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Series GSE218242 Query DataSets for GSE218242
Status Public on Feb 28, 2024
Title Circadian rhythm-dependent programs control inflammatory responses and drug metabolism in primary human hepatocytes I.
Organisms Homo sapiens; Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary 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.
 
Overall design Two or three replicates each of primary human hepatocytes cultured with supporting J2-3T3 fibroblasts collected collected at three hour intervals over 48 hours.
 
Contributor(s) Nerurkar N, March S, Whittaker CA, Bhatia S
Citation missing Has this study been published? Please login to update or notify GEO.
Submission date Nov 17, 2022
Last update date Feb 28, 2024
Contact name Charles Arthur Whittaker
E-mail(s) charliew@mit.edu
Organization name Koch Institute
Street address 77 Mass Ave 76-189
City Cambridge
State/province MA
ZIP/Postal code 02152
Country USA
 
Platforms (1)
GPL25526 Illumina NovaSeq 6000 (Homo sapiens; Mus musculus)
Samples (49)
GSM6737747 UBV PHH at 24hr rep1
GSM6737748 UBV PHH at 24hr rep2
GSM6737749 UBV PHH at 24hr rep3
This SubSeries is part of SuperSeries:
GSE218244 Circadian rhythm-dependent programs control inflammatory responses and drug metabolism in primary human hepatocytes
Relations
BioProject PRJNA902796

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE218242_190712Bha_set1_intCt.txt.gz 1.9 Mb (ftp)(http) TXT
GSE218242_190712Bha_set1_l2tpm.txt.gz 4.0 Mb (ftp)(http) TXT
SRA Run SelectorHelp
Raw data are available in SRA
Processed data are available on Series record

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