by transcriptional activation, translational precision, and post-translational modification. By extending the classical "clock-transcription-protein" paradigm, our findings highlight enhancer-level control mediated by BMAL1 and Rev-erbα as an important mechanism contributing to the stabilization of cardiac circadian timing.

Key numbers

31 of 4958

RNA-Protein Rhythmicity Overlap

Genes rhythmic at both RNA and protein levels.

2552

Rhythmic Transcripts Identified

Total rhythmic transcripts identified in the study.

139

Rhythmic Proteins Identified

Total rhythmic proteins identified in the study.

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Multilayer Timing of Cardiac Circadian Regulation Informs Prevention and Treatment of Cardiovascular Disease

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