Beta thalassemias and sickle cell anemia are among the most common hereditary disorders affecting red blood cells. These disorders are caused by mutations in the β globin gene, leading to alterations in adult hemoglobin. Many factors can alter their gravity, in particular the ability of some patients to produce fetal hemoglobin, which is normally kept ‘silent’ in adults. In some individuals, this hemoglobin ‘escapes’ this natural suppression without any consequence to their health. However, specifically in patients with thalassemias and sickle cell anemia, it produces a beneficial effect by compensating for the adult hemoglobin defects.

Non-coding regions of the genome, formerly called “junk DNA”, now have a recognized role in gene regulation. Their mutations or variations may thus be involved in the occurrence or severity of many diseases (e.g. diabetes, cardiovascular diseases, and cancers). More than 10 years ago, genetic variants associated with the production of fetal hemoglobin were identified in adults, located in a non-coding ‘genetic desert’ on chromosome 6q23, tens of thousands of base pairs away from the closest genes.

Starting with samples taken from thalassemic patients, the researchers combined the use of techniques for analyzing chromosome folding with high-throughput analyses of DNA to elucidate the molecular mechanisms that explain how non-coding variants exert their action and improve the symptoms of thalassemias and sickle cell anemia.

The researchers showed that in a normal context these variants physically interact with the MYB gene more than 80,000 base pairs away, thanks to the folding of chromosomes. However, in patients with beta-thalassemias or sickle cell anemia and carriers of these variants, there is a decrease in chromosomal folds. The variants access the MYB gene with more difficulty and activate it less efficiently. This decreased expression in thalassemic patients and carriers of these variants leads to a reactivation of healthy fetal globins, enabling the recreation of a functional hemoglobin.