5-hydroxymethylcytosine (5hmC) is a newly discovered modification of DNA that originates from the oxidation of 5-methylcytosine (5mC) by the Ten-eleven translocation 1-3 (Tet1-3) proteins. This modification is essential for several complex processes requiring dynamic changes in DNA methylation patterns. In fact, 5hmC represents both a new epigenetic state in genomic DNA and an intermediate in the process of DNA demethylation. More importantly, this exciting discovery has begun to shed light on the dynamic nature of 5mC in many disorders, including neurodegenerative diseases. Consistently, deregulation of the 5hmC metabolisms and alteration of 5hmC genomic patterns have been linked to neurodegeneration in Huntington's disease and Alzheimer's disease.
Our group has recently proposed that defective 5hmC regulation is also involved in Multiple Sclerosis (MS). We showed that global levels of 5hmC are decreased in MS PBMCs, probably as a result of the diminished expression of the methylcytosine dioxygenase TET2. Significantly, further recent data, which form the preliminary results background of this proposal, indicate that the very same alterations are actually observed in the post-mortem NAWM of MS brains. Overall, these data indicate that MS may have an epigenetic component that manifests itself as a loss of 5hmC most likely due to the defective expression of the TET2 enzyme. Based on this background, we propose to perform further experimental strategies in order to better investigate the origin of the 5hmC loss in the MS Brain. We will determine if the origin of the altered expression of TET2 and other proteins that co-operate in its function, can be attributed to epigenetic modifications of their promoters, as is the case in other pathologies. Results would be fruitful not only to understand the molecular features of MS, but also to set the stage for the future development of strategies to counteract the disease via epigenetic drugs.
