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HapMap Project - Finding variants in the human genome.
New findings show the value of genetic studies across human populations and the value of the latest DNA sequencing technologies to interrogate genetic variation.
The results from the third phase of the international HapMap Project, of which Emmanouil Dermitzakis is one of the coordinators, are reported in the September 2nd 2010 edition of Nature.
The researchers’ extensive study of genetic variation in multiple populations will form a framework for future genetic studies of variation and disease: their findings highlight the need to examine various populations in order to tease out the widest collection of genetic variants, as well as the requirement to deploy sequencing technologies to find as many variants as possible.
• Details in press release (PDF; 2 pages, 197 KB) or on UNIGE website (In French)
• Publication in Nature
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Retinitis pigmentosa - Genetic reactivation restores vision in blind animals.
Mice suffering from Retinitis pigmentosa, a hereditary disease, recovered vision after gene therapy aimed at specific retinal photoreceptors.
An international team driven by Botond Roska used tailor-made gene vectors expressing a photosensitive protein, halorhodopsin, to target the remaining but non-functional retinal cones of these rodents.
This prompted reactivation of all retinal cone pathways and restored complex visual responses as well as visually guided behaviour.
The biological photoelectric system recreated by the scientists was then tested in light-insensitive human retinas in vitro.
The study, which is published in the June 24th 2010 edition of Science, shows that these retinas responded to light after treatment.
The researchers have also found a means of identifying blind patients with persisting, light-insensitive cones for potential halorhodopsin-based therapy.
• Details in FMI press release (PDF; 2 pages, 32.7 KB)
• Publication in Science
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Multitask protein - The existence of a heavyweight of gene expression modulation is revealed.
To protect the DNA and to serve the cell. Such are the missions of a versatile protein, Tbf1, whose diverse facets have been uncovered in yeast by David Shore’s team.
This molecule, known for its role in protecting telomeres, is in fact assigned to various tasks within the cell.
The protein indeed modulates the expression of about 3% of all genes, a hitherto unreported function. This stunning molecular organizer also influences the activity of other gene modulators, such as those involved in ribosome synthesis.
This study is published in the May 28th 2010 edition of Molecular Cell.
• Details on UNIGE website (In French)
• Publication in Molecular Cell
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Gene regulation - MicroRNA metabolism is particularly high in neurons and linked to neuronal activity.
MicroRNAs are short ribonucleic acid molecules that act as regulators of gene expression.
Botond Roska’s team identified in the mouse retina a cluster of microRNAs that are themselves modulated by different levels of light.
This specific subset of molecules is indeed reversibly up and down-regulated during adaptation to light and dark conditions, respectively.
The scientists identified a specific glutamate transporter, a key protein in synaptic transmission, as one of the microRNAs’ targets in photoreceptor cells.
The high turnover observed in retinal neurons was also discovered to be a common property of microRNAs in other types of neuronal cells, in response to synaptic stimulation by glutamate.
The presence of the neurotransmitter indeed accelerates the turnover of these specific microRNAs.
Thus, as detailed in the May 14th 2010 edition of Cell, the expression and metabolism of the tiny gene modulators are fine-tuned by neural activity in the retina and the brain.
• Details on FMI website
• Publication in Cell
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Cell reprogramming - Regeneration of insulin-producing cells in diabetic mice.
Type 1 diabetes, one of the most frequent chronic diseases in children, is characterized by a near complete destruction of insulin-producing cells in the pancreas, the beta-cells, through an autoimmune mechanism.
Until now, it was not known whether this organ was able to regenerate new beta-cells in such a case, either in a spontaneous or induced way.
Pedro Herrera’s team has now provided an answer to this question, thanks to transgenic mice it created.
The scientists demonstrate in the April 4th on line edition of Nature that rodents affected with this type of diabetes are able to generate new insulin-producing cells.
Surprisingly, most of the latter derive from a population of differentiated cells that was formerly synthesizing glucagon, a hormone whose properties are opposite to those of insulin.
Such spontaneous cell conversion could be harnessed to develop methods of producing beta-cells for diabetes therapies.
• Details in press release (PDF; 2 pages, 58 KB) or on UNIGE website (In French)
• Publication in Nature
• See also a short video report by Pedro Herrera (MOV; 1’21’’, 5 MB)
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Epigenetic regulation - Unveiling how the largest family of repressors mediates gene silencing.
