“A dynamic in vitro model of Down Syndrome neurogenesis with Trisomy 21 gene dosage correction”

Abstract

ABSTRACT/SUMMARYExcess gene dosage from human chromosome 21 (HSA21), due to trisomy or translocation of HSA21 material, causes Down syndrome (DS). Trisomy 21 (T21) results in a large number of developmental and ongoing cellular phenotypes, raising the critical question of whether some of the latter may remain amenable to intervention after development. To generate an in vitro model of DS neurogenesis with dynamic T21 dosage, we derived T21 human induced pluripotent stem cells (hiPSCs) alongside otherwise isogenic euploid controls from mosaic DS fibroblasts, and equipped one distinct HSA21 copy with a new inducible XIST transgene. Phased genotyping enables us to apply this unique biological resource to allelic transcriptome analyses that demonstrate that T21 silencing by XIST is largely complete and irreversible in hiPSCs. Differential expression analysis reveals T21 neural lineages and hiPSCs share suppressed translation and mitochondrial pathways, and activate cellular stress responses. When XIST is induced prior to the neural progenitor stage, T21 dosage correction suppresses a pronounced skew towards excessive astrogenesis in T21 neural differentiation. Because our XIST transgene remains inducible in post-mitotic T21 neurons and astrocytes, this dynamic model of HSA21 gene dosage will empower systematic exploration of cellular and transcriptional T21 phenotypes that depend on acute T21 gene dosage in differentiated cell types.