Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA398233 | 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 [Bmal1 KO]
| PRJNA398232 | ENA
Project description:Circadian clocks are the time-keeping cellular apparatuses that are photoentrained according to the day-night photocycles on Earth 1,2. Cryptochromes (CRYs) are photoreceptors mediating photoentrainment of the circadian clock in plants and animals but how CRYs mediate light regulation of the molecular clock remains unclear 1,3. Here we show that CRYs mediate photoresponses of the circadian clock by regulating the activity of N6-methyladenosine (m6A) RNA methyltransferase and photoresponses of the epitranscriptome. In contrast to the presently known CRY complexome, the CRY2-methyltransferase complex exbibits multivalent interactions and photoresponsive condensation in response to blue light. We show that photoexcited CRY2 undergoes phosphorylation-assisted demixing to form photobodies with the properties of condensed liquid phase, which facilitates assembly of the CRY2-methyltransferase complex in the condensed liquid phase of CRY2 in vivo. The mta mutant impaired in m6A methyltransferase and the cry1cry2 mutant missing CRY photoreceptors share common defects of lengthened circadian period, reduced m6A RNA methylation, and accelerated degradation of mRNAs encoding core components of the molecular clock. These results argue for a photoentrainment mechanism by which blue light elicits liquid-liquid phase separation of the CRY2-methyltransferase complex to regulate m6A mRNA methylation, consequently suppressing mRNA degradation and period lengthening of the circadian clock
2021-07-12 | GSE152465 | GEO
Project description:Circadian clocks are the time-keeping cellular apparatuses that are photoentrained according to the day-night photocycles on Earth 1,2. Cryptochromes (CRYs) are photoreceptors mediating photoentrainment of the circadian clock in plants and animals but how CRYs mediate light regulation of the molecular clock remains unclear 1,3. Here we show that CRYs mediate photoresponses of the circadian clock by regulating the activity of N6-methyladenosine (m6A) RNA methyltransferase and photoresponses of the epitranscriptome. In contrast to the presently known CRY complexome, the CRY2-methyltransferase complex exbibits multivalent interactions and photoresponsive condensation in response to blue light. We show that photoexcited CRY2 undergoes phosphorylation-assisted demixing to form photobodies with the properties of condensed liquid phase, which facilitates assembly of the CRY2-methyltransferase complex in the condensed liquid phase of CRY2 in vivo. The mta mutant impaired in m6A methyltransferase and the cry1cry2 mutant missing CRY photoreceptors share common defects of lengthened circadian period, reduced m6A RNA methylation, and accelerated degradation of mRNAs encoding core components of the molecular clock. These results argue for a photoentrainment mechanism by which blue light elicits liquid-liquid phase separation of the CRY2-methyltransferase complex to regulate m6A mRNA methylation, consequently suppressing mRNA degradation and period lengthening of the circadian clock
2021-07-12 | GSE152464 | GEO
Project description:The circadian clock is intricately connected with metabolism, however the precise details of these connections are incomplete. Here we used high temporal resolution metabolite profiling to determine circadian regulation of mouse liver and cell autonomous metabolism. In mouse liver, we found ~50% of metabolites were circadian, with strong enrichment of the nucleotide, amino acid, and methylation pathways. In U2OS cells, 27% of metabolites were circadian, including amino acids and NAD biosynthesis, also clock controlled in liver. To assess whether cell autonomous metabolite rhythms were clock-dependent, we used RNAi to perturb Bmal1, Cry1, and Cry2. Bmal1 knockdown eliminated most metabolite rhythms, while Cry1 generally shortened and Cry2 lengthened rhythms. Surprisingly, we found Cry1 knockdown induced 8 hr rhythms in amino acid, methylation, and vitamin metabolites, decoupling metabolite and transcriptional rhythms. These results provide the first comprehensive views of circadian liver and cell autonomous metabolism.
