Characterization of chromatin and gene expression changes during fasting in mouse liver
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ABSTRACT:
PROVIDER: PRJNA292909 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2163820.fastq.gz | Fastqsanger.gz | |||
| SRR2163830.fastq.gz | Fastqsanger.gz | |||
| SRR2163860.fastq.gz | Fastqsanger.gz | |||
| SRR2163860_1.fastq.gz | Fastqsanger.gz | |||
| SRR2163860_2.fastq.gz | Fastqsanger.gz |
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Project description:Characterization of chromatin and gene expression changes during fasting and refeeding in mouse liver
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Project description:During fasting the liver supplies the organism’s energy demands by producing glucose and ketones. Fuel production during fasting is temporally organized whereby glucose serves as the major fuel produced in short-term fasting while ketones are produced in longer fasts as gluconeogenic precursors deplete1. However, the regulatory process dictating this temporally-organized metabolic output is unexplored. Here we show that a cascade of transcription factors (TFs) sequentially activated by hormonal signals, TF gene expression and assisted loading onto specific ‘fasting enhancers’ generate a framework for the temporal organization of fuel production during fasting. Fasting led to massive chromatin re-organization, exposing enhancers in which a complex set of regulatory signals converge to regulate transcription. Glucagon secreted in early fasting activates cAMP responsive element binding protein (CREB) leading to increased expression of many TF genes, including CCAAT enhancer binding protein β (C/EBPβ) which relaxes chromatin, thereby potentiating glucocorticoid receptor (GR) binding to fasting enhancers upon its activation by corticosterone in mid-term fasting. Then, GR augments glucagon-dependent gluconeogenesis but also supports a peroxisome proliferator receptor α (PPARα)-dependent ketogenic gene program to sustain ketogenesis during prolonged fasting. Our results bridge over a long-lasting gap between the characterized temporal organization of fuel output during fasting and the undefined role of transcription and chromatin regulation in generating this output. Because a de-regulated response to fasting is a hallmark of diabetes progression, these findings may promote our understanding of this complex disease
2016-12-20 | GSE72086 | GEO
Project description:During fasting the liver supplies the organism’s energy demands by producing glucose and ketones. Fuel production during fasting is temporally organized whereby glucose serves as the major fuel produced in short-term fasting while ketones are produced in longer fasts as gluconeogenic precursors deplete1. However, the regulatory process dictating this temporally-organized metabolic output is unexplored. Here we show that a cascade of transcription factors (TFs) sequentially activated by hormonal signals, TF gene expression and assisted loading onto specific ‘fasting enhancers’ generate a framework for the temporal organization of fuel production during fasting. Fasting led to massive chromatin re-organization, exposing enhancers in which a complex set of regulatory signals converge to regulate transcription. Glucagon secreted in early fasting activates cAMP responsive element binding protein (CREB) leading to increased expression of many TF genes, including CCAAT enhancer binding protein β (C/EBPβ) which relaxes chromatin, thereby potentiating glucocorticoid receptor (GR) binding to fasting enhancers upon its activation by corticosterone in mid-term fasting. Then, GR augments glucagon-dependent gluconeogenesis but also supports a peroxisome proliferator receptor α (PPARα)-dependent ketogenic gene program to sustain ketogenesis during prolonged fasting. Our results bridge over a long-lasting gap between the characterized temporal organization of fuel output during fasting and the undefined role of transcription and chromatin regulation in generating this output. Because a de-regulated response to fasting is a hallmark of diabetes progression, these findings may promote our understanding of this complex disease
2016-12-20 | GSE72085 | GEO
Project description:Characterization of chromatin and gene expression changes during fasting and refeeding in mouse liver [RNA-Seq]
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Project description:Characterization of chromatin and gene expression changes during fasting and refeeding in mouse liver [ChIP-Seq]
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Project description:During fasting transcriptional programs lead to glucose and ketone production. The major TFs, their crosstalk and the enhancers driving it are unknown. We show that fasting massively reorganizes liver chromatin to expose 'fasting enhancers'. By tracking TF footprints, we implicated the major TFs regulating fuel production by two modules. The ketogenic module is executed by a temporally-organized TF cascade. Conversely, in the gluconeogenic module glucocorticoid receptor (GR) augments cAMP-response element-binding protein (CREB) activity in an enhancer-selective manner. Using genomics and single-molecule tracking, we show that GR enhances the number of bound CREB molecules and the quantity, intensity and accessibility of CREB binding sites; leading to synergistic gene expression and glucose production. Our findings reveal that TFs dynamically and cooperatively respond to environmental signals to restore homeostasis.
