Epigenetic Dysregulation in the Developing Down Syndrome Brain

Using Illumina 450K arrays, 1.85% of analyzed CpG sites were hypermethylated and 0.31% hypomethylated in fetal Down syndrome (DS) cortex throughout the genome. The vast majority of differentially methylated promoters and genes was hypermethylated in DS and located outside chromosome 21, including the γ-protocadherin (PCDHG) cluster on chromosome 5q31, which is crucial for neural circuit formation in the developing brain. Bisulfite pyrosequencing and targeted RNA sequencing showed that several genes of PCDHG subfamilies A and B are hypermethylated and transcriptionally downregulated in fetal DS cortex. Decreased PCDHG expression is expected to reduce dendrite arborization and growth in cortical neurons. Dysregulation of CPT1B and NOX5 may be associated with mitochondrial dysfunction and increased cell damage in the developing DS brain. Since constitutive hypermethylation of PCDHG and other genes affects multiple tissues, including blood, it may provide useful biomarkers for DS brain development and pharmacologic targets for therapeutic interventions. Bisulphite converted DNA from the 72 samples were hybridised to the Illumina HumanMethylation450 BeadChip