The regulation of gene activity by transcription factors is crucial to the function of all cells.
Didier Trono’s team has studied the mechanisms of action of the largest family of transcriptional repressors encoded by the human genome, the so-called KRAB-ZFPs.
These proteins act as epigenetic repressors, as they are able to inhibit gene expression by modifying DNA structure without affecting the underlying DNA sequence.
The researchers determined molecular features of KRAB-ZFPs-mediated gene silencing by taking advantage of a novel lentiviral-vector based system.
The latter, developed in the professor’s lab, provides genetically-modified viruses that function as carriers and deliver selected genes to mice germinal cells.
The transgenic mice thus obtained are used to investigate the function and regulation of genes of interest.
The scientists found that the KRAB-ZFPs proteins were able to inhibit gene activity over long distances, after binding to DNA.
The transcription factors-mediated repression is in fact established by the long-range spreading of epigenetic signals.
This study, published in the March 5th 2010 edition of PLoS Genetics, provides new insights into the molecular modes of action of the largest family of transcription factors.
• Publication in PLoS Genetics
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Variation in gene activity of a population - New insight into cell functions and disease susceptibility.
A group of researchers led by Emmanouil Dermitzakis report the most extensive and comprehensive study regarding impact of genetic variations on gene activity.
This publication reveals how the unprecedented resolution for RNA sequencing allows the deep exploration of genetic effects into cellular processes.
It uses novel technologies to obtain a detailed picture of how gene activity in blood cells differs among people and to describe the variations in DNA responsible for such differences.
Results of this research have important implications for understanding genetic susceptibility to common and rare diseases as well as the basis of natural variation in human characters.
The proceeds of this study are published in the March 11th 2010 edition of Nature.
• Details in press release (PDF; 2 pages, 100 KB) or on UNIGE website (In French)
• Publication in Nature
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Architect genes - An invasion of jumping genes may have sparked off reptile diversity.
Among all reptiles, squamates are the ones that deserve the gold medal of diversity.
This group, which comprises lizards and snakes, displays indeed an amazing realm of morphologies.
Understanding how the body plan of these animals has evolved and led to the formation of such drastically different organisms is a challenge that was taken up by the team of Denis Duboule.
The researchers reveal in the 4th March 2010 edition of Nature various subterfuges employed during the evolution of architect genes.
The latter, named Hox genes, are essential for coordinating body patterning during embryonic development.
Rearrangements and mutations discovered within these genes enable to visualise the transition between lizards and snakes.
The geneticists also show that an invasion of transposons, genes capable of moving within the genome, may be at the root of the flexibility observed in the squamates’ body plan.
• Details in press release (PDF; 2 pages, 441 KB) or on UNIGE website (In French)
• Publication in Nature
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Embryonic stem cells - Epigenetic repressors control endogenous retroviruses.
About one tenth of our genome is derived from endogenous retroviruses, some of them being present since hundreds of millions of years.
These pathogens, which are members of the same family as the HIV, have penetrated the germ cells’ DNA of our ancestors.
Fortunately, the colonizing viruses are maintained in a quiescent state.
Didier Trono’s team has uncovered the mechanism used by the cells to neutralize these intruders, transmitted from generation to generation.
The researchers explain in the 14th January 2010 issue of Nature that about 400 inhibitory proteins are involved in this manoeuvre.
These molecules, all members of the same family, are able to recognize a viral sequence in our DNA and neutralize it.
They are considered as “epigenetic” repressors, since they don’t induce any change in the sequence of DNA.
The key actor of this molecular feat is a protein named KAP1. In mice, KAP1 is recruited by the 400 inhibitory proteins army, during the five or six first days of embryonic life.
This is the first step of the cascade of events orchestrated by KAP1 and necessary to put the viral sequences to sleep.
The discovery could be of use in the search of new therapeutic approaches, in particular against AIDS.
“It may be our own cells that inhibit the HIV, in order to defend the organism. This could represent the same process, albeit imperfect. We could therefore envisage waking up the quiescent viruses during therapy to eliminate them too”, explains the professor.
• Details on EPFL website
• Publication in Nature
• See also an interview with Didier Trono on YouTube
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