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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: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.

| S-EPMC8805993 | biostudies-literature

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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Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and function

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Chemotherapy-induced CAR cell senescence disrupts bone homeostasis to induce bone loss

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FBP1 loss disrupts liver metabolism and promotes tumourigenesis through a hepatic stellate cell senescence secretome

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Gene expression profiling in senescence leaves from senescence-inducible LEC2 in Arabidopsis

Project description:The profiling was conducted with the 385K Microarray manufactured at NimbleGen, Inc (http://www.nimblegen.com/) designed from 30,386 genes of Arabidopsis (TAIR v.6). RNA samples of leaves of S1 (100% green leaf from 40 days plant) and S3 (more than 50% yellow leaf) senescence stages from senescence-inducible LEC2 transgenic plant, OIL21 were subjected for analysis of Arabidopsis 385K transcriptome. Expression of 3,025 genes were significantly changed with log2 ratios greater than 1.0 or less than -1.0 in S1 or S3 stage (p value <0.05), among which 1491 were up-regulated and 1534 were down regulated. Gene annotation revealed that 7.4% genes, 223 out of 3,025 changed by LEC2 were encoded transcription factors (TF). 106 TFs were up-regulated and 115 TFs were down-regulated. A total of 9 chips were used for microarray. Total RNAs were extracted from senescence leaves at S1 and S3 stages of wild-type and senescence-inducible LEC2 transgenic Arabidopsis. Experiments were triplicated.

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