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Project description:The discovery of FoxO1 as an effector of insulin action on gene expression filled a gap in our knowledge of insulin signaling. The metabolic impact of hepatic FoxO1 has been demonstrated in genetic mouse models showing that FoxO1 inhibition can reverse diabetes. However, the gamut of FoxO1 targets is unknown, due to the lack of robust genome-wide chromatin occupancy data. To elucidate the genomic architecture of the FoxO1 effect on liver metabolism, we integrated genome-wide ChIP-seq and RNA-seq. During the physiological transition from fasting to refeeding, hepatic FoxO1 translocated from the nucleus to the cytoplasm. At the same time points, cistrome analysis demonstrated that 60% of FoxO1 target sites were cleared by refeeding. RNA-seq from mice following acute liver-specific FoxO1 ablation allowed us to integrate the data in a comprehensive FoxO1 regulome. We identified four distinct classes of FoxO1 targets. Class I targets are enriched in genes regulating cell homeostasis, have FoxO1 sites clustered in promoters and do not show regulation with fasting/refeeding. Class II is comprised of canonical FoxO1 metabolic targets coordinately regulated with other fasting-inducible TFs, such as PPARA, CREB, and GR through promoters. Class III is enriched in glucose metabolic genes regulated through active enhancers, as detected by H3K4me1 and H3K27ac histone marks. Class IV is comprised of triglyceride (TG) and lipoprotein metabolism genes, regulated through intron sites, and characterized by an uneven response to fasting/refeeding regulation.
2022-05-24 | GSE151545 | GEO
Project description:The discovery of FoxO1 as an effector of insulin action on gene expression filled a gap in our knowledge of insulin signaling. The metabolic impact of hepatic FoxO1 has been demonstrated in genetic mouse models showing that FoxO1 inhibition can reverse diabetes. However, the gamut of FoxO1 targets is unknown, due to the lack of robust genome-wide chromatin occupancy data. To elucidate the genomic architecture of the FoxO1 effect on liver metabolism, we integrated genome-wide ChIP-seq and RNA-seq. During the physiological transition from fasting to refeeding, hepatic FoxO1 translocated from the nucleus to the cytoplasm. At the same time points, cistrome analysis demonstrated that 60% of FoxO1 target sites were cleared by refeeding. RNA-seq from mice following acute liver-specific FoxO1 ablation allowed us to integrate the data in a comprehensive FoxO1 regulome. We identified four distinct classes of FoxO1 targets. Class I targets are enriched in genes regulating cell homeostasis, have FoxO1 sites clustered in promoters and do not show regulation with fasting/refeeding. Class II is comprised of canonical FoxO1 metabolic targets coordinately regulated with other fasting-inducible TFs, such as PPARA, CREB, and GR through promoters. Class III is enriched in glucose metabolic genes regulated through active enhancers, as detected by H3K4me1 and H3K27ac histone marks. Class IV is comprised of triglyceride (TG) and lipoprotein metabolism genes, regulated through intron sites, and characterized by an uneven response to fasting/refeeding regulation.
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Project description:Transcriptional profiling coupled with blood metabolite analyses were used to identify porcine genes and pathways that respond to a fasting treatment or to a D298N missense mutation in the melanocortin-4 receptor (MC4R) gene. Gilts (12 homozygous for D298 and 12 homozygous for N298) were either fed ad libitum or fasted for 3 days. Fasting decreased body weight and backfat and increased serum concentrations of non-esterified fatty acid and urea. In response to fasting, 7,029 genes in fat and 1,831 genes in liver were differentially expressed (DE, q value less than 0.05). MC4R genotype did not affect gene expression, body weight, backfat depth, and any measured serum metabolite concentration. Pathway analyses of fasting-induced DE genes indicated that both liver and fat down-regulated energetically costly processes such as lipid and steroid synthesis and up-regulated efficient energy utilization pathways. Fasting increased expression of genes in involved in glucose sparing pathways in liver and extracellular matrix pathways in adipose tissue. Within the DE genes, transcription factors (TF) that regulate many DE genes were identified, confirming the involvement of TF that are known to regulate fasting response and implicating additional TF that are not known to be involved in energy homeostatic responses. Interestingly, estrogen receptor 1 transcriptionally controls fasting induced genes in fat that are involved in cell matrix morphogenesis. Our findings indicate a transcriptional response to fasting in two key metabolic tissues of pigs that was corroborated by changes in blood metabolites; and involvement of novel putative transcriptional regulators in the immediate adaptive response to fasting.
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Project description:water only fasting changes gut microbiota
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