Signal transduction and targeted therapyApr 30, 2026

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

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 27, 2026

Abstract

Essence

BMAL1 phase separation helps form transcriptional hubs needed for circadian rhythms in cells and mice.

Evidence

Mechanistic cell and mouse experiments mapped BMAL1 condensates to a phosphorylated N-terminal IDR and tested rescue in Bmal1-KO cells and SCN-specific Bmal1-KO mice.

Caveat

The evidence is preclinical and centered on BMAL1 loss-and-rescue systems, so human circadian effects were not tested.

Simplified

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.