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Targeting cancer heterogeneity by breaking a stem cell and epithelial niche interaction loop

ABSTRACT: Targeting cancer heterogeneity by breaking a stem cell and epithelial niche interaction loop

PROVIDER: PRJNA933086 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23379523_1.fastq.gz	Fastqsanger.gz
	SRR23379523_2.fastq.gz	Fastqsanger.gz
	SRR23379524_1.fastq.gz	Fastqsanger.gz
	SRR23379524_2.fastq.gz	Fastqsanger.gz
	SRR23379525_1.fastq.gz	Fastqsanger.gz

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Project description:Stem cell functions require activation of stem cell-intrinsic transcriptional programs as well as intimate extracellular interactions with a niche microenvironment. How the core pluripotency transcriptional machinery controls residency of stem cells in the niche microenvironment is unknown. Here we show that the helix loop helix transcriptional regulators Id (Inhibitors of DNA binding) are the master regulators that coordinate stem cell activities with anchorage of neural stem cells (NSCs) to the embryonic and postnatal niche. Conditional inactivation of Id genes (Id1, Id2 and Id3) in the mouse NSC compartment triggered detachment of embryonic and post-natal NSCs from the ventricular and vascular niche respectively, followed by premature differentiation. Through an unbiased interrogation of the gene modules directly targeted by deletion of Id genes in NSCs, we discovered that Id proteins repress the bHLH-mediated activation of Rap1GAP, thus serving to maintain the GTPase activity of RAP1, a key mediator of cell adhesion. Preventing the elevation of Rap1GAP efficiently countered the consequences of Id loss on NSC-niche interaction and stem cell identity. Thus, by preserving anchorage to the extracellular environment of NSCs, Id activity synchronizes NSC functions to residency in the specialized niche. We generated Id-cTKO mice carrying a Cre-recombinase-oestrogen-receptor-T2 (Cre-ER) allele targeted to the ubiquitously expressed ROSA26 locus (Id-cTKO-Rosa-Cre-ER). In this system, 4-hydroxytamoxifen (4-OHT) releases the Cre recombinase inhibition and allows recombination of genomic loxP sites. Indeed, efficient deletion of Id1 and Id2 with complete loss of Id protein expression was detectable after treatment of NSCs with 4-OHT for 72 h. Total RNA was extracted from triplicate samples of Id-cTKO-Rosa-Cre-ER NSCs treated for different times (6 h, 12 h, 18 h, 24 h, 48 h, 96 h, 144 h) with 4-OHT or control vehicle and used for analysis on Illumina MouseWG-6 expression BeadChip. The raw array data was normalized using the Bioconductor package Lumi using quantile normalization.

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Targeting cancer heterogeneity by breaking a stem cell and epithelial niche interaction loop

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