Allelic Expression Imbalance in Trisomy 21

Summary/Abstract The neurological, Down syndrome diagnosis is associated with various disease phenotypes that include cardiovascular, haematological and immunological disease processes.The increase in DNA copy number in Down syndrome, as a result of Trisomy 21, has led to the DNA dosage hypothesis, which posits that the level of gene expression is proportional to the gene's DNA copy number. The study of rare cases of partial Trisomy 21 has led to the identification of the dosage sensitive “Down Syndrome Critical Region”. Down syndrome individuals also experience cognitive decline in a syndrome that resembles Alzheimer's disease with its onset one to two decades earlier than typical Alzheimer's disease. The underlying hypothesis of this proposal is that epigenetic regulation at dosage sensitive genes on chromosome 21 contribute to the disease phenotypes associated with both Down syndrome and the co-occurring Alzheimer's disease. This hypothesis stems from our recent identification of >200 “Inactivation/Stability Centers” located on human autosomes. Inactivation/Stability Centers are ~1 megabase in size, are characterized by a novel epigenetic program that results in stochastic allelic inactivation of both protein coding and non-coding RNA genes. Inactivation/Stability Centers are also characterized by variability in allelic replication timing, where each allele can display either early or late replication timing. Two of the recently mapped Inactivation/Stability Centers are located on chromosome 21: one of them contains the Down Syndrome Critical Region, and the other contains the dosage sensitive, autosomal dominant, Alzheimer's disease gene APP (Amyloid Precursor Protein). This proposal is designed to elucidate the epigenetic mechanisms that are responsible for the allelic inactivation of the protein coding genes within the Down Syndrome Critical Region as well as at the APP gene. We have also found that the Down Syndrome Critical Region and the APP gene are syntenic regions in the mouse genome that are also within Inactivation/Stability Centers. This proposal is designed to use human and mouse cell-based assays to elucidate the molecular and cellular mechanisms associated with stochastic allelic inactivation of these dosage sensitive genes, and to determine the cellular phenotypes associated with the different expression states that are generated by stochastic allelic inactivation at these two critical locations on chromosome 21. This proposal challenges the existing models for autosomal random monoallelic expression, and if successful will establish a new paradigm for Down syndrome and the co-occurring early onset Alzheimer's disease that would include allelic inactivation of dosage sensitive genes in the generation of the cellular and disease phenotypes in patients with trisomy 21.