Epigenetics of Down Syndrome

Down syndrome (DS) can show a wide clinical range in terms of type/severity of presentations/defects.This extensive heterogeneity/pleiotropy is surprising because DS is rooted in a fairly restricted genetic zone; nearly 95% have a freely segregating triplication of human chromosome 21 (Homo sapiens 21, Hsa21).The remaining 5% may carry translocated 21 or mosaicism of mixed clones.As in most genetic disorders, gene-dosage/copy number variations are a consideration.However, a possibility of epigenetic modifications is also being considered; this is an attractive area for study because many epigenetic marks are reversible, which might provide opportunities for therapeutic interventions aimed at prophylaxis/treatment/ remission/reversal aimed at cure/rehabilitation of these patients.In this article, we have reviewed epigenetic changes in DS.Ongoing efforts show that these changes in DS might not be limited to Hsa21 but could be genome-wide; DNA methylation, post-translational histone modifications, and histone core variants have been noted.Existing data emphasize two trans-acting molecular mechanisms.The first involves enhanced expression of regulatory genes through histone modifications such as Hsa21-linked S-adenosylmethionine (SAM)-dependent methylation; and the effect of transcription factors such as Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1A (DYRK1A), ETS2, high mobility group nucleosome binding domain 1 (HMGN1), Bromodomain and WD repeat domain containing 1 (BRWD1), and RUNX family transcription factor 1 (RUNX1).The second involves Hsa21q21 microRNAs (miRNAs) lethal-7c (let7c), miRNA-99a, and miRNA-125b encoded at the band q21.1; miRNA-802 at q21.12, and miRNA-155 at q21.3.Wherever possible, we focused on the protein-coding gene EURL (early undifferentiated retina and lens) as a read-out; Early undifferentiated retina and lens is the Chromosome 21 open reading frame 91 (C21ORF91) located at the centromeric boundary of the DS critical region (DSCR).We have assimilated research findings from our own laboratory with an extensive review of the literature utilizing key terms in multiple databases including PubMed, EMBASE, and Science Direct.To avoid bias in the identification of studies, keywords were short-listed a priori from anecdotal experience and PubMed's Medical Subject Heading (MeSH) thesaurus.