Bmal1 regulates inflammatory response in macrophage
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE95712 | GEO | 2017/08/31
SECONDARY ACCESSION(S): PRJNA378204
REPOSITORIES: GEO
Similar Datasets
Project description:Circadian (~24 hour) clocks exist in almost all types of living organism and play a fundamental role in regulating daily physiological and behavioural processes. The transcription factor BMAL1 (ARNTL) is thought to be one of the principal drivers of the molecular clock in mammals since its deletion abolishes 24-hour activity patterning, an important physiological output of the clockwork. However, whether or not Bmal1-/- mice can nevertheless display molecular 24-hour rhythms is unknown. Here, we determined whether Bmal1 function is necessary for daily molecular oscillations in two tissues – skin fibroblasts and liver. Unexpectedly, both tissues exhibited robust 24-hour oscillations over 2-3 days in the absence of any exogenous synchronizers such as daily light or temperature cycles. This demonstrates a competent 24-hour molecular pacemaker in Bmal1 knockouts. Indeed, molecular oscillations were pervasive throughout the transcriptome, proteome and phosphoproteome of Bmal1-/- mice. In particular, several proteins exhibited rhythmic phosphorylation in both Bmal1-proficient and -deficient cells, highlighting an unanticipated role for post-translational regulators in 24-hour rhythms in the absence of any known clock mechanisms.
2020-02-17 | PXD009243 | Pride
Project description:In spite of lacking circadian rhythms, several master clock regulators are readily expressed in embryonic stem cells (ESCs). In particular, the role of Brain and Muscle ARNT-Like 1 (Bmal1, also known as Arntl) remains to be addressed. Here, we generated Bmal1 CRISPR/cas9 knock-out ESCs to elucidate the role of BMAL1 in pluripotency maintenance and differentiation. Our findings indicate that although BMAL1 is dispensable for ESC maintenance, it is required for proper differentiation. Moreover, we find that Bmal1 participates in the transcriptional regulation of lineage specification programs during differentiation and gastrulation in vitro. In particular, loss-of-function of Bmal1 changes the metabolic state of ESCs by promoting more oxidation at the expense of glycolysis. Our data points to a circadian clock-independent function of BMAL1 during early developmental stages, and will help in the understanding of the mechanisms that control exit from pluripotency and early cell-fate decisions.
2020-04-13 | GSE133908 | GEO
Project description:Circadian clocks exist in almost all levels of living organisms and play elementary roles in the persistence of regular physiological and behavioural processes. Canonical transcription/translation feedback loop models portray BMAL1 (ARNTL) as one of the principal drivers of circadian periodicity in mammalian systems. In this integrated multi-omics study, we demonstrate, for the first time, 24 hr circadian oscillations in the expression levels of several transcripts and proteins in dexamethasone-synchronized Bmal1-/- mouse fibroblast cells and liver tissue slices. Intriguingly, daily oscillations were also observed in phosphoproteome profiles in the absence of this core clock gene. Our findings reveal that Bmal1 knockout radically alters the expression and phosphorylation patterns of mice hepatic proteome, which possibly attributes to considerably different sets of rhythmic candidates compared to wild-type. It is, therefore, reasonable to accentuate that circadian rhythms are not obliterated in mammalian systems due to deletion of the core clock genes.
2020-02-14 | GSE111696 | GEO
Project description:Circadian clocks exist in almost all levels of living organisms and play elementary roles in the persistence of regular physiological and behavioural processes. Canonical transcription/translation feedback loop models portray BMAL1 (ARNTL) as one of the principal drivers of circadian periodicity in mammalian systems. In this integrated multi-omics study, we demonstrate, for the first time, 24 hr circadian oscillations in the expression levels of several transcripts and proteins in dexamethasone-synchronized Bmal1-/- mouse fibroblast cells and liver tissue slices. Intriguingly, daily oscillations were also observed in phosphoproteome profiles in the absence of this core clock gene. Our findings reveal that Bmal1 knockout radically alters the expression and phosphorylation patterns of mice hepatic proteome, which possibly attributes to considerably different sets of rhythmic candidates compared to wild-type. It is, therefore, reasonable to accentuate that circadian rhythms are not obliterated in mammalian systems due to deletion of the core clock genes.
2020-02-14 | GSE134333 | GEO
Project description:The circadian clock regulates many aspects of immunity. Bacterial infections are affected by time of day, but the mechanisms involved remain undefined. Here we show that loss of the core clock protein BMAL1 in macrophages confers protection against pneumococcal pneumonia. RNAseq was performed on peritoneal macrophages from wild type and BMAL1 knock out mice.
2019-12-20 | E-MTAB-8411 | biostudies-arrayexpress
Project description:Hepatocyte Nuclear Factor 4 alpha (HNF4α), a master regulator of hepatocyte differentiation, and circadian regulator Aryl Hydrocarbon-Like Receptor-Like 1 (ARNTL, or BMAL1) though robustly co-expressed in healthy liver, are incompatible within the context of HCC. Differential expression of Bmal1 and Hnf4α may control susceptibility to liver disease and ultimately, hepatocellular carcinoma. We compared gene expression profiles under conditions of inducible loss of hepatic Hnf4α and inducible loss of Hnf4a and Bmal1 in this RNA-seq experiment. Hepatic Hnf4a (H-KO) or Hnf4a and Bmal1 (BH-KO) were inducibly knocked out after 5 days tamoxifen treatment in eight week-old mice (H-KO) or (BH-KO) followed by vivarium chow or high fat feeding (BH-HF-KO). Littermate control mice (H-WT, BH-WT and BH-HF-WT ) were also treated with tamoxifen at eight weeks of age, but since they lacked the Cre transgene, Hnf4a and Bmal1 expression remained intact. Livers were harvested at 10 weeks of age (BH-WT/KO, H-WT/KO) or 45 weeks ( BH-HF-WT/KO) of age after high fat diet feeding, and liver tissue was flash frozen in liquid nitrogen.
