Scientists at the École polytechnique fédérale de Lausanne (EPFL), Switzerland, and the Weizmann Institute of Science, Israel, have uncovered that the expression of many liver genes is dually regulated—in both space and time. This indicates that genes in the liver are regulated by both their location in the multilobed organ and the time of the day.
The study uses single-cell RNA sequencing and single-molecule fluorescent in situ hybridization (smFISH) to monitor over 5,000 genes throughout a day to demonstrate that liver gene expression is periodic and restricted to specific zones of the organ, with most gene expression patterns revealing many space-time regulatory paradigms.
Led by professors Felix Naef, PhD, at EPFL’s School of Life Sciences, and Shalev Itzkovitz, PhD, at the Weizmann Institute, the study employs mixed-effect models to pinpoint the variations in the expressions of these genes in space and time. Such dually regulated genes, the authors noted, encompass the gamut of liver functions, including lipid, carbohydrate, and amino acid metabolism, as well as unexpected molecular machineries such as chaperone-aided assembly or rearrangement of protein conformations in three-dimensional space.
The authors noted that this spatio-temporal systemic approach reveals that the rhythmic and localized expression of intricately regulated target genes, such as Wnt signaling targets, could be explained by the periodic expression of ligands in the microenvironment, such as the expression of Wnt ligands from non-parenchymal cells near the central vein.
Of note, the study reported that the expression of core circadian clock genes is not localized to a particular lobule or sub-lobule of the liver whereas the expression of other liver genes show spatial shifts within liver lobules in relationship to the circadian clock.
These findings are published in an article titled, “Space-time logic of liver gene expression at sub-lobular scale,” in Nature Metabolism.
“The work reveals a richness of space-time gene expression dynamics of the liver and shows how compartmentalization of liver function in both space and time is a hallmark of metabolic activity in the mammalian liver,” said Naef.
Earlier studies have taken a static and restricted approach in tackling the mechanisms and implications of spatially and temporally regulated gene expression in the liver, focusing on either the expression of a few or a single gene over time or on a specific locale of the liver independent of related regions.
Earlier research from the Naef lab has shown interplays between the circadian clock and specific liver proteins, cell cycles, and the packaging of DNA in the cell nucleus.
The current study adopts a combinatorial approach by studying the variations in expression of a large number of genes throughout a 24-hour period in the entire organ, to reveal physiologically relevant insights on liver biology. The power of the current study stems from the mixed modeling approach that statistically classifies the space-time patterns uncovered, to capture both spatial and temporal variations in the levels of transcripts.
Systemic metabolic homeostasis is largely controlled by the liver in mammals. All that we consume is processed in the liver to separate nutrients from waste and regulate the body’s metabolic balance. The function of the liver is regulated in time through a set of genes that constitute an internal metronome, as well as biochemical signals from other organs such as the brain and muscles, as well as our idiosyncratic eating rhythms.
This metabolic hub is structurally compartmentalized into lobes and lobules, with each sub-lobular zone dedicated to performing distinct functions. For instance, the breakdown of sugars during digestion takes place preferentially in the central zone of the lobule whereas the production of glucose from fat stores as we sleep, occurs preferentially at the portal side.
In addition to this spatial compartmentalization, gene expression in the liver is also temporally orchestrated by the complex interplay of the circadian clock, systemic cues, and feeding routines.
Since biological processes fluctuate over time, piecing together accurate insights on liver biology mandates both spatial and temporal considerations—the purview of the field of chronobiology.