How the circadian clock regulates liver genes in time and space

January 11, 2021

Nothing in biology is static. Biological processes fluctuate over time, and if we are to put together an accurate picture of cells, tissues, organs etc., we have to take into account their temporal patterns. In fact, this effort has given rise to an entire field of study known as "chronobiology".

The liver is a prime example. Everything we eat or drink is eventually processed there to separate nutrients from waste and regulate the body's metabolic balance. In fact, the liver as a whole is extensively time-regulated, and this pattern is orchestrated by the so-called circadian clock, our body's internal metronome, as well as biochemical signals and eating rhythms.

But the liver is actually divided into small repeating units called "lobules", in which distinct zones perform different functions. This intricate spatial organization is known as "liver zonation". For example, the breakdown of sugars during digestion takes place preferentially on one side of the lobule, the so-called central zone, while the production of glucose while we rest from stores such as fat, occurs on the other side of the liver, at the portal side.

So far, liver zonation has only been studied statically, looking into what each zone does independently of time, and vice-versa. And given how central the liver is in mammalian physiology, the two research approaches have to join efforts to understand how temporal and spatial liver programs interact.

In a first ever study, scientists at EPFL and the Weizmann Institute of Science, led by Professors Felix Naef at EPFL's School of Life Sciences and Shalev Itzkovitz at the Weizmann, have been able to monitor the spatial shifts of gene expression within liver lobules in relationship to the circadian clock. Studying this link is a focus of Naef's research, which has previously uncovered connections between the circadian clock and the liver's proteins, our cell cycles, and even the 3D structure of chromatin, the tightly packaged DNA in the cell nucleus.

The study came out of a EPFL-Weizmann joint grant from the Rothschild Caesarea Foundation.

By exploiting the ability to analyze liver tissue in every individual cell, the researchers studied approximately 5000 genes in liver cells at several timepoints throughout the 24-hour day. They then statistically classified the space-time patterns they uncovered with a model that can capture both spatial and temporal variations in the levels of messenger RNA (mRNA), a marker of gene expression.

The study revealed that many of the liver's genes seem to be both zonated and rhythmic, meaning that they are regulated by both their location in the liver and the time of the day. These dually regulated genes are mostly linked to key functions of the liver, e.g. the metabolism of lipids, carbohydrates, and amino acids, but also include a few genes that have never been associated with metabolism, e.g. genes related to chaperone proteins, which help other biomolecules change their 3D structure or even assemble and disassemble.

"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 hallmark of metabolic activity in the mammalian liver," says Felix Naef.
-end-


Ecole Polytechnique Fédérale de Lausanne

Related Circadian Clock Articles from Brightsurf:

Pinpointing the cells that keep the body's master circadian clock ticking
UT Southwestern scientists have developed a genetically engineered mouse and imaging system that lets them visualize fluctuations in the circadian clocks of cell types in mice.

The discovery of new compounds for acting on the circadian clock
The research team comprised of Designated Associate Professor Tsuyoshi Hirota and Postdoctoral Fellows Simon Miller and Yoshiki Aikawa, of the Nagoya University Institute of Transformative Bio-Molecules, has succeeded in the discovery of novel compounds to lengthen the period of the circadian clock, and has shed light on their mechanisms of action.

Let there be 'circadian' light
Researchers publishing in Current Biology describe the science behind creating lighting to make us all happy and productive indoors.

U of M research discovers link between stress and circadian clock health
New research from the University of Minnesota Medical School found a little stress can make the circadian clock run better and faster.

The role of GABA neurons in the central circadian clock has been discovered
Temporal order of physiology and behavior is regulated by the central circadian clock located in the SCN.

Researchers take aim at circadian clock in deadly brain cancer
Scientists at USC and UC San Diego have discovered a potential novel target for treating glioblastoma, the deadly brain cancer that took the life of Sen.

Circadian clock and fat metabolism linked through newly discovered mechanism
Princeton University researchers found that the enzyme Nocturnin, known for its role in fat metabolism and circadian rhythm, acts on two well-established molecules in metabolism.

Dead zones in circadian clocks
Circadian clocks of organisms respond to light signals during night but do not respond in daytime.

Circadian clock plays unexpected role in neurodegenerative diseases
Northwestern University researchers induced jet lag in a fruit fly model of Huntington disease and found that jet lag protected the flies' neurons.

Researchers locate circadian clock that controls daily rhythms of aggression
Synchronized by light and darkness, the circadian clock exerts control over wake/sleep cycles, body temperature, digestion, hormonal cycles and some behavior patterns.

Read More: Circadian Clock News and Circadian Clock Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.