The effect of circadian rhythm on gene expression in human skin III
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE139301 | GEO | 2020/07/20
REPOSITORIES: GEO
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Project description:Skin is the largest organ in the body and serves important barrier, regulatory, and sensory functions. Like other tissues, skin is subject to temporal fluctuations in physiological responses under both homeostatic and stressed states. To gain insight into these fluctuations, we investigated the role of the circadian clock in the transcriptional regulation of skin The purpose of this study was to gain insight into the evolutionarily-conserved rhythmic patterns of the circadian transcriptome in human skin and how it relates to published transcriptomes from other human tissues.
2020-07-20 | GSE139300 | GEO
Project description:Skin is the largest organ in the body and serves important barrier, regulatory, and sensory functions. Like other tissues, skin is subject to temporal fluctuations in physiological responses under both homeostatic and stressed states. To gain insight into these fluctuations, we investigated the role of the circadian clock in the transcriptional regulation of human epidermal samples collected in a time-ordered fashion. We also determined whether this circadian patterning could be applied to unordered (i.e., randomly collected) human epidermal samples. The purpose of this study was to gain insight into the evolutionarily-conserved rhythmic patterns of the circadian transcriptome in human skin and how it relates to published transcriptomes from other human tissues.
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Project description:Rhythmic oscillations of physiological processes depend on integrating the circadian clock and diurnal environment. DNA methylation is epigenetically responsive to daily rhythms, as a subset of CpG dinucleotides in brain exhibit diurnal rhythmic methylation. A major genetic effect on rhythmic methylation was identified in a mouse Snord116 deletion model of the imprinted disorder Prader-Willi syndrome (PWS). > 23,000 diurnally rhythmic CpGs were identified in wild-type cortex, with nearly all lost or phase-shifted in PWS. Circadian dysregulation of a second imprinted Snord cluster at the Temple/Kagami-Ogata syndrome locus was observed at the level of methylation, transcription, and chromatin, providing mechanistic evidence of cross-talk. Genes identified by diurnal epigenetic changes in PWS mice overlapped rhythmic and PWS-specific genes in human brain and were enriched for PWS-relevant phenotypes and pathways. These results support the proposed evolutionary relationship between imprinting and sleep, and suggest possible chronotherapy in the treatment of PWS and related disorders.
2018-02-27 | GSE103249 | GEO
Project description:Over the past decade, genome-wide assays have underscored the broad sweep of circadian gene expression. A substantial fraction of the transcriptome undergoes oscillations in many organisms and tissues, which governs the many biochemical, physiological and behavioral functions under circadian control. Based predominantly on the transcription feedback loops important for core circadian timekeeping, it is commonly assumed that this widespread mRNA cycling reflects circadian transcriptional cycling. To address this issue, we directly measured dynamic changes in mouse liver transcription using Nascent-Seq. Many genes are rhythmically transcribed over the 24h day, which include precursors of several non-coding RNAs as well as the expected set of core clock genes. Surprisingly however, nascent RNA rhythms overlap poorly with mRNA abundance rhythms assayed by RNA-seq. This is because most mouse liver genes with rhythmic mRNA expression manifest poor transcriptional rhythms, indicating a prominent role of post-transcriptional regulation in setting mRNA cycling amplitude. To gain further insight into circadian transcriptional regulation, we also characterized the rhythmic transcription of liver genes targeted by the transcription factors CLOCK and BMAL1; they directly target other core clock genes and sit at the top of the molecular circadian clock hierarchy in mammals. CLK:BMAL1 rhythmically bind at the same discrete phase of the circadian cycle to all target genes, which not surprisingly have a much higher percentage of rhythmic transcription than the genome as a whole. However, there is a surprisingly heterogeneous set of cycling transcription phases of direct target genes, which even include core clock genes. This indicates a disconnect between rhythmic DNA binding and the peak of transcription, which is likely due to other transcription factors that collaborate with CLK:BMAL1. In summary, the application of Nascent-Seq to a mammalian tissue provides surprising insights into the rhythmic control of gene expression and should have broad applications beyond the analysis of circadian rhythms. CLK and BMAL1 DNA binding profile in the mouse liver at ZT8, sequenced along an Input sample using GAII (ChIP-Seq) Supplementary file ChIPSeq_Mouse_Liver_Processed_data_Table1.txt represents annotated CLK and BMAL1 peaks.
