BMAL1 regulates circadian rhythms via phase separation–mediated transcriptional hub formation

Apr 30, 2026Signal transduction and targeted therapy

BMAL1 controls daily body rhythms by forming clusters that organize gene activity

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

The positive limb factor BMAL1 forms dynamic biomolecular condensates essential for circadian transcription and behavior.

Endogenous BMAL1 forms nuclear puncta that oscillate with the circadian cycle.
A specific 90-amino acid region within BMAL1 is crucial for its phase separation and is influenced by phosphorylation.
BMAL1 condensates selectively recruit other proteins like CLOCK, p300, and MED1, which are promoted by E-box DNA.
An IDR-deleted BMAL1 mutant does not restore rhythmic transcription in Bmal1-KO cells.
Reintroduction of the mutant into SCN-specific Bmal1-KO mice fails to restore locomotor rhythms.

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The mechanisms by which core clock components are spatially organized to ensure robust oscillations in mammals remain unclear. Here, we identify the positive limb factor BMAL1 as a phase-separating protein that forms dynamic biomolecular condensates essential for circadian transcription and behavior. Endogenous BMAL1 forms nuclear puncta that oscillate in sync with the circadian cycle. Deletion analysis and optogenetic clustering identify an N-terminal 90-amino acid intrinsically disordered region whose phosphorylation state tunes BMAL1 phase separation. Besides, BMAL1 condensates behave as multi-molecular assemblies that selectively recruit CLOCK, p300, MED1, and are specifically promoted by E-box DNA. Functionally, an IDR-deleted BMAL1 mutant fails to rescue rhythmic transcription in Bmal1-KO cells and cannot restore locomotor rhythms when reintroduced into SCN-specific Bmal1‑KO mice. These findings establish BMAL1 condensates as dynamic transcriptional hubs that couple phase separation to circadian rhythm in cells and in vivo.