Chargé de recherche Inserm
Unité Inserm 967 « Stabilité génétique, cellules souches et radiations »
+33 (0)1 46 54 89 39
Beta-thalassaemia and sickle cell anaemia are genetic disorders caused by mutations in a single gene but non-coding genomic regions seem to have a strong influence on disease severity. The teams of Eric Soler, researcher at Inserm unit 967, Fontenay-aux-Roses, France (Inserm / CEA), Swee Lay Thein, Clinical Director of the Red Cell Centre in King’s college London and King’s College Hospital, London, UK, and Frank Grosveld, professor of Cell Biology at the Erasmus Medical center, Rotterdam, unraveled the molecular mechanisms explaining how non-coding genomic variants, located far away from genes, were able to modify the clinical severity of beta thalassaemia and sickle cell anaemia. To reach this goal, the researchers have combined different expertise, including the study of spatial chromosome architecture. This work will be published in The Journal of Clinical Investigation and will be accessible online starting from March 10th 2014.
It is now clear that the vast majority of mutations and genetic variations uncovered by Genome-Wide Association Studies (GWAS), associated with common and rare diseases (diabetes, cardiovascular diseases, cancers) lie within non-coding sequences in the genome, i.e. do not directly hit the structural part of genes. Surprisingly, these genomic variants, found in the human population may be located at considerable distances from genes. This fact strongly complicates their functional analysis, and illustrates the complexity of the human genome organization and its relationship with diseases.
Beta-thalassaemias and sickle cell anaemia are among the most common inherited disorders affecting red blood cells. In particular, sickle cell anaemia which affects 300,000 newborns annually, is fast becoming the most common serious genetic disease in UK, France, and the rest of Europe. These disorders are caused by mutations affecting a single gene – the beta globin gene- leading to alterations of the adult haemoglobin. Despite being single gene mutations, both disorders display an extremely variable range of disease severity, many factors modify the disease severity including the ability to produce fetal haemoglobin. Fetal haemoglobin is normally ‘silenced’ in adults, but some adults are able to escape this silencing and continue to produce fetal haemoglobin, and although harmless in healthy adults, fetal haemoglobin can compensate for the altered adult haemoglobin in patients with beta thalassaemia and sickle cell anaemia, reducing the severity of the anaemia. In 2007, Swee Lay Thein’s lab identified a number of variants in a “gene desert” on chromosome 6q23, at tens of thousands of base-pairs from the closest genes, as affecting the ability to produce fetal haemoglobin in adults. How these genetic variants and the mechanism involved in ‘reactivating’ fetal haemoglobin were the focus of the three labs.
The researchers used a combination of chromosome conformation technologies and high throughput DNA analyses on thalassemia patient samples to elucidate the molecular mechanisms of how non-coding variants exert their action and improve the symptoms of thalassaemia and sickle cell anaemia.
The researchers showed that these variants, in a normal context, physically interact with the MYB gene, located at a distance of more than 80 000 base-pairs, via chromosome folding. In individuals carrying the variants, chromosome folding is diminished leading to a decrease in expression of the MYB gene.
These data identify directly and for the first time the MYB gene as the target of chromosome 6q23 non-coding variants. Thus, the MYB gene represents a major therapeutic target for the induction of fœtal haemoglobin, a potential therapeutic approach for beta thalassaemia and sickle cell anaemia, Eric Soler and Swee Lay Thein suggest.
Une analyse de la cohorte CANTO, réalisée par des médecins-chercheurs de Gustave Roussy, de l’Inserm et de l’université Paris-Saclay, démontre pour la première fois à l’aide d’une mesure biologique que les jeunes femmes qui ne suivent pas leur traitement d’hormonothérapie (tamoxifène) pour ...
Teams from Dijon-Bourgogne University Hospital, Inserm and CEA have recently established the results of the whole-genome analysis of severely ill neonates, hospitalized in neonatal ICUs – the time of which was slashed from the current 18-month average to just 38 days. ...
HBS1L-MYB intergenic variants modulate fetal hemoglobin via long-range MYB enhancers Ralph Stadhouders1*, Suleyman Aktuna2*, Supat Thongjuea3,4, Ali Aghajanirefah1, Farzin Pourfarzad1, Wilfred van IJcken5, Boris Lenhard3,6, Helen Rooks2, Steve Best2, Stephan Menzel2, Frank Grosveld1,7, Swee Lay Thein2,8# and Eric Soler1,7,9# The Journal of Clinical Investigation, 10 mars 2014