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2017-12-01 | E-MTAB-5330 | biostudies-arrayexpress
Project description:Various aspects of physiology and cell function present self-sustained ~24h variations termed circadian rhythms, enabling anticipation and adaptation to the 24-h cycle produced by the Earth’s rotation. The circadian clock system consists of a central clock located in the suprachiasmatic nucleus in the hypothalamus, and peripheral clocks present in distinct tissues. In particular, peripheral clocks in the liver have fundamental roles in maintaining liver homeostasis. Here, we established and characterized a human hepatocyte in vitro system in which human primary hepatocytes displayed self-sustained oscillations independently of external cues a distinguishing feature of circadian clocks. We then used this experimental system to study the impact of circadian oscillations in human liver pathophysiology. By generating hepatocyte circadian transcriptomes, we demonstrated that the transcriptional state of cultured human hepatocytes is dynamic across 24h. Analyses of gene expression data identified a set of cycling genes, including a subset of well-established ‘core clock genes’ and oscillating genes related to inflammation, drug metabolism, and energy homeostasis. We documented a circadian-dependent induction of the pro-inflammatory cytokines IL-1b, IL-6, TNF-a CXCLl1 and CXCL10 triggered by LPS or IFN-b in human hepatocytes. We also demonstrated circadian fluctuations of a subset of drug metabolism enzymes, which regulate drug pharmacokinetics. Among these enzymes, we identified CYP3A4, as one displaying circadian fluctuations at activity levels and a time-dependent induction with rifampin. Finally, we showed the impact of applying chronopharmacotherapy by designing a treatment protocol to minimize atorvastatin and acetaminophen induced hepatotoxicity. Collectively, our findings document that circadian time can influence the magnitude of the inflammatory response in the liver and the efficacy, toxicity, and/or the therapeutic index of drugs.
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Project description:Various aspects of physiology and cell function present self-sustained ~24h variations termed circadian rhythms, enabling anticipation and adaptation to the 24-h cycle produced by the Earth’s rotation. The circadian clock system consists of a central clock located in the suprachiasmatic nucleus in the hypothalamus, and peripheral clocks present in distinct tissues. In particular, peripheral clocks in the liver have fundamental roles in maintaining liver homeostasis. Here, we established and characterized a human hepatocyte in vitro system in which human primary hepatocytes displayed self-sustained oscillations independently of external cues a distinguishing feature of circadian clocks. We then used this experimental system to study the impact of circadian oscillations in human liver pathophysiology. By generating hepatocyte circadian transcriptomes, we demonstrated that the transcriptional state of cultured human hepatocytes is dynamic across 24h. Analyses of gene expression data identified a set of cycling genes, including a subset of well-established ‘core clock genes’ and oscillating genes related to inflammation, drug metabolism, and energy homeostasis. We documented a circadian-dependent induction of the pro-inflammatory cytokines IL-1b, IL-6, TNF-a CXCLl1 and CXCL10 triggered by LPS or IFN-b in human hepatocytes. We also demonstrated circadian fluctuations of a subset of drug metabolism enzymes, which regulate drug pharmacokinetics. Among these enzymes, we identified CYP3A4, as one displaying circadian fluctuations at activity levels and a time-dependent induction with rifampin. Finally, we showed the impact of applying chronopharmacotherapy by designing a treatment protocol to minimize atorvastatin and acetaminophen induced hepatotoxicity. Collectively, our findings document that circadian time can influence the magnitude of the inflammatory response in the liver and the efficacy, toxicity, and/or the therapeutic index of drugs.
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Project description:Over the past decade, genome-wide assays have underscored the broad sweep of circadian gene expression. A substantial fraction of the transcriptome undergoes oscillations in many organisms and tissues, which governs the many biochemical, physiological and behavioral functions under circadian control. Based predominantly on the transcription feedback loops important for core circadian timekeeping, it is commonly assumed that this widespread mRNA cycling reflects circadian transcriptional cycling. To address this issue, we directly measured dynamic changes in mouse liver transcription using Nascent-Seq. Many genes are rhythmically transcribed over the 24h day, which include precursors of several non-coding RNAs as well as the expected set of core clock genes. Surprisingly however, nascent RNA rhythms overlap poorly with mRNA abundance rhythms assayed by RNA-seq. This is because most mouse liver genes with rhythmic mRNA expression manifest poor transcriptional rhythms, indicating a prominent role of post-transcriptional regulation in setting mRNA cycling amplitude. To gain further insight into circadian transcriptional regulation, we also characterized the rhythmic transcription of liver genes targeted by the transcription factors CLOCK and BMAL1; they directly target other core clock genes and sit at the top of the molecular circadian clock hierarchy in mammals. CLK:BMAL1 rhythmically bind at the same discrete phase of the circadian cycle to all target genes, which not surprisingly have a much higher percentage of rhythmic transcription than the genome as a whole. However, there is a surprisingly heterogeneous set of cycling transcription phases of direct target genes, which even include core clock genes. This indicates a disconnect between rhythmic DNA binding and the peak of transcription, which is likely due to other transcription factors that collaborate with CLK:BMAL1. In summary, the application of Nascent-Seq to a mammalian tissue provides surprising insights into the rhythmic control of gene expression and should have broad applications beyond the analysis of circadian rhythms.
