Diet-induced circadian enhancer remodeling synchronizes opposing hepatic lipid metabolic processes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA428990 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6453430.fastq.gz | Fastqsanger.gz | |||
| SRR6453431.fastq.gz | Fastqsanger.gz | |||
| SRR6453432.fastq.gz | Fastqsanger.gz | |||
| SRR6453433.fastq.gz | Fastqsanger.gz | |||
| SRR6453434.fastq.gz | Fastqsanger.gz |
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Project description:Overnutrition disrupts circadian rhythms leading to dysregulated metabolism by mechanisms that are not well understood. Here we show that diet-induced obesity (DIO) causes massive remodeling of circadian enhancer activity and gene transcription in mouse liver. Remarkably, DIO triggers synchronous, high amplitude circadian rhythms of both fatty acid (FA) synthesis and oxidation. This gain of circadian rhythmicity in lipid metabolic pathways that oppose each other emphasizes the importance of balance and flux in normal hepatic lipid metabolism. DIO-promoted rhythmicity of Sterol Regulatory Element-Binding Protein (SREBP) activation, which was required not only for the induction of FA synthesis but also, surprisingly, for FA oxidation (FAO). DIO also brought about a high amplitude circadian rhythm of peroxisome proliferated receptor a (PPARa), which was required for FAO. Provision of a pharmacological ligand for PPARa abrogated the requirement of SREBP for FA oxidation (but not FA synthesis), suggesting that SREBP indirectly controls FA oxidation via production of an endogenous PPARa ligand. Moreover, the high amplitude circadian rhythm of PPARa imparts time-of-day-dependent responsiveness to lipid-lowering drugs. Thus, acquisition of rhythmicity for the non-core clock components PPARa and SREBP1 remodels metabolic gene transcription in response to a challenging nutritive environment and enables a chronopharmacological approach to metabolic disorders.
2018-07-26 | GSE108878 | GEO
Project description:Overnutrition disrupts circadian metabolic rhythms by mechanisms that are not well understood. Here, we show that diet-induced obesity (DIO) causes massive remodeling of circadian enhancer activity in mouse liver, triggering synchronous high-amplitude circadian rhythms of both fatty acid (FA) synthesis and oxidation. SREBP expression was rhythmically induced by DIO, leading to circadian FA synthesis and, surprisingly, FA oxidation (FAO). DIO similarly caused a high-amplitude circadian rhythm of PPAR?, which was also required for FAO. Provision of a pharmacological activator of PPAR? abrogated the requirement of SREBP for FAO (but not FA synthesis), suggesting that SREBP indirectly controls FAO via production of endogenous PPAR? ligands. The high-amplitude rhythm of PPAR? imparted time-of-day-dependent responsiveness to lipid-lowering drugs. Thus, acquisition of rhythmicity for non-core clock components PPAR? and SREBP1 remodels metabolic gene transcription in response to overnutrition and enables a chronopharmacological approach to metabolic disorders.
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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.
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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:Rhythmic regulation of transcriptional processes is intimately linked to lipid homeostasis, to anticipate daily changes in energy access. Rev-erbα/HDAC3 complex was previously discovered to execute the rhythmic repression of lipid genes, however, the epigenetic switch that turns on these genes is less clear. Here, we show that genomic recruitment of MRG15 displays a significant circadian rhythm and activates lipid genes in mouse liver. Pol II recruitment and histone acetylation correspond to MRG15 binding, and the rhythm is impaired upon MRG15 depletion, establishing MRG15 as a key modulator in global rhythmic transcriptional regulation. Rather than known core clock proteins, MRG15 interacts with nuclear receptor LRH-1, and is recruited to genomic loci near lipid genes via its association with LRH-1. Blocking MRG15 by CRISPR targeting or FDA-approved drug argatroban, which is an antagonist to MRG15, attenuates liver steatosis. This work highlights MRG15 as a targetable master regulator in rhythmic regulation of hepatic lipid metabolism.
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Project description:Rhythmic regulation of transcriptional processes is intimately linked to lipid homeostasis, to anticipate daily changes in energy access. Rev-erbα/HDAC3 complex was previously discovered to execute the rhythmic repression of lipid genes, however, the epigenetic switch that turns on these genes is less clear. Here, we show that genomic recruitment of MRG15 displays a significant circadian rhythm and activates lipid genes in mouse liver. Pol II recruitment and histone acetylation correspond to MRG15 binding, and the rhythm is impaired upon MRG15 depletion, establishing MRG15 as a key modulator in global rhythmic transcriptional regulation. Rather than known core clock proteins, MRG15 interacts with nuclear receptor LRH-1, and is recruited to genomic loci near lipid genes via its association with LRH-1. Blocking MRG15 by CRISPR targeting or FDA-approved drug argatroban, which is an antagonist to MRG15, attenuates liver steatosis. This work highlights MRG15 as a targetable master regulator in rhythmic regulation of hepatic lipid metabolism.
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Project description:Rhythmic regulation of transcriptional processes is intimately linked to lipid homeostasis, to anticipate daily changes in energy access. Rev-erbα/HDAC3 complex was previously discovered to execute the rhythmic repression of lipid genes, however, the epigenetic switch that turns on these genes is less clear. Here, we show that genomic recruitment of MRG15 displays a significant circadian rhythm and activates lipid genes in mouse liver. Pol II recruitment and histone acetylation correspond to MRG15 binding, and the rhythm is impaired upon MRG15 depletion, establishing MRG15 as a key modulator in global rhythmic transcriptional regulation. Rather than known core clock proteins, MRG15 interacts with nuclear receptor LRH-1, and is recruited to genomic loci near lipid genes via its association with LRH-1. Blocking MRG15 by CRISPR targeting or FDA-approved drug argatroban, which is an antagonist to MRG15, attenuates liver steatosis. This work highlights MRG15 as a targetable master regulator in rhythmic regulation of hepatic lipid metabolism.
| OEX002226 | NODE
Project description:Rhythmic regulation of transcriptional processes is intimately linked to lipid homeostasis, to anticipate daily changes in energy access. Rev-erbα/HDAC3 complex was previously discovered to execute the rhythmic repression of lipid genes, however, the epigenetic switch that turns on these genes is less clear. Here, we show that genomic recruitment of MRG15 displays a significant circadian rhythm and activates lipid genes in mouse liver. Pol II recruitment and histone acetylation correspond to MRG15 binding, and the rhythm is impaired upon MRG15 depletion, establishing MRG15 as a key modulator in global rhythmic transcriptional regulation. Rather than known core clock proteins, MRG15 interacts with nuclear receptor LRH-1, and is recruited to genomic loci near lipid genes via its association with LRH-1. Blocking MRG15 by CRISPR targeting or FDA-approved drug argatroban, which is an antagonist to MRG15, attenuates liver steatosis. This work highlights MRG15 as a targetable master regulator in rhythmic regulation of hepatic lipid metabolism.
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