Space-time logic of liver gene expression at sub-lobular scale.
IF: 19.865
Cited by: 66


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.


Gene Expression

MeSH terms

Amino Acids
Carbohydrate Metabolism
Circadian Clocks
Gene Expression
Gene Expression Profiling
Lipid Metabolism
Mice, Inbred C57BL
Molecular Chaperones
Period Circadian Proteins
RNA, Messenger
Wnt Signaling Pathway


Droin, Colas
Kholtei, Jakob El
Bahar Halpern, Keren
Hurni, Clémence
Rozenberg, Milena
Muvkadi, Sapir
Itzkovitz, Shalev
Naef, Felix

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