2012-11-10 | GSE36874 | GEO
Project description:Over the past decade, genome-wide assays have underscored the broad sweep of circadian gene expression. A substantial fraction of the transcriptome undergoes oscillations in many organisms and tissues, which governs the many biochemical, physiological and behavioral functions under circadian control. Based predominantly on the transcription feedback loops important for core circadian timekeeping, it is commonly assumed that this widespread mRNA cycling reflects circadian transcriptional cycling. To address this issue, we directly measured dynamic changes in mouse liver transcription using Nascent-Seq. Many genes are rhythmically transcribed over the 24h day, which include precursors of several non-coding RNAs as well as the expected set of core clock genes. Surprisingly however, nascent RNA rhythms overlap poorly with mRNA abundance rhythms assayed by RNA-seq. This is because most mouse liver genes with rhythmic mRNA expression manifest poor transcriptional rhythms, indicating a prominent role of post-transcriptional regulation in setting mRNA cycling amplitude. To gain further insight into circadian transcriptional regulation, we also characterized the rhythmic transcription of liver genes targeted by the transcription factors CLOCK and BMAL1; they directly target other core clock genes and sit at the top of the molecular circadian clock hierarchy in mammals. CLK:BMAL1 rhythmically bind at the same discrete phase of the circadian cycle to all target genes, which not surprisingly have a much higher percentage of rhythmic transcription than the genome as a whole. However, there is a surprisingly heterogeneous set of cycling transcription phases of direct target genes, which even include core clock genes. This indicates a disconnect between rhythmic DNA binding and the peak of transcription, which is likely due to other transcription factors that collaborate with CLK:BMAL1. In summary, the application of Nascent-Seq to a mammalian tissue provides surprising insights into the rhythmic control of gene expression and should have broad applications beyond the analysis of circadian rhythms.
2012-11-10 | GSE36873 | GEO
Project description:Over the past decade, genome-wide assays have underscored the broad sweep of circadian gene expression. A substantial fraction of the transcriptome undergoes oscillations in many organisms and tissues, which governs the many biochemical, physiological and behavioral functions under circadian control. Based predominantly on the transcription feedback loops important for core circadian timekeeping, it is commonly assumed that this widespread mRNA cycling reflects circadian transcriptional cycling. To address this issue, we directly measured dynamic changes in mouse liver transcription using Nascent-Seq. Many genes are rhythmically transcribed over the 24h day, which include precursors of several non-coding RNAs as well as the expected set of core clock genes. Surprisingly however, nascent RNA rhythms overlap poorly with mRNA abundance rhythms assayed by RNA-seq. This is because most mouse liver genes with rhythmic mRNA expression manifest poor transcriptional rhythms, indicating a prominent role of post-transcriptional regulation in setting mRNA cycling amplitude. To gain further insight into circadian transcriptional regulation, we also characterized the rhythmic transcription of liver genes targeted by the transcription factors CLOCK and BMAL1; they directly target other core clock genes and sit at the top of the molecular circadian clock hierarchy in mammals. CLK:BMAL1 rhythmically bind at the same discrete phase of the circadian cycle to all target genes, which not surprisingly have a much higher percentage of rhythmic transcription than the genome as a whole. However, there is a surprisingly heterogeneous set of cycling transcription phases of direct target genes, which even include core clock genes. This indicates a disconnect between rhythmic DNA binding and the peak of transcription, which is likely due to other transcription factors that collaborate with CLK:BMAL1. In summary, the application of Nascent-Seq to a mammalian tissue provides surprising insights into the rhythmic control of gene expression and should have broad applications beyond the analysis of circadian rhythms.
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