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Down Syndrome Induced Senescence Disrupts the Nuclear Architecture of Neural Progenitors

ABSTRACT: Down Syndrome Induced Senescence Disrupts the Nuclear Architecture of Neural Progenitors

PROVIDER: PRJNA769437 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16242100_1.fastq.gz	Fastqsanger.gz
	SRR16242100_2.fastq.gz	Fastqsanger.gz
	SRR16242101_1.fastq.gz	Fastqsanger.gz
	SRR16242101_2.fastq.gz	Fastqsanger.gz
	SRR16242102_1.fastq.gz	Fastqsanger.gz

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Down Syndrome Induced Senescence Disrupts the Nuclear Architecture of Neural Progenitors

Project description: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.

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Project description:Crosstalk between deregulated hepatocyte metabolism and cells within the tumour microenvironment, and consequent effects on liver tumourigenesis, are incompletely understood. We show here that hepatocyte specific loss of the gluconeogenic enzyme fructose 1,6-bisphosphatase 1 (FBP1) disrupts liver metabolic homeostasis and promotes tumour progression. FBP1 is universally silenced in both human and murine liver tumours, and hepatocyte-specific Fbp1 deletion results in steatosis, concomitant with activation and senescence of hepatic stellate cells (HSCs), exhibiting a senescence-associated secretory phenotype (SASP). Depleting senescent HSCs by senolytic treatment with dasatinib/quercetin or ABT-263 inhibits tumour progression. We further demonstrate that FBP1-deficient hepatocytes promote HSC activation by releasing HMGB1; blocking its release with the small molecule inflachromene limits FBP1-dependent HSC activation, subsequent SASP development, and tumour progression. Collectively, these findings provide genetic evidence for FBP1 as a metabolic tumour suppressor in liver cancer and establish a critical link between hepatocyte metabolism and HSC senescence that promotes tumour growth.

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Project description:Immunohistochemical analysis of thymic tissue showed signs of accelerated thymic aging in down syndrome (DS) patients, normally seen in older healthy subjects. We then performed RNA-Seq analysis on human Epcam-enriched thymic epithelial cells (hTEC), isolated from three DS children, which revealed disease-specific transcriptomic alterations. Gene set enrichment analysis (GSEA) of DS TEC revealed an enrichment in genes involved in cellular response to stress, epigenetic histone DNA modifications and senescence. Analysis of senescent markers and oxidative stress in hTEC and thymocytes confirmed these findings. We detected senescence features in DS TEC, thymocytes and peripheral T cells, such as increased -galactosidase activity, increased levels of the cell cycle inhibitor p16, telomere markers and increased levels of reactive oxygen species (ROS), all factors contributing to cellular damage.

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