Down-syndrome-induced senescence disrupts the nuclear architecture of neural progenitors

Down syndrome (DS) is a genetic disorder driven by the triplication of chromosome 21 (T21) and characterized by a wide range of neurodevelopmental and physical disabilities. Transcriptomic analysis of tissue samples from individuals with DS has revealed that T21 induces a genome-wide transcriptional disruption. However, the consequences of T21 on the nuclear architecture and its interplay with the transcriptome remain unknown. In this study, we find that unlike human induced pluripotent stem cells (iPSCs), iPSC-derived neural progenitor cells (NPCs) exhibit genome-wide “chromosomal introversion,” disruption of lamina-associated domains, and global chromatin accessibility changes in response to T21, consistent with the transcriptional and nuclear architecture changes characteristic of senescent cells. Treatment of T21-harboring NPCs with senolytic drugs alleviates the transcriptional, molecular, and cellular dysfunctions associated with DS. Our findings provide a mechanistic link between T21 and global transcriptional disruption and indicate that senescence-associated phenotypes may play a key role in the neurodevelopmental pathogenesis of DS. [Display omitted] •Trisomy 21 disrupts nuclear architecture and transcriptome of neural progenitors•Trisomy 21 harboring neural progenitors display signatures of cellular senescence•Senolytic drugs ameliorate trisomy-21-associated molecular and cellular dysfunctions In this issue of Cell Stem Cell, Meharena et al. (2021) show that Down syndrome or trisomy 21 disrupts the 3D-genome, epigenome, and transcriptome of neural progenitors similar to that observed in senescent cells and find that the senolytic drug combination of dasatinib and quercetin ameliorates these disruptions.