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

ABSTRACT: The mechanisms by which core clock components are spatially organized to ensure robust oscillations in mammals remains 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 punctate that oscillate in sync with the circadian cycle. Deletion analysis and optogenetic clustering identify an N_x001E_-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 the 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE325862 | GEO | 2026/03/31

REPOSITORIES: GEO

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Similar Datasets

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

Project description:The mechanisms by which core clock components are spatially organized to ensure robust oscillations in mammals remains 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 punctate that oscillate in sync with the circadian cycle. Deletion analysis and optogenetic clustering identify an N_x001E_-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 the 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.

2026-03-31 | GSE325358 | GEO

Circadian clock regulation by compartmentalized protein translation

Project description:Cells exquisitely compartmentalize many biochemical reactions through phase-separated membrane-less organelles. Besides spatial organization, many biological processes are temporally regulated. While both transcription and translation oscillate in a rhythmic manner, the regulatory mechanism of the latter is understudied. Here we report that the translational regulation during circadian cycles is associated with oscillating phase separation controlled by Ataxin-2 and Ataxin-2L. Ataxin-2/2L forms rhythmic condensates through phase separation in the mammalian central clock suprachiasmatic nucleus to selectively concentrate the transcripts of the core clock genes and recruit the mRNA translation machinery. The rhythmic translational activation is abolished in cells and mouse circadian behavior is altered in the absence of Ataxin-2/2L. During aging or neurodegeneration, Ataxin-2/2L form large, irreversible puncta that no longer regulate translation. Overall, our results unveil Ataxin-2/2L’s role as the master regulators of rhythmic translation via a oscillating phase-separation, and explained the reason for their dysfunction in disease states.

2023-06-24 | GSE222433 | GEO

PBAF/cBAF reorganization on H3.3 chromatin regulates BMAL1 activity in the absence of circadian negative feedback.

Project description:Circadian rhythms in gene expression are coincident with 24hr dynamics in the recruitment of the core-clock transcription factor heterodimer CLOCK-BMAL1 to chromatin. In the liver, circadian chromatin is characterized by rhythmic histone modifications and the deposition of histone variant H2A.Z. However, other histone variants and the remodelers that work in conjunction with CLOCK-BMAL1 on variant chromatin remain poorly understood. Here, we reveal that H3.3 variant histone deposition peaks during the daytime in liver chromatin and that CLOCK-BMAL1 is recruited to H3.3 nucleosomes. Moreover, H3.3:CLOCK-BMAL1 associates with PBAF and BRG1/cBAF complexes - members of the SWI/SNF remodeler family - only during the active phase of the circadian cycle. In clock-disrupted Per1-/-; Per2-/- livers, we observe a depletion in ARID2, the central cog in the molecular assembly of the PBAF complex, accompanied by an increase in H3.3 incorporation. Remarkably, a disassembly of PBAF complex and the concurrent reduction in BRG1 triggers a remodeler reorganization in Per knockout livers, where BRM/cBAF now targets BMAL1 at readily-accessible genomic sites. An abundance of fragile acetylated H3.3 nucleosomes and a remodeler reorganization provide a mechanistic basis for BMAL1 activity in the absence of PER-mediated negative feedback.

2025-08-22 | PXD061974 | Pride

Deletion of Bmal1 in Intestinal Epithelium Protects against Colonic Inflammation by Suppressing the Apoptosis Pathway (CUT&Tag)

Project description:The circadian clock has been shown to regulate inflammatory bowel disease (IBD), but the underlying mechanisms remain unclear. Here, we observed that the mice in the active phase of the circadian clock were more tolerant to dextrose sodium sulfate (DSS)-induced colitis, compared to those in the resting phase. Furthermore, we found that the circadian gene Bmal1 displayed a dynamic expression pattern in mouse colonic epithelium during the circadian clock, with a high level in the resting phase and a low in the active phase. Ablation of Bmal1 in the intestinal epithelium reduced inflammatory symptoms in the colon of the DSS-treated mice. The mice with Bmal1 deletion exhibited no obvious disruption on intestinal homeostasis, rather were more resistant to DSS-induced inflammation, with less body weight change, fewer pathological symptoms, and greater epithelial integrity, compared to the control group. Mechanistically, BMAL1 promoted apoptosis by binding to the apoptosis-related genes, such as Bax, P53 and Bak1, and transcriptionally activating their expression. Collectively, our results reveal the Bmal1-centered circadian clock is involved in intestinal repair upon injure. Clinically, targeting Bmal1 function may be a promising approach to treat inflammation-related gastrointestinal tract diseases.

