rDNA methylation in Down Syndrome

Control of ribosome biogenesis is a critical aspect of the regulation of cell metabolism. As ribosomal genes (rDNA) are organized in repeated clusters on chromosomes 13, 14, 15, 21 and 22, trisomy of chromosome 21 confers an excess of rDNA copies to persons with Down Syndrome (DS). Previous studies showed an alteration of ribosome biogenesis in children with DS, but the epigenetic regulation of rDNA genes has not been investigated in adults with DS so far.In this study we used a targeted deep-sequencing approach to measure DNA methylation (DNAm) of rDNA units in whole blood from 69 adults with DS and 95 euploid controls.We found that rDNA promoter is hypermethylated in DS with respect to the control group. The analysis of epihaplotypes (the combination of methylated and unmethylated CpG sites along the same DNA molecule) showed a significantly lower intra-individual diversity in the DS group, which at the same time was characterized by a higher inter-individual variability.Collectively, our results suggest that the epigenetic regulation of rDNA is rearranged in DS, possibly to compensate for the extranumerary rDNA copies.