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RNA sequencing to analyze trasncriptional profiles and screen potential regulators in confined migration

ABSTRACT: RNA sequencing to analyze trasncriptional profiles and screen potential regulators in confined migration

PROVIDER: PRJNA1210621 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31999090_1.fastq.gz	Fastqsanger.gz
	SRR31999090_2.fastq.gz	Fastqsanger.gz
	SRR31999091_1.fastq.gz	Fastqsanger.gz
	SRR31999091_2.fastq.gz	Fastqsanger.gz
	SRR31999092_1.fastq.gz	Fastqsanger.gz

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RNA sequencing to analyze trasncriptional profiles and screen potential regulators in confined migration

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Project description:Purpose: Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and infiltration of leukemic cells is critical for disease progression and relapse. In spite of the canonical functions of epigenetics in transcription and DNA homeostasis, its contribution to the nuclear deformability of migrating leukemic cells remains unclear. The objective was to evaluate the role of WDR5 (a core subunit of the histone H3K4 methyltransferases) during leukemia cell migration. Experimental design: We used ALL cell lines and primary samples from patients to study their response and migration in 3D environments and how they extravasate in a mouse xenograft model. We also performed, biophysical, transcriptional and ChIP-sequencing analyses to determine the mechanism by which WDR5 controls ALL progression. Results: We observed that WDR5 activity is critical for ALL cell invasion into 3D collagen matrices. Notably, blocking WDR5 activity also decreased the extravasation of ALL cells in an in vivo model. We identified that 3D constrained conditions promoted H3K4 methylation in ALL cells that altered the global chromatin configuration and transcriptional changes related to cell cycle and DNA replication. WDR5 inhibition did not impair cell adhesion or cell response to chemokines; but we demonstrated that 3D conditions affected the deformation and biophysical behavior of the nucleus in ALL cells. Conclusions: We conclude that confined conditions have a fundamental role in ALL cell biology and provide novel molecular and biophysical mechanisms used by leukemia cells to disseminate. Targeting WDR5 might be a promising therapeutic strategy against ALL infiltration and dissemination.

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