DNA Methylation Changes in Response to Ribosomal DNA Copy Number Variation and in Premature Aging Disorders

The human ribosomal DNA (rDNA) copy number (CN) has been challenging to analyze and its sequence has been excluded from reference genomes due to its highly repetitive nature. The 45S rDNA locus encodes essential components of the cell, nevertheless, rDNA displays high inter-individual CN variation that could influence human health and disease. CN alterations in rDNA have been hypothesized as a possible factor in autism spectrum disorders (ASD) and was shown to be altered in Schizophrenia patients. We tested whether whole genome bisulfite sequencing can be used to simultaneously quantify rDNA CN and measure DNA methylation at the 45S rDNA locus. Using this approach, we observed high inter-individual variation in rDNA CN, and limited intra- individual copy differences in several postmortem tissues. Furthermore, we did not observe any significant alterations in rDNA CN or DNA methylation in Autism Spectrum Disorder (ASD) brains and in neurons or oligodendrocytes from Schizophrenia patients. However, our analysis revealed a strong positive correlation between CN and DNA methylation at the 45 rDNA locus. In this study, a positive association between rDNA CN variation and DNA Methylation was detected in multiple tissues. This should shed light on a possible dosage compensation mechanism controlled by DNA methylation that silences additional rDNA copies to ensure homeostatic regulation of ribosome biogenesis.Moreover, a genome-wide DNA methylation was performed using Infinium Methylation EPIC arrays in 15 progeroid laminopathies patients (Classical HGPS and non- classical HGPS) where 61 significant CpG sites were observed. These regions showed enrichment for biosynthetic processes of phospholipid, phosphatidylinositol, glycerolipid, and glycerophospholipid, phosphatidylinositol metabolic process, and sarcoplasmic reticulum. This should help elucidate molecular processes linked with premature aging in progeroid syndromes and processes implicated in normal biological aging.