Space-time logic of liver gene expression at sub-lobular scale

Area of Science:

• Cellular Biology
• Genomics
• Chronobiology

Background:

• The mammalian liver maintains metabolic homeostasis through spatially organized hepatocytes within lobules and distinct sub-lobular zones.
• Liver function is temporally regulated by circadian rhythms, systemic signals, and feeding patterns.
• Previous analyses treated liver zonation as static and chronobiology at a tissue level, limiting understanding of their interplay.

Purpose of the Study:

• To investigate the interplay between spatial zonation and temporal regulation (chronobiology) of gene expression in the mammalian liver.
• To analyze gene regulation at the single-cell level to understand spatio-temporal compartmentalization of liver function.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) was employed to profile gene expression in individual liver cells.
• Mixed-effect models were used to analyze messenger RNA expression patterns.
• Spatial gene expression was validated using single-molecule fluorescence in situ hybridization (smFISH).

Main Results:

• Many liver genes exhibit both spatial zonation and temporal rhythmicity, with most showing multiplicative space-time effects.
• Dually regulated genes are involved in key metabolic pathways (lipid, carbohydrate, amino acid) and protein chaperone processes.
• Rhythmic Wnt target gene expression may be driven by rhythmically expressed Wnt ligands from non-parenchymal cells.
• Core circadian clock genes are expressed uniformly across zones, indicating robustness to liver zonation.

Conclusions:

• Liver function is dynamically compartmentalized at the sub-lobular level through the integration of spatial and temporal gene regulation.
• The study reveals previously unassociated processes regulated by spatio-temporal gene expression in the liver.
• The liver clock mechanism is resilient to the spatial zonation of hepatocytes.