CLOCK/BMAL1 interactome uncovers homeodomain factors as tissue regulators Aygenli, Fatih Huschet, Lukas A. Popp, Tanja Ribeiro, Andrea Barkhatova, Darina ; https://orcid.org/0000-0002-0062-2817 Jouffe, Céline Trozzo, Ricardo Menet, Jerome S. Rad, Roland Dyar, Kenneth A. Lech, Maciej Straub, Tobias Michael, Alicia ; https://orcid.org/0000-0002-6080-839X Robles, Maria S. ddc:570 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. Springer Nature 2026 info:eu-repo/semantics/article doc-type:article text http://purl.org/coar/resource_type/c_2df8fbb1 https://research-explorer.ista.ac.at/record/22720 Aygenli F, Huschet LA, Popp T, et al. CLOCK/BMAL1 interactome uncovers homeodomain factors as tissue regulators. <i>Nature Cell Biology</i>. 2026. doi:<a href="https://doi.org/10.1038/s41556-026-02041-4">10.1038/s41556-026-02041-4</a> eng info:eu-repo/semantics/altIdentifier/doi/10.1038/s41556-026-02041-4 info:eu-repo/semantics/altIdentifier/issn/1465-7392 info:eu-repo/semantics/altIdentifier/e-issn/1476-4679 info:eu-repo/semantics/altIdentifier/pmid/42562924 info:eu-repo/semantics/openAccess