Diurnal profiling of mouse liver of hepatocyte specific BMAL1 KO mice (Bmal1 HepKO)
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PROVIDER: PRJNA786461 | ENA |
REPOSITORIES: ENA
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Project description:Obesity and liver diseases are associated with the disruption of the circadian clock that orchestrates mammalian physiology to optimize nutrient metabolism and storage. We show here that the activity of the circadian clock regulator BMAL1 is perturbed during liver fibrosis in humans. To understand the impact of BMAL1 perturbation in obesity and liver diseases, we assessed the impact of a high fat diet or leptin deficiency on Bmal1 knockout mice. While Bmal1 knockout mice were prone to obesity, they were protected against insulin resistance, hepatic steatosis, inflammation, and fibrosis. In addition to direct transcriptional regulation of metabolic programs by BMAL1, we show that adaptation of the growth hormone and sex hormone pathways plays a critical role in this protection. Similar endocrine perturbations correlate with the development of liver fibrosis in humans, suggesting that endocrine perturbation associated with circadian disruption is critical for the pathogenesis of metabolic and liver diseases.
2022-01-26 | GSE190221 | 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: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:The diurnal variation in acetaminophen (APAP) hepatotoxicity (“chronotoxicity”) is thought to be due to oscillations in xenobiotic metabolism that are influenced by the circadian phases of feeding or fasting. Because of APAP’s relevance to human poisoning, we set out to determine the relative contributions of the central clock in the SCN and the autonomous clock in the hepatocyte in modulating the chronotoxicity of APAP. Using a conditional null allele of Mop3 (ArntL, Bmal1) we are able to delete the clock from hepatocytes while keeping the central and other peripheral clocks intact (eg, those controlling food intake). Our data from this hepatocyte-null mouse model suggests that, while the central circadian clock modulates some detoxification pathways indirectly by driving activity patterns and feeding rhythms, the autonomous hepatocyte circadian clock controls major aspects of APAP bioactivation independent of feeding rhythms.
2013-08-30 | GSE34442 | GEO
Project description:The circadian clock protein Bmal1 is critical for maintain circadian transcriptional funciton and rhythms. Global deleiton of Bmal1 renders whole mice behaviorally arrhythmic. However, cell-specific deletion of Bmal1 can reveal specific transcripts regulated by Bmal1 in a cell-specific manner. Here we used a BAC-transgenic Camk2a-iCre line to delete Bmal1 in a pan-neuronal manner. This mouse has previously been shown to have widespread Bmal1 deletion in neurons and to be arrhythmic (PMID: 25525750). We performed bulk RNAseq on cerebral cortex tissue from Camk2a-iCre+;Bmal1(fx/fx) and Cre- control littermates. Appropriate Bmal1 targets were disregulated as expetced in these mice. Pathways analysis revealed transcripts involved in Parkinson Disease and oxidative phosphorylation to be enriched.
2023-08-23 | GSE241218 | GEO
Project description:Transcriptomic analysis to reveal the impact of muscle-specific Bmal1 knockout on daily cycles of gene expression in the liver
2023-04-05 | GSE171432 | GEO
Project description:Liver metabolism in mice lacking Bmal1 in adipocytes. Comparison between WT and KO revealed no differentially expressed genes at ZT12 and ZT16, and only revealed one gene at ZT8 and ZT20. In contrast many genes were differential at ZT0 and ZT4. With ZT4 having substantially more than ZT0.
2020-06-01 | GSE115264 | GEO
Project description:The diurnal variation in acetaminophen (APAP) hepatotoxicity (“chronotoxicity”) is thought to be due to oscillations in xenobiotic metabolism that are influenced by the circadian phases of feeding or fasting. Because of APAP’s relevance to human poisoning, we set out to determine the relative contributions of the central clock in the SCN and the autonomous clock in the hepatocyte in modulating the chronotoxicity of APAP. Using a conditional null allele of Mop3 (ArntL, Bmal1) we are able to delete the clock from hepatocytes while keeping the central and other peripheral clocks intact (eg, those controlling food intake). Our data from this hepatocyte-null mouse model suggests that, while the central circadian clock modulates some detoxification pathways indirectly by driving activity patterns and feeding rhythms, the autonomous hepatocyte circadian clock controls major aspects of APAP bioactivation independent of feeding rhythms. 10-20 week old Mop3fxfx mice positive or negative for Cre-recombinase driven by the albumin promoter, housed in 12 hour light:12 dark, ad lib feeding and drinking conditions were sacrificed every four hours over two separte days beginning at ZT0. A two color, reference design experiment in which liver RNA from at least 3 mice per timepoint were pooled and labeled with Cy3 and hybridized according to Agilent protocols against a reference pool of RNA madeup from respective tissue taken from 10 week Mop3fxfx and Mop3fxfxCreAlb mice which was labeled with Cy5.
2013-08-30 | E-GEOD-34442 | biostudies-arrayexpress
Project description:Deletion of the circadian clock proteins Bmal1 or Nr1d1 (also known as Rev-Erb-alpha) can not only cause circadian dysfunction, but also neuroinflammation in the hippocampus. In this array, 3 wt, 2 Bmal1 KO, and 2 Nr1d1 KO mice, all 5mo, were kept in standard 12h:12h light:dark condition, then anesthetized and perfused with PBS+heparin. Mice were harvest in between noon and 3pm. Whole hippocampus was removed and flash frozen, then RNA was extracted using Trizol reagent and PureLink RNA columns, per manufacturers instructions. RNA microarray analysis was performed by the Washington Univ. Genome Technology Access Center using Agilent Mouse 4x44K mouse V2 array.
2019-02-11 | E-MTAB-7590 | biostudies-arrayexpress
Project description:rRNA-depleted RNA isolated from livers of control male and female mice and from male mice with hepatocyte-specific STAT5ab-KO was analyzed by RNA-seq. This study revealed a substantial, albeit incomplete loss of liver sex bias in hepatocyte-specific STAT5a/STAT5b (collectively, STAT5)-deficient mouse liver. Notably, in male liver, many male-biased genes were down regulated in direct association with the loss of STAT5 binding; many female-biased genes, which show low STAT5 binding, were de-repressed, indicating an indirect mechanism for repression by STAT5.
2020-12-01 | GSE103885 | GEO