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Space-time logic of liver gene expression at sub-lobular scale
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Abstract
The mammalian liver is a central hub for systemic metabolic homeostasis. Liver tissue is spatially structured, with hepatocytes operating in repeating lobules, and sub-lobule zones performing distinct functions. The liver is also subject to extensive temporal regulation, orchestrated by the interplay of the circadian clock, systemic signals and feeding rhythms. However, liver zonation has previously been analysed as a static phenomenon, and liver chronobiology has been analysed at tissue-level resolution. Here, we use single-cell RNA-seq to investigate the interplay between gene regulation in space and time. Using mixed-effect models of messenger RNA expression and smFISH validations, we find that many genes in the liver are both zonated and rhythmic, and most of them show multiplicative space-time effects. Such dually regulated genes cover not only key hepatic functions such as lipid, carbohydrate and amino acid metabolism, but also previously unassociated processes involving protein chaperones. Our data also suggest that rhythmic and localized expression of Wnt targets could be explained by rhythmically expressed Wnt ligands from non-parenchymal cells near the central vein. Core circadian clock genes are expressed in a non-zonated manner, indicating that the liver clock is robust to zonation. Together, our scRNA-seq analysis reveals how liver function is compartmentalized spatio-temporally at the sub-lobular scale.
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“For example, gluconeogenesis-regulating genes are induced in periportal hepatocytes following prolonged starvation at the end of the resting phase.9,26”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [26]
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“Beyond metabolism, morphogen expression, such as that of Wnt-family members, is also shaped by this zonation and can vary in time7.”
From Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution (2025) · cites this paper as [7]
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“Collectively, these observations suggest that spatial gene expression in human hepatocytes is better described by a continuous variable determined by the relative distance between the portal and central areas of the lobule, similar to observations in mouse7,26,27.”
From Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution (2025) · cites this paper as [7]
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“Close to the inlet, where oxygen concentrations are highest, we observed increased levels of the periportal marker proteins ARG1, BAAT, PYGL, FBP1 and ASL ( Fig. 6 a).”
From 3D microperfusion of mesoscale human microphysiological liver models improves functionality and recapitulates hepatic zonation (2023) · cites this paper as [34]
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“In contrast, expression of perivenous markers was significantly elevated close to the outlet where oxygenation is lower.”
From 3D microperfusion of mesoscale human microphysiological liver models improves functionality and recapitulates hepatic zonation (2023) · cites this paper as [34]
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“Further, the expression of WNT ligands is influenced by diurnal mRNA fluctuations, suggesting that WNT signalling may fluctuate throughout the day.26”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [26]
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“For example, mutations in a single enzyme (AGXT), predominantly expressed in periportal hepatocytes, results in a life-threatening condition, primary hyperoxaluria type 1.26,156”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [26]
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“we confirmed that the animals that were fed ad libitum mapped to early zeitgeber timepoints, while samples for which food was removed the night before mapped to late zeitgeber timepoints”
From Enhancer grammar of liver cell types and hepatocyte zonation states (2022) · cites this paper as [34]
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“To correct for batch effects, we used Harmony on the selected principal components (34), using Leiden clustering with resolution 0.6, resulting in 15 clusters.”
From Enhancer grammar of liver cell types and hepatocyte zonation states (2022) · cites this paper as [34]
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Metadata
- Authors
- Droin, C., Kholtei, J. E., Bahar Halpern, K., Hurni, C., Rozenberg, M., Muvkadi, S., Itzkovitz, S., & Naef, F.
- Affiliations
- École Polytechnique Fédérale de Lausanne (CH)
- Weizmann Institute of Science (IL)
- Corresponding author
- Itzkovitz, Shalev
- Venue
- Nature Metabolism
- Published
- 2021-01-11
- Volume
- 3
- Issue
- 1
- Pages
- 43-58
- ISSN
- 2522-5812 (ISSN-L)
- PMC
- PMC7116850
- OpenAlex
- W3119677722
- Cited by
- 148
- References
- 71
- Citations by year
- 2026: 23 · 2025: 26 · 2024: 27 · 2023: 31 · 2022: 26 · 2021: 13
- FWCI
- 7.61
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Metabolism (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030_173079)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- liver zonation, circadian clock, gene expression rhythms, hepatocyte heterogeneity, Wnt signaling, central vein, non-parenchymal cells, molecular chaperones, lipid metabolism, carbohydrate metabolism, amino acid metabolism
- MeSH terms
- Algorithms, Amino Acids, Animals, Liver, Male, Mice, Inbred C57BL, Periodicity, RNA, Messenger, Gene Expression, Molecular Chaperones, Gene Expression Profiling, Hepatocytes, Carbohydrate Metabolism, Lipid Metabolism, Mice, Period Circadian Proteins, Circadian Clocks, Wnt Signaling Pathway
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