Microglial gene expression in Bmal1 cKO and WT mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE214514 | GEO | 2023/03/01
REPOSITORIES: GEO
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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:The objective is to elucidate the role of the circadian clock in the parathyroid glands. We investigate the parathyroid transcriptome of wildtype mice (Bmal1 flox/flox) and of mice with parathyroid-specific excision of the circadian clock gene Bmal1 (PTHcre;Bmal1 flox/flox) harvested at 4 hour interval for 24 hours. Rhythmic genes were identified by JTK_CYCLE analysis and revealed 1455 rhythmic genes of the Bmal1 flox/flox and 1055 rhythmic genes of the PTHcre;Bmal1 flox/flox. We found global damepning of circadian clock genes with abolished rhythmicity of Cry1, Cry2, Clock, Npas2, Rorc, and Usp2. We used GSEA analysis to investigate differential expression at each timepount and found downregulation of genes involved in ATP synthesis in PTHcre;Bmal1 flox/flox mice at 4 consecutive timepoints during the active period of the mouse.
2021-12-23 | GSE191264 | GEO
Project description:Circadian clocks are cell autonomous, transcriptionally-based, molecular mechanisms that confer the selective advantage of anticipation, enabling cells/organs to respond to environmental factors in a temporally appropriate manner. Critical to circadian clock function are two transcription factors, CLOCK and BMAL1. Previous studies in our laboratory have highlighted roles for CLOCK in cardiac physiology/pathophysiology. Here, we describe transcriptional, metabolic, and functional consequences of cardiomyocyte-specific Bmal1 knockout (CBK). Microarray analysis revealed 2037 differentially expressed genes in CBK hearts, many of which were previously identified in cardiomyocyte-specific Clock mutant (CCM) hearts. Subsequent analysis showed that Beta-hydroxybutyrate dehydrogenase 1 mRNA, protein, and enzymatic activity are markedly depressed in both CBK and CCM hearts, as is myocardial Beta-hydroxybutyrate oxidation, revealing a novel role for the circadian clock in ketone body utilization. A number of genes encoding for collagen isoforms were identified as oscillating in a time-of-day-dependent manner in wild-type, but not CBK, hearts, including col3a1, col4a1, and col4a2. Chronic induction of collagen isoform genes in CBK hearts was associated with severe age-dependent depression of cardiac function. Development of cardiomyopathy in CBK mice was associated with early mortality; all CBK mice die by one year of age. These studies highlight novel critical functions for BMAL1 in the heart, including regulation of ketone body metabolism and the extracellular matrix. RNA from whole hearts collected every 3 hours for 24 hours from wildtype and CBK mice was isolated and analyzed using MouseRef-8_V2 BeadChips (Illumina, Inc.). The 24-hour data were examined for rhythmicity using cosinor analysis and differences in rhythmicity between genotype groups were further examined for differences in the model fitting parameters.
2014-01-01 | E-GEOD-43073 | biostudies-arrayexpress
Project description:Cellular senescence and circadian dysregulation are biological hallmarks of aging. Whether they are interdependent has not been thoroughly studied. We hypothesize that BMAL1, a pioneer transcription factor and master regulator of the molecular circadian clock, plays a role in the senescence program. In this study, we show that BMAL1 in is uniquely localized to genomic motifs associated with AP-1 in senescent cells and contributes to AP-1 transcriptional control of the senescence program.
2023-08-22 | GSE229009 | GEO
Project description:Cellular senescence and circadian dysregulation are biological hallmarks of aging. Whether they are interdependent has not been thoroughly studied. We hypothesize that BMAL1, a pioneer transcription factor and master regulator of the molecular circadian clock, plays a role in the senescence program. In this study, we show that BMAL1 in is uniquely localized to genomic motifs associated with AP-1 in senescent cells and contributes to AP-1 transcriptional control of the senescence program.
2023-08-22 | GSE229011 | GEO
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
Project description:The circadian clock and rhythmic food intake are both important regulators of rhythmic gene expression in the liver. It remains, however, elusive to which extent the circadian clock network and natural feeding rhythms contribute to rhythmic gene expression. To systematically address this question, we developed an algorithm to investigate differential rhythmicity between a varying number of conditions. Mouse knockout models of different parts of the circadian clock network (Bmal1, Cry1/2, and Hlf/Dbp/Tef) exposed to controlled feeding regimens (ad libitum, night restricted feeding) were generated and analyzed for their temporal hepatic transcriptome. A genetical ablation of core loop elements altered feeding patterns that were restored by night restricted feeding. Mainly genes with a high amplitude were driven by the circadian clock but natural feeding patterns equally contributed to rhythmic gene expression with lower amplitude. We observed that Bmal1 and Cry1/2 KOs differed in rhythmic gene expression and identified differences in mean expression levels as a predictor for rhythmic gene expression. In Hlf/Dbp/Tef KO, mRNA levels of Hlf/Dbp/Tef target genes were decreased, albeit rhythmicity was overall preserved potentially due to the activity of the D-Box binding repressor NFIL3. Genes that lost rhythmicity in Hlf/Dbp/Tef KOs were identified to be no direct targets of PARbZip factors and presumably lost rhythmicity due to indirect effects. Collectively, our findings provide unprecedent insights into the diurnal transcriptome in mouse liver and defines the contribution of subloops of the circadian clock network and natural feeding cycles. The developed algorithm and a webapp to browse the outcomes of the study are publicly available to serve as a resource for the scientific community.
2020-12-03 | GSE135898 | GEO
Project description:Circadian rhythm dysfunction is a hallmark of Parkinson Disease (PD), and diminished expression of the core clock gene Bmal1 has been described in PD patients. BMAL1 is required for core circadian clock function, but also serves non-rhythmic functions. Germline Bmal1 deletion can cause brain oxidative stress and synapse loss in mice, and can exacerbate dopaminergic neurodegeneration in response to MPTP. Here we examined the impact of cell type-specific Bmal1 deletion on dopaminergic neuron viability in vivo. We observed that global, post-natal deletion of Bmal1 caused spontaneous loss of tyrosine hydroxylase-positive (TH+) dopaminergic neurons in the substantia nigra pars compacta (SNpc). This was not due to disruption of behavioral circadian rhythms, and was not induced by astrocyte- or microglia-specific Bmal1 deletion. However, either pan-neuronal or TH neuron-specific Bmal1 deletion caused cell-autonomous loss of TH+ neurons in the SNpc. Finally, global Bmal1 deletion exacerbated TH+ neuron loss following injection of alpha-synclein fibrils. Transcriptomic analysis of neuron-specific Bmal1 KO brain revealed dysregulation of pathways involved in oxidative phosphorylation and Parkinson Disease.
2023-08-18 | GSE241200 | GEO
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
Project description:Cellular senescence and circadian dysregulation are biological hallmarks of aging. Whether they are interdependent has not been thoroughly studied. We hypothesize that BMAL1, a pioneer transcription factor and master regulator of the molecular circadian clock, plays a role in the senescence program. In this study, we show that BMAL1 in is uniquely localized to genomic motifs associated with AP-1 in senescent cells and contributes to AP-1 transcriptional control of the senescence program.
2023-08-22 | GSE229010 | GEO