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Telomeres - New insights into the tiny cellular biological clocks.
Telomeres, which compose chromosomes’ extremities and protect them, also play a role as cellular biological clocks.
Each time a cell divides the telomeres loose part of their content until they become too short.
This in turn triggers a signal to stop the division process.
This event is however delayed in stem cells or tumor cells, due to the activity of telomerase, an enzyme capable of elongating the extremities of DNA strands.
Joachim Lingner’s group, who deciphered mechanisms involved in telomere elongation in cancerous cells, is turning its attention to yeast.
This unicellular mushroom often serves as a model organism, since it functions as a mammalian cell, while being easier to manipulate.
The scientist’s work, which is published in the November 2008 edition of Molecular Cell, demonstrates that yeast telomeres are also transcribed into RNA.
These molecules, named TERRA, exert an inhibitory role on the telomerase.
The researchers also describe how telomeric RNA is in turn modulated by an enzyme, the Rat1p exonuclease, capable of degrading it.
“We suspect that TERRA production may have a physiological role for the regulation of telomerase and the establishment of telomere length homeostasis”, adds the professor.
Identifying this biological clockwork is essential for understanding and treating diseases that involve telomerase misregulation.
• Publication in Molecular Cell
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Damaged genes - The DNA repair shop is located at the edge of the cell nucleus.
The cell nucleus, the fortress protecting our precious DNA, just revealed one of its secrets.
Recent work from the NCCR had already shown that nuclear pores could influence gene expression.
Susan Gasser’s team discovers now that these structures also contain repair shops for certain types of damaged DNA.
Nuclear pores, which are essential to import-export functions of molecules between the nucleus and the cytoplasm, are in fact sophisticated structures involved in different tasks.
In the Science issue of October 24th 2008, the researchers demonstrated how defective DNA is shunted to the pores in order to be mended.
The studies were done with baker’s yeast, a unicellular fungus used as an experimental model.
The artificial breaks induced within its DNA were marked with fluorescent proteins, in order to track the process in living cells.
The scientists noted that damaged genetic material was tagged with a signal molecule called SUMO, before being shunted to a specialized subgroup of nucleoporins.
The interaction with these structural pore proteins activates a pore-bound enzyme, a SUMO-dependent E3 ligase, which recognises the defective tagged DNA.
The enzyme induces the destruction of proteins bearing the SUMO tag, as a prelude to the process of repair.
These nucleoporins, as well as the enzyme, are also present in human cells. In addition, the latter is highly expressed in cancer cells.
The professor’s studies contribute to understanding the repair mechanisms of the genome, an important step towards developing more efficient therapies.
• Publication in Science
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Genetic engineering - Ulrich Laemmli develops a kit to analyze nuclear gene function.
How do the various structures present in the nucleus influence gene expression?
Until now, the researchers could only use a limited approach to answer this question, due to the lack of tools adapted to this type of functional analysis.
“Since our main research interest concerns nuclear structure and function, we aimed to deplete the cell nucleus of target proteins in order to assess the consequences”, explains Ulrich Laemmli.
The scientists of his group, who just set up a technique to export these proteins out of the nucleus and sequester them in the cytoplasm, are publishing their results in the 26th September 2008 edition of Molecular Cell magazine.
This sophisticated approach was realised in yeast. This unicellular mushroom is indeed often used as a model organism, since it functions as a mammalian cell, while being easier to manipulate.
The researchers synthesized cytoplasmic receptors able to anchor targeted nuclear proteins upon receiving a signal.
The binding of the receptor to the protein is ensured by a system of molecular “Velcro” comprising two components.
The receptors were fused with the first one, and the chosen proteins with the second one.
The reaction starts when a compound serving as chemical glue is added.
This technique, which functioned for all the 43 nuclear genes tested with remarkable efficiency and rapidity, represents a powerful bioengineering tool to study the functions of nuclear genes.
The professor’s kit, in principle usable in mammal cells, could become a sine qua non in biological and medical research.
• Publication in Molecular Cell
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Circadian genes - Ueli Schibler discovers how cells’ appetite interferes with our internal clockwork.
The organism’s diverse functions fluctuate according to a regular pattern during the day.
Whereas the conductor in charge of coordinating these oscillations is located in the brain, the message is relayed by subsidiary oscillators within our cells.
The mechanisms of control ensured by the central pacemaker remain however unsolved.
The professor’s group, which has established a connexion between the cell metabolism and the main circadian circuit, uncovers the key role of an enzyme named SIRT1.
This protein, involved in the control of metabolism, also modulates the activity of several core clock genes.
This molecular dialogue is described in the Cell magazine edition of the 25th of July.
