Intellectual disability is the most profound neurological features of Down syndrome and studies on synaptic plasticity are essential to understand its pathological mechanisms.

 

We recently observed global hypermethylation in the fetal brain of Down syndrome compared to that of normal people, and over-expression of chromosome 21 gene DNMT3L changed the expressions of some synaptic proteins. Thus we hypothesize that over-expression of DNMT3L causes global hypermethylation through stimulating DNMT3A and DNMT3B, or alters histone methylation through histone methyltransferases; both may alter the downstream gene expression and cause some Down syndrome phenotypes including lowered synaptic plasticity and learning and memory deficits.

 

Therefore, in the current project, we aim to build neural cell and animal models with three-copy DNMT3L, examine the genomic DNA methylation and gene expression, search for DNMT3L targeting genes, explore the molecular mechanisms of DNMT3L over-expression causing hypermethylation of targeting genes and altered gene expression, and observe its effects on abnormal neural development to prove the above hypothesis and provide theoretical and experimental basis for the early diagnosis and therapy of this disorder.