Bursting with Activity


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The heart gets all the glory in poetry and aphorisms, but it is the liver that plays a truly central role in orchestrating the entire body’s metabolism. In carrying out its many and varied tasks, the liver faces the tremendous challenge of constantly adjusting to changing conditions – for instance, keeping blood glucose at a steady level despite large mealtime fluctuations in the glucose supply. Weizmann Institute scientists have now revealed that genes in the liver operate in bursts rather than continuously – a pattern that may help optimize their activity, assisting the liver in coping with ongoing challenges. An in-depth understanding of this mechanism may shed new light on the way the liver, and perhaps other organs too, function in health and disease.
A similar mechanism had been earlier known to exist in bacteria: When it comes to bacterial genes, the initial stage of activity, the production of a messenger molecule called mRNA, often proceeds in bursts that vary randomly in length, resulting in widely varying mRNA levels in different bacterial cells. This pattern suggests a strategy that has been described as “bet-hedging”: The diversity in mRNA production ensures the survival of at least some of the bacteria, i.e., the ones for which mRNA levels happen to be best suited to the current circumstances.   
Dr. Shalev Itzkovitz
In the new study, reported in Molecular Cell, scientists led by Dr. Shalev Itzkovitz of the Molecular Cell Biology Department set out to explore the question: Do genes in the mammalian body resort to the same mechanism; that is, do they produce mRNA in bursts? The scientists used an innovative method developed in Itzkovitz’s lab that has, for the first time, made it possible to visualize individual mRNA molecules as they are being manufactured in intact mammalian tissue. The method combines advanced microscopy with computational approaches.   
Using this method, they showed that, just as in bacteria, genes in mouse liver tissue work in random bursts of varying length. The lifetimes of different mRNA molecules, it turns out, also vary; the mRNAs of some genes are longer-lasting than others. The combination of these two variables renders the control of liver gene activity extremely flexible. Thus an mRNA of a particular gene can be generated in long bursts; but if this mRNA itself is short-lived, stopping the bursts will rapidly put an end to the gene’s activity.
Activity of a glucose-manufacturing gene in mouse liver tissue, viewed under a fluorescence microscope. A high concentration of mRNA (red dots) reveals that this activity is highest near a blood vessel (PP) that bathes the tissue in oxygen-rich blood, essential for glucose manufacture
This flexibility can be crucial in performing the liver’s dynamic functions – for example, in regulating blood glucose. As part of ongoing maintenance, the liver takes up extra glucose when its levels are too high, then gradually releases it or synthesizes new glucose when levels drop. As glucose levels rise within minutes after a meal, the synthesis of new glucose must be able to stop instantly. The short-lived mRNA, which quickly disappears from the cell once gene activity is shut down, is perfectly suited to this end.
Indeed, the Weizmann study found that the mRNAs of two genes essential for glucose production are extremely short-lived. To compensate for their brief life span, they are produced in longer than average bursts, presumably to reduce the variability among cells caused by the bursts. On the other hand, other mRNAs, with a longer life span, are produced in shorter bursts.
Fluorescence microscope image of mouse liver cells. Cell membranes are in green; the cell nuclei (blue) contain different numbers of DNA strands, from the usual 2 to as many as 8
The scientists believe the bursty expression of genes could have evolved because it can protect the DNA from damage: Genes are physically more exposed when active, so by being active only at intervals, rather than permanently, they are less vulnerable to surrounding toxins. This feature is particularly important in an organ like the liver, which is involved in filtering out harmful substances.
The scientists also believe that the bursty activity may help explain a baffling feature of many liver cells: the presence of multiple copies of the genome, comprising four or eight DNA strands instead of the usual two. Their proposed explanation goes as follows: The bursts cause mRNA levels to fluctuate at random, but thanks to the extra DNA copies, each of which produces mRNA, this randomness is averaged out among cells. As a result, different liver cells end up producing a particular mRNA in a uniform manner. Indeed, in a “factory” such as the liver, where cells work together towards a common physiological goal, excessive variability among cells caused by such bursts could have been a disadvantage. 
Fluorescence microscope snapshots of mouse liver tissue revealing new mRNA, an indicator of gene activity (bright dots marked by white triangles). The lone new mRNA (left) indicates that its gene operates only in infrequent bursts; in contrast, the presence of numerous new mRNAs (right) suggests gene activity that proceeds in long, frequent bursts
The team that performed this research included Dr. Keren Bahar Halpern, Sivan Tanami, Shanie Landen, Michal Chapal, Liran Szlak, Anat Hutzler and Anna Nizhberg. 

Further clarification of the bursty gene expression in the liver may help reveal such mechanisms of faulty liver function as defective glucose metabolism, which leads to diabetes. The scientists have also found indications that bursty gene expression may be found in organs other than the liver, a finding that opens new ways of investigating the control of gene activity in different tissues.