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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE254225 | GEO | 2025/04/29

REPOSITORIES: GEO

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

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.

2025-04-27 | 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

E-MTAB-6384

Project description:RNASeq of Circadian clock genes form wild type and Bmal1 knockout mice of airway epithelial cells

2019-01-16 | E-MTAB-6384 | ExpressionAtlas

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

Expression profiling of Clock mutant dorsal skin at telogen

2009-07-17 | GSE13579 | GEO

Expression profiling of mouse dorsal skin during hair follicle cycling

2009-07-17 | GSE11186 | GEO

Genome-Wide And Phase-Specific DNA-Binding Rhythms Of BMAL1 Control Circadian Output Functions In Mouse Liver

Project description:Using chromatin immuno-precipitation (ChIP) combined with deep sequencing (ChIP-seq) we obtained a time resolved and genome-wide map of BMAL1 binding in mouse liver, which allowed to identify over two thousand binding sites with peak binding narrowly centered around Zeitgeber time (ZT) 6. Annotation of BMAL1 targets confirms carbohydrate and lipid metabolism as the major output of the circadian clock in mouse liver. Moreover, transcription regulators are largely overrepresented, several of which also exhibit circadian activity. Genes of the core circadian oscillator stand out as strongly bound, often at promoter and distal sites. Genomic sequence analysis of the sites identified E- boxes and tandem E1-E2 consensus elements. Electromobility shift assays (EMSA) showed that E1-E2 sites are bound by a dimer of BMAL1/CLOCK heterodimers with a spacing-dependent cooperative interaction that was further validated in transactivation assays. BMAL1 target genes showed cyclic mRNA expression profiles with a phase distribution centered at ZT10. Importantly, sites with E1-E2 elements showed tighter phases both in binding and mRNA accumulation. Finally, comparing the temporal accumulation of precursor mRNA and mature mRNA helped distinguish direct BMAL1 targets from targets with more complex regulation, and showed how transcriptional and post-transcriptional regulation contribute differentially to circadian expression phase. Together, our analysis of a dynamic protein-DNA interactome uncovered how genes of the core circadian oscillator are wired together and drive phase-specific circadian output programs in a complex tissue. ChIP-Seq of BMAL1 in mouse liver during one circadian cycle at 4 hour time resolution presented in this Series (GSE26602). mRNA profiling data used in this study are already published (Kornmann et al, PLoS Biol 2007) and have been deposited on ArrayExpress repository (accession number: E-MEXP-842).

2011-02-23 | E-GEOD-26602 | biostudies-arrayexpress

BMAL1 associates with NOP58 in the nucleolus and contributes to pre-rRNA processing

Project description:The transcription factor BMAL1 is a core element of the circadian clock that contributes to cyclic control of genes transcribed by RNA polymerase II. By using biochemical cellular fractionation and immunofluorescence analyses we reveal a previously uncharacterized nucleolar localization for BMAL1. We used an unbiased approach to determine the BMAL1 interactome by mass spectrometry and identified NOP58 as a prominent nucleolar interactor. NOP58, a core component of the box C/D small nucleolar ribonucleoprotein complex, associates with Snord118 to control specific pre-ribosomal RNA (rRNA) processing steps. These results suggest a non-canonical role of BMAL1 in rRNA regulation. Indeed, we show that BMAL1 controls NOP58-associated Snord118 nucleolar levels and cleavage of unique pre-rRNA intermediates. Our findings identify an unsuspected function of BMAL1 in the nucleolus that appears distinct from its canonical role in the circadian clock system

2020-08-25 | PXD018946 | Pride

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