Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA398232 | ENA |
REPOSITORIES: ENA
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Project description:Circadian transcriptional rhythms are necessary for lipid metabolic homeostasis. Disruptions can lead to metabolic diseases. Whether epigenetic N6-methyladenosine (m6A) mRNA methylation impacts circadian regulation of lipid metabolism is unclear. Here, we show m6A mRNA methylation oscillations in murine liver depend upon a functional circadian clock. Hepatic deletion of Bmal1 increased m6A mRNA methylation, particularly of PPaRα. Inhibition of m6A methylation via knockdown of m6A methyltransferase METTL3 decreased PPaRα m6A abundance and increased PPaRα mRNA lifetime and expression, reducing lipid accumulation in cells in vitro. Our data suggest YTH domain family 2 (YTHDF2, a m6A binding protein) binds to PPaRα, prolonging its lifetime and mRNA expression. Reactive oxygen species accumulation increased PPaRα transcript m6A levels, revealing a possible mechanism for circadian clock disruption on m6A mRNA methylation. These data suggest m6A RNA methylation is important for circadian clock regulation of downstream genes and lipid metabolism that impacts metabolic outcome.
2018-10-25 | GSE102619 | GEO
Project description:Circadian transcriptional rhythms are necessary for lipid metabolic homeostasis. Disruptions can lead to metabolic diseases. Whether epigenetic N6-methyladenosine (m6A) mRNA methylation impacts circadian regulation of lipid metabolism is unclear. Here, we show m6A mRNA methylation oscillations in murine liver depend upon a functional circadian clock. Hepatic deletion of Bmal1 increased m6A mRNA methylation, particularly of PPaRα. Inhibition of m6A methylation via knockdown of m6A methyltransferase METTL3 decreased PPaRα m6A abundance and increased PPaRα mRNA lifetime and expression, reducing lipid accumulation in cells in vitro. Our data suggest YTH domain family 2 (YTHDF2, a m6A binding protein) binds to PPaRα, prolonging its lifetime and mRNA expression. Reactive oxygen species accumulation increased PPaRα transcript m6A levels, revealing a possible mechanism for circadian clock disruption on m6A mRNA methylation. These data suggest m6A RNA methylation is important for circadian clock regulation of downstream genes and lipid metabolism that impacts metabolic outcome.
2018-06-21 | GSE102620 | GEO
Project description:Circadian Clock Regulation of Hepatic Lipid Metabolism by Modulation of m6A mRNA Methylation [siMettl3]
| PRJNA398233 | ENA
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
Project description:To investigate the role of the circadian clock gene Bmal1 in skeletal muscle, we compared the circadian transcriptomes of fast tibialis anterior (TA) and slow soleus (SOL) skeletal muscles from muscle-specific Bmal1 KO (mKO) and their control Cre- littermates (Ctrl). Keyword: Circadian Transcriptome, time course
2014-01-01 | GSE43071 | GEO
Project description:Peripheral circadian clocks regulate many aspects of physiology. In this study we deleted the core circadian clock component Bmal1 specifically in mouse adipocytes in order to study the role of the adipocyte clock in energy homeostasis and body weight. We used microarrays to indentify changes in gene expression in the adipose tissue of mice lacking a functional adipocyte circadian clock and identified a small number of up- and down- regulated genes. Adipose tissues were isolated from inguinal adipose fat pads at four different times of the diurnal cycle under constant darkness (circadian time, CT) for RNA extraction and hybridization on Affymetrix microarrays. Adipocyte-specific Bmal1 KO (Ad-Bmal1-/-) and control mice were used for isolation of tissues at CT0, CT6, CT12, CT18 where CT0 the beginning of the subjective day.
2012-10-21 | E-GEOD-35026 | biostudies-arrayexpress
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.
2011-02-23 | GSE26602 | GEO
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 disruption 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, but were absent in hepatocyte specific Bmal1 knockout mice. This suggestsing that systemic endocrine perturbation associated with circadian disruptionthe disruption of BMAL1 activity is critical for the pathogenesis of metabolic and liver diseases.
2022-01-26 | GSE150102 | GEO
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: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