2025-04-29 | GSE254225 | GEO

Deletion of Bmal1 in Intestinal Epithelium Protects against Colonic Inflammation by Suppressing the Apoptosis Pathway I

2025-04-27 | GSE253421 | GEO

Deletion of Bmal1 in Intestinal Epithelium Protects against Colonic Inflammation by Suppressing the Apoptosis Pathway

2025-04-28 | GSE271174 | GEO

Transcriptional Repressor Gm129 Modulates the Circadian Gene Expression by Inhibiting CLOCK:BMAL1 Activity

Project description:The mammalian circadian clock is a molecular oscillator composed of a feedback loop that involves transcriptional activators CLOCK and BMAL1, and repressors Cryptochrome (CRY) and Period (PER). Here we show that a direct CLOCK-BMAL1 target gene, Gm129, is a novel regulator of the feedback loop. ChIP analysis revealed that the CLOCK:BMAL1:CRY1 complex strongly occupies the promoter region of Gm129. Both mRNA and protein levels of GM129 exhibit high amplitude circadian oscillations in mouse liver, and Gm129 gene encodes a nuclear-localized protein that directly interacts with BMAL1 and represses CLOCK:BMAL1 activity. In vitro and in vivo protein-DNA interaction results demonstrate that, like CRY1, GM129 functions as a repressor by binding to the CLOCK:BMAL1 complex on DNA. Although Gm129-/- or Cry1-/- Gm129-/- mice retain a robust circadian rhythm, the peaks of Nr1d1 and Dbp mRNAs in liver exhibit significant phase delay compared to control. Our results suggest that, in addition to CRYs and PERs, GM129 protein contributes to the transcriptional feedback loop by modulating CLOCK:BMAL1 activity as a transcriptional repressor. Examination of 3 transcriptional regulators in mouse liver

2014-01-07 | E-GEOD-53828 | biostudies-arrayexpress

Gene Model 129 (Gm129) Encodes a Novel Transcriptional Repressor that Modulates Circadian Gene Expression

2014-01-07 | GSE53828 | GEO

Regulatory logic of the coupled diurnal and feeding cycles in the mouse liver [array]

Project description:In mammals, the circadian clock controls behavioral, physiological and cellular rhythms. Part of this daily variation is controlled by transcription-translation feedback loops in sync with the light-dark phase. On the other hand, daily rhythms in expression of a multitude of genes are related to nutrient-response cycles. Time-resolved mapping of DNase I hypersensitive sites (DHS) throughout the day can identify details of the regulatory interplay between metabolism and the internal clock at a molecular level. Here, we report a genome-wide analysis of mammalian DHS using high‐throughput sequencing of DNase tags from mouse liver with a resolution of 4 h (12 h light/12 h dark). Among the 65’000 DHS sites identified, a significant proportion of distal DHS showed a diurnal cycle, suggesting a fine regulation of oscillating genes by enhancers, which we seek to understand better. Using PolII and H3K27ac ChIP-seq, we characterize the DHS and study the dynamics of each mark in wild-type and Bmal1-KO mice. We use the sequence motif content of each DHS and a linear regression model to explain DHS temporal behaviour in terms of phase and amplitude. We monitor the temporal expression of target genes in order to understand the phase-specific regulation in the circadian context. Interestingly, DHS associated with circadian genes tend to be time-correlated with expression, Pol II and H3K27ac marks. The Bmal1-KO phenotype in light-dark conditions show a proportion of DHS with circadian rhythms associated with transcription factors related to metabolism, due to food entrainment and systemic cues.

2016-12-31 | GSE60577 | GEO

Expression profiling of Bmal mutant dorsal skin at telogen of hair follicle cycling

Project description:Hair follicles undergo recurrent cycling of controlled growth (anagen), regression (catagen), and relative quiescence (telogen) with a defined periodicity. Taking a genomics approach to study gene expression during synchronized mouse hair follicle cycling, we discovered that, in addition to circadian fluctuation, CLOCK-regulated genes are also modulated in phase with the hair growth cycle. During telogen and early anagen, circadian clock genes are prominently expressed in the secondary hair germ, which contains precursor cells for the growing follicle. Analysis of Clock and Bmal1 mutant mice reveals a delay in anagen progression, and the secondary hair germ cells show decreased levels of phosphorylated Rb and lack mitotic cells, suggesting that circadian clock genes regulate anagen progression via their effect on the cell cycle. Consistent with a block at the G1 phase of the cell cycle, we show a significant upregulation of p21 in Bmal1 mutant skin. While circadian clock mechanisms have been implicated in a variety of diurnal biological processes, our findings indicate that circadian clock genes may be utilized to modulate the progression of non-diurnal cyclic processes.

2009-07-17 | GSE14006 | GEO

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