2017-04-05 | MTBLS292 | MetaboLights
Project description:N6-methyladenosine RNA (m6A) is the most abundant internal modification on mRNA which influences most steps of mRNA metabolism and is involved in several biological functions, including circadian clock, metabolism and embryonic stem cell differentiation. The E3 ubiquitin ligase Hakai was previously found in complex with components of the m6A methylation machinery in plants and mammalian cells but its precise function remained to be investigated. Here we show that Hakai is a conserved component of the methyltransferase complex in Drosophila. Its depletion results in reduced m6A levels and altered m6A-dependent functions including sex determination. We show that its ubiquitination domain is required for dimerisation and interaction with other members of the m6A machinery, while its catalytic activity seems dispensable. Finally, we demonstrate that the loss of Hakai destabilizes the level of several subunits of the methyltransferase complex, resulting in impaired m6A deposition. Thus, our work adds new functional and molecular insights into the mechanism of the m6A mRNA writer complex.
2021-04-26 | GSE158663 | GEO
Project description:The circadian regulation of transcriptional processes has a broad impact on cell metabolism. Here, we compared the diurnal transcriptome of human skeletal muscle conducted on serial muscle biopsies in vivo with profiles of human skeletal myotubes synchronized in vitro. Extensive rhythmic transcription was observed in human skeletal muscle in comparison to in vitro cell culture. However, nearly half of the in vivo rhythmicity was lost at the mRNA accumulation level. siRNA-mediated clock disruption in primary myotubes significantly affected the expression of ~8% of all genes, with impact on glucose homeostasis and lipid metabolism. Genes involved in GLUT4 expression, translocation and recycling were negatively affected, whereas lipid metabolic genes were altered to promote activation of lipid utilization. Moreover, basal and insulin stimulated glucose uptake were significantly reduced upon CLOCK depletion. Altogether, our findings suggest an essential role for cell-autonomous circadian clocks in coordinating muscle glucose homeostasis and lipid metabolism in humans.
2018-04-12 | GSE109825 | GEO
Project description:The circadian regulation of transcriptional processes has a broad impact on cell metabolism. Here, we compared the diurnal transcriptome of human skeletal muscle conducted on serial muscle biopsies in vivo with profiles of human skeletal myotubes synchronized in vitro. Extensive rhythmic transcription was observed in human skeletal muscle in comparison to in vitro cell culture. However, nearly half of the in vivo rhythmicity was lost at the mRNA accumulation level. siRNA-mediated clock disruption in primary myotubes significantly affected the expression of ~8% of all genes, with impact on glucose homeostasis and lipid metabolism. Genes involved in GLUT4 expression, translocation and recycling were negatively affected, whereas lipid metabolic genes were altered to promote activation of lipid utilization. Moreover, basal and insulin stimulated glucose uptake were significantly reduced upon CLOCK depletion. Altogether, our findings suggest an essential role for cell-autonomous circadian clocks in coordinating muscle glucose homeostasis and lipid metabolism in humans.
2018-04-16 | GSE108539 | GEO
Project description:Aims/hypothesis: Obesity and elevated circulating lipids may impair metabolism by disrupting the molecular circadian clock. We tested the hypothesis that lipid-overload may interact with the circadian clock and alter the rhythmicity of gene expression through epigenetic mechanisms. Methods: We determined the effect of the saturated fatty acid palmitate on circadian transcriptomics and examined the impact on histone H3 lysine K27 acetylation (H3K27ac) and the regulation of circadian rhythms in primary human skeletal muscle myotubes. Total H3 abundance and histone H3K27ac was assessed in vastus lateralis muscle biopsies from men with either obesity or normal weight. Results: Palmitate reprogrammed the circadian transcriptome in myotubes without altering the mRNA rhythm of core clock genes. Genes with enhanced cycling in response to palmitate were associated with post-translational modification of histones. Cycling of histone 3 lysine 27 acetylation (H3K27ac), a marker of active gene enhancers, was modified by palmitate treatment in myotubes. Chromatin immunoprecipitation and sequencing confirmed that palmitate altered the cycling of DNA regions associated with H3K27ac. Overlap of mRNA and DNA regions associated with H3K27ac and pharmacological inhibition of histone acetyl transferases revealed novel cycling genes associated to lipid exposure in human myotubes. Conclusion/interpretation: Palmitate disrupts transcriptomic rhythmicity and modifies histone H3K27ac in circadian manner, suggesting acute lipid-overload alters the circadian chromatin landscape and reprograms circadian gene expression of skeletal muscle.
2022-09-27 | GSE205677 | GEO