Down Syndrome Induced Senescence Disrupts the Nuclear Architecture of Neural Progenitors

ABSTRACT: We utilized human derived induced pluripotent stem cells (iPSCs) and iPSC derived neural progenitor cells (NPCs) from individuals with Down syndrome and sex matched controls to interrogate the cell type consequences of trisomy 21 (T21). We report the consequences of T21 on the spatial chromatin organization (Hi-C), lamina-associated domains (ChIP-seq), chromatin state (ATAC-seq), and transcriptome (RNA-seq) in an isogenic pair (euploid: Iso-E and trisomic: Iso-T cells derived from the same individual), pair of male individuals with euploid (Ma-E) and trisomic (Ma-T), pair of female individuals with euploid (Fe-E) and trisomic (Fe-T). Our findings show that T21 induces chromosomal introversion, disrupts lamina-associated domains (LADs) and alters the genome-wide chromatin-accessibility of NPCs but not iPSCs. While the overall organization of A/B compartments and location of TAD-boundaries are conserved in NPCs harboring T21, we observe loss of chromatin-accessibility within the A-compartment that is associated with transcriptional downregulation, and increased long-range chromatin interactions in the B-compartment that is associated with transcriptional upregulation. We find that these architectural changes are similar to those observed in senescent cells, and our transcriptional analysis confirms that differentially expressed genes (DEGs) identified in NPCs harboring T21 are highly correlated with DEGs identified in oxidative stress induced senescent cells. Finally, we demonstrate that the senolytic drug combination of dasatinib and quercetin alleviates the genome-wide transcriptional disruption, as well as deficits in cellular migration and proliferation observed in NPCs harboring T21.

ORGANISM(S): Homo sapiens

PROVIDER: GSE185192 | GEO | 2021/10/11

REPOSITORIES: GEO