Epigenetic changes in fibroblast from patients with mucopolysaccharidoses

Even when mucopolysaccharidoses (MPS) are monogenic diseases, heterogeneity in phenotypes, disease progress, and therapy response indicate that genotype/phenotype association is not absolute. In this sense, it has been proposed that epigenetic regulation plays a role in different aspects of inborn errors of metabolism (EIMs). Indeed, some studies have reported that DNA methylation plays an important role in the development of Hunter syndrome (MPS II) and Niemann-Pick disease type C (NPC). Also, histone hypoacetylation has been observed in peripheral blood cells from patients with Gaucher disease, and fibroblast from patients with NPC disease show increased histone deacetylases (HDACs) expression. Interestingly, HDAC inhibitors (HDACi) rescue some of these changes. However, no reports have tested the potential epigenetic changes associated with the enzyme deficiency present in MPS IIIB or IVA, or whether HDACs could reverse such putative changes. To test this, we compare the levels of DNA methylation (5mC), histone acetylation (H3K14ac), and histone methylation (H3K9me3) in skin fibroblast from patients with MPS IIIB (GM02931 and GM01426) and MPS IVA (GM01361 and GM00593) and a non-affected person (GM00613) using immunocytochemistry and confocal microscopy. Furthermore, the potential to reverse such epigenetic changes by the HDACi Trichostatin A (TSA) was tested. Using Cell Profiler to analyze cell nuclei, we found that cells from MPS IIB and IVA patients have marked changes in total levels of histone acetylation and methylation, as well as in foci intensity, size, and distribution. Significantly, treatment with TSA in the nanomolar range partially rescues such changes. Taken together, these results show the potential role of epigenetic regulation in the development of MPS IIIB and IVA, as well as the potential of HDACs for disease treatment.