• Details on UNIGE website (In French)
• Publication in Cell
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Gene therapy - A breakthrough technique developed by Botond Roska’s team restores vision to blind mice.
Many people suffer blindness due to retinal degeneration, with no currently available treatment for about 1.5 million persons among them.
This pathology is associated with the destruction of photoreceptor cells. Light can thus no longer be converted to electrical signals in order to transmit the message to the visual cortex.
In collaboration with researchers from Harvard, Botond Roska’s team has adopted an original approach, published in Nature Neuroscience on the 27th April 2008.
The scientists administered a gene of a light-activated protein to blind mice, in a selective way. The cells targeted, named bipolar ON, are part of a specific type of neuronal retinal circuits that normally respond to increases in light levels (ON circuits).
Activation of these artificial photoreceptors in blind mice enabled them to perform visually guided behavioural tasks.
This breakthrough technique represents an unprecedented therapeutic hope for persons affected by retinitis pigmentosa or late-stage macular degeneration.
It also opens the way to clinical trials in humans.
• Details in FMI News (PDF; 1 page, 784 KB)
• Publication in Nature Neuroscience
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Personality 2008 - Ariel Ruiz i Altaba joins the “Forum of the 100” of the magazine L’Hebdo.
The professor, project leader at the NCCR Frontiers in Genetics, becomes one of the “100 personalities of the French-speaking part of Switzerland”, according to L’Hebdo.
In its May edition dedicated to this annual event, the magazine emphasizes the versatility of the researcher. Ariel Ruiz i Altaba, expert in developmental biology, has namely studied the mechanisms involved in the growth of stem cells.
The scientist has been rewarded for his pioneer work on the role of stem cells in tumor expansion, as well as for the development of a potential treatment.
He was also the key player in the creation of the Swiss Stem Cell Network. Another of his objectives was achieved last December: to convince the Swiss National Fund to establish a priority program of research on stem cells.
• Article from L’Hebdo (PDF; in French; 2 pages, 1.1 MB)
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Walter Wahli collaborates to a project of genetic archaeology - The study describes the changes that led mammals to feed their offspring via the placenta and with milk, while progressively abandoning eggs.
Although all mammals produce milk, they display diverse strategies to nourish their young before birth.
Humans and kangaroos both deliver food via the placenta, whereas for the duck-billed platypus, one of the rare oviparous mammals, this function is assumed by the egg yolk.
This substance notably contains one essential protein named vitellogenin.
The study to which Walter Wahli participates, published in the March 2008 edition of PLoS Biology, compares DNA from these three mammal lineages.
The researchers discovered that the emergence of genes coding for milk proteins, between 200 and 310 million years ago, led to a progressive loss of those producing vitellogenin.
This has allowed our common ancestors to break free from their nutritional dependence to the egg, therefore enabling the development of placenta.
The missing links are none other than the platypus and his echidna cousins. These strange exotic animals still lay eggs, although they are scarce in vitellus, before feeding their young with rudimentary mammary glands.
• Press release on UNIL website (PDF; in French; 1 page, 105.1 KB)
• Publication in PLoS Biology
• Analysis and comments in PLoS Biology
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The genetic architects - The team of Denis Duboule reveals how the same group of genes is responsible for the formation of each of our five fingers, while inducing them to become asymmetrical. The recipe ? Molecular constraints and gene dosage.
Evolution has taken advantage of recycling long before us. This function has indeed been used for millions of years by the “architect” genes, which are responsible for the distribution of our structures during embryonic development.
The team of Denis Duboule, director of the NCCR Frontiers in Genetics, unveils how structures as distinct as the thumb and the others digits are conceived from the same genetic kit.
The difference results from the regulation of the expression of these genes, named Hox.
The mechanism involved imposes a reduced activity of the architect genes within the future thumb.
This in turn promotes a lower growth, with the formation of two phalanxes only.
The studies, published in February in Genes and Development, also describe how the researchers developed a mathematical model of this complex strategy of regulation.
The same genetic modules are also used for other purposes.
Thomas Montavon, first author of the article, explains how this model applies to the regulation of Hox genes during the emergence of external genitalia.
A molecular mock-up for the construction of our limbs
During limbs development, Hox genes are in charge of coordinating the execution of operations.
Denis Duboule, who has been focusing on this area for twenty years, showed that they are aligned on the chromosomes according to the order of appearance of the future structures.
The sequential activation of these genes thus translates into the development of the shoulder, followed by the arm, the forearm, before the emergence of the fingers.
In other terms, there is a concordance between the linear organisation of the genes and the three-dimensional organisation of our members.
• Details on UNIGE website (In French)
• Publication in Genes & Development
• Analysis and comments in Genes & Development
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