Nature cell biologyAug 7, 2026

Proteins CLOCK and BMAL1 reveal key tissue regulators involved in gene control

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Aug 8, 2026

Abstract

A total of 1,510 associated proteins were detected in CLOCK/BMAL1 protein complexes across mouse liver, kidney, and lung.

Most identified proteins displayed tissue-specific interactions that were not solely explained by their abundance.
Homeodomain transcription factors PROX1, HNF1B, and HOXA5 were found to be enriched in specific tissues and interact with BMAL1.
These transcription factors co-occupy many genomic sites associated with BMAL1, influencing circadian gene expression in an organ-specific manner.
Tissue-specific transcription factors may play a crucial role in defining the cellular identity of the core circadian clock.

Simplified

Circadian clocks underlie daily rhythms in physiology by coordinating temporal patterns of gene expression and protein function throughout the body. At the core of this system in mammals is CLOCK/BMAL1, a ubiquitously expressed heterodimeric transcription factor complex that orchestrates tissue-specific circadian gene expression. The basis for this specificity remains unclear, but tissue-specific interactions at chromatin could provide one. Here we used chromatin immunoprecipitation coupled to mass spectrometry to map CLOCK/BMAL1-associated protein complexes on chromatin in mouse liver, kidney and lung. We detected 1,510 associated proteins, most of which were tissue-specific and not explained by protein abundance. Among these, we identified the homeodomain transcription factors PROX1, HNF1B and HOXA5 as tissue-enriched interactors that bind BMAL1, co-occupy most BMAL1 genomic sites and establish organ-restricted circadian transcription. Our findings demonstrate that tissue-specific transcription factors confer cellular identity on the core clock, thereby contributing to organ-specific patterns of rhythmic gene expression.