2022-08-01 | GSE173968 | GEO
Project description:To define regulation of tissue proteomes by Bmal1, daily feeding rhythm, and the interaction, we employed Bmal1-stopFL mice, which do not express the main transcriptional activator of the molecular clock, Bmal1, except in cre recombinase-expressing cells1,2 (Figure 1A). Bmal1-stopFL mice lacking cre (Bmal1 knockout, KO) are analogous to Bmal1-null mice and display severely impaired behavioral and molecular rhythms1-3. Hepatocyte-specific Alfp-cre and skeletal muscle-specific Hsa-cre genes were introduced to generate a single line wherein both hepatocyte and skeletal muscle Bmal1 were reconstituted (Liver+Muscle-RE), i.e., rescued (Smith, Koronowski et al. 2023). This approach had the benefit of analyzing liver and muscle from the same mice but comes with the qualification that the abundance of some proteins may be influenced by Bmal1 function in the other tissue, or by a synergistic effect of Bmal1 in both tissues, rather than through rescue of local Bmal1 function alone. Proteomic anlaysis was performed in liver and skeletal muscle.
2024-01-26 | PXD040362 | Pride
Project description:Advances in circadian research revealed an intricate relationship between aging and circadian rhythms. However, whether and how the circadian machinery contribute to stem cell aging, especially in primates, remains poorly understood. In this study, we investigated the role of BMAL1, the only non-redundant circadian clock component, during aging in mesenchymal progenitor cells (MPCs). We observed an accelerated aging phenotype in both BMAL1 deficient human and cynomolgus monkey MPCs. Notably, this phenotype is mainly attributed to a transcriptional-independent role of BMAL1 in stabilizing the heterochromatin and thus preventing LINE1 activation. In senescent MPCs from human and cynomolgus monkeys, dampened LINE1 binding capacity of BMAL1 and synergistically activated LINE1 transcripts were observed. Furthermore, similar de-stabilized heterochromatin and aberrant LINE1s transcription was observed in the skin and muscle tissues from BMAL1-deficient cynomolgus monkey. Altogether, these findings uncover a noncanonical role of BMAL1 in stabilizing heterochromatin to inactivate LINE1 that drives aging in primates.
2022-03-18 | PXD030570 | Pride
Project description:Purpose: quantitavive RT-PCR and ChIP analyses suggested that the MYC-Associated factor X, MAX, and the essential circadian regulator, BMAL1, might be recruited on the same E-box containing regulatory regions within the promoters of clock target genes. To explore this possibility, we performed ChIP-seq experiments in human cancer MDA-MB-231 cells. Methods: Chromatin samples from human cancer MDA-MB-231 cells were immunoprecipitated with specific antibodies against BMAL1 and MAX proteins. Immunoprecipitated DNA was sequenced using Illumina HiSeq 2000 sequencer. Results: ChIP-seq analysis revealed a large number of genomic regions bound by MAX (around 13000 peaks), while BMAL1 binding was limited to about 800 regions. BMAl1 and MAX bound regions comprised both promoters and distal sites. Coherently with the circadian role of BMAL1 and its preference for E-box-containing sites, ontological annotation of BMAL1 bound regions showed a significant enrichment for circadian regulated genes and E-box motifs. The 85% of the BMAL bound sites overlapped with MAX bound regions. MAX enrichment was higher on the genomic regions co-bound by BMAL1 compared with MAX binding loci sites in which BMAL1 was not present, thus indicating that MAX/BMAL1 sites are bound by MAX with high affinity. Strikingly, MAX enrichment was observed on all E-box-containing promoters of the clock core genes.
2020-04-29 | GSE127192 | GEO
Project description:Enhancers determine tissue-specific gene expression programs. Enhancers are marked by high histone H3 lysine 4 mono-methylation (H3K4me1) and by the acetyl-transferase p300, which has allowed genome-wide enhancer identification. However, the regulatory principles by which subsets of enhancers become active in specific developmental and/or environmental contexts are unknown. We exploited inducible p300 binding to chromatin to identify, and then mechanistically dissect, enhancers controlling endotoxin-stimulated gene expression in macrophages. In these enhancers, binding sites for the lineage-restricted and constitutive Ets protein PU.1 coexisted with those for ubiquitous stress-inducible transcription factors such as NF-kappaB, IRF, and AP-1. PU.1 was required for maintaining H3K4me1 at macrophage-specific enhancers. Reciprocally, ectopic expression of PU.1 reactivated these enhancers in fibroblasts. Thus, the combinatorial assembly of tissue- and signal-specific transcription factors determines the activity of a distinct group of enhancers. We suggest that this may represent a general paradigm in tissue-restricted and stimulus-responsive gene regulation. Chromatin immuno-precipitations of p300, PU.1 and mono-methylated H3 lysine 4 followed by multiparallel sequencing were performed in bone marrow-derived macrophages. Experiments for p300 and PU.1 were also carried out in cells treated for 2hrs with lipopolysaccharide (LPS). In case of p300, reads obtained from two different biological replicates were merged.
2010-03-05 | E-GEOD-19553 | biostudies-arrayexpress