bims-ciryme 2026-08-09 papers

Proc Natl Acad Sci U S A. 2026 Aug 11. 123(32): e2618203123

Unveiling previously undescribed circadian clock regulators and action mechanisms via TurboID-based profiling of the LWD1 interactome in Arabidopsis thaliana.

Chun-Kai Huang, Chuan-Chih Hsu, Huang-Lung Tsai, Wen-Dar Lin, Jing-Fen Wu, Shu-Hsing Wu.

The synchronization of the internal circadian clock with the external 24-h diel cycle is critical for plant growth and fitness. LIGHT-REGULATED WD proteins (LWDs) are essential for sustaining a precise and robust circadian clock in Arabidopsis [Y. Wang et al., Plant Cell 23, 486-498 (2011); J. F. Wu et al., Nat Commun. 7, 13181 (2016)]. However, the action mechanisms by which LWDs orchestrate the expression of clock genes remain largely elusive. We systematically identified 219 LWD1-interacting protein partners at three Zeitgeber times (ZTs) using a TurboID-mediated proximity labeling approach. Selected interacting proteins were experimentally verified as new regulators of the Arabidopsis circadian clock. Our data also support that LWD1-PSEUDO RESPONSE REGULATORS (PRRs)-TOPLESS (TPL) complex represses the morning gene CIRCADIAN CLOCK ASSOCIATED (CCA1), shaping the expression trough of CCA1 in the late afternoon/early evening under diel cycles. Our results revealed a new corepressor role of LWD1, working in conjunction with epigenetic regulators and transcription factors to underpin the precise operation of the circadian clock.

Keywords: TurboID; circadian clock; epigenetic regulators; proximity labeling; transcriptional repressors

DOI: https://doi.org/10.1073/pnas.2618203123

Nat Cell Biol. 2026 Aug 06.

CLOCK/BMAL1 interactome uncovers homeodomain factors as tissue regulators.

Fatih Aygenli, Lukas A Huschet, Tanja Popp, Andrea Ribeiro, Darina Barkhatova, Céline Jouffe, Ricardo Trozzo, Jerome S Menet, Roland Rad, Kenneth A Dyar, Maciej Lech, Tobias Straub, Alicia K Michael, Maria S Robles.

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.

DOI: https://doi.org/10.1038/s41556-026-02041-4

Neuron. 2026 Aug 07. pii: S0896-6273(26)00570-2. [Epub ahead of print]

Temporal changes in metabolism guide oligodendrocyte precursor cell dynamics in aging and multiple sclerosis.

Tess Dierckx, Sarah E Wilson, Rebecca Buchanan, Themistoklis M Tsarouchas, Yuhsiang Cheng, Maria Sacconi Nunez, Kelly Strickland, Dena Kumsa, Yohan S S Auguste, Sam Vanherle, Sander Bouwman, Daniela Rojo, Louisa Dal Cengio, Celia Lerma-Martin, Yassene Mohammed, Lucas Schirmer, Jeroen F J Bogie, Bart J L Eggen, Erin M Gibson.

Impaired oligodendrocyte precursor cell (OPC) differentiation limits myelin renewal in aging and contributes to multiple sclerosis (MS) progression. How aging drives OPC deficits remains incompletely understood. We find dysregulation of genes associated with the circadian clock, including Bmal1, and metabolism in aged compared with young OPCs. Targeted loss of Bmal1 in OPCs drives metabolic dysfunction, leading to cellular senescence and impaired dynamics. OPC proliferation and differentiation occur at different rates throughout the day in young adult mice and become disrupted with aging. Chronotherapeutic targeting of BMAL1-controlled sirtuin signaling restores Bmal1-disrupted OPC dynamics after demyelination via sirtuin 2 (Sirt2)-dependent mechanisms. Induced pluripotent stem cell (iPSC)-derived OPCs from MS patients and MS lesion oligodendroglia recapitulate BMAL1 and SIRT2 disruptions. These findings establish BMAL1 as a key regulator of OPC energy metabolism, sirtuin homeostasis, and senescence. We anticipate that this work will provide a foundation for future studies investigating the interconnected roles of aging, circadian disruption, and myelin biology.

Keywords: BMAL1; OPCs; aging; circadian; iPSC; metabolism; multiple sclerosis; myelination; oligodendrocyte precursor cells; oligodendrocytes

DOI: https://doi.org/10.1016/j.neuron.2026.07.015