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HyperTRIBE uncovers MSI2 increased RNA binding activity and differential regulation in leukemic stem cells [LSC and LSK]

ABSTRACT: HyperTRIBE uncovers MSI2 increased RNA binding activity and differential regulation in leukemic stem cells [LSC and LSK]

PROVIDER: PRJNA549511 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9323090_1.fastq.gz	Fastqsanger.gz
	SRR9323090_2.fastq.gz	Fastqsanger.gz
	SRR9323100_1.fastq.gz	Fastqsanger.gz
	SRR9323100_2.fastq.gz	Fastqsanger.gz
	SRR9323091_1.fastq.gz	Fastqsanger.gz

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HyperTRIBE uncovers MSI2 increased RNA binding activity and differential regulation in leukemic stem cells [LSC and LSK]

Project description:Understanding RBPs’ molecular functions as well as their cell-type specific activity requires identification of RBPs’ direct mRNA targets. However, efforts to identify RNA targets of RNA binding proteins in stem cells have been hindered by limited cell numbers. Here we adapted the HyperTRIBE method using an RBP fused to a Drosophila RNA editing enzyme (ADAR) to allow for global mapping of mRNA targets of the RBP MSI2 in rare mammalian adult stem cells. We applied this method to identify MSI2 RNA binding targets in mouse HSPCs (Lin- Sca1+ Kit+ or LSK cells) and mouse leukemic stem cells (LSCs). MSI2 fusion with the catalytic domain of the Hyperactive ADAR mutant (MSI2-ADA) or with the dead catalytic mutant (MSI2-DCD) were overexpressed for 48 hours in LSKs and LSCs, followed by RNA-seq. As ADAR converts A to I (G), the fusion leaves a "finger-print" where MSI2 binds. MSI2-DCD and empty vector controls were used to normalize the background editing. We show that despite comparable expression of the MSI2-ADA fusion protein and endogenous MSI2 in LSCs vs LSKs, MSI2 RNA binding activity (number of targets and editing frequency) in LSCs is significantly higher than that in LSKs. This elevated RNA binding activity is independent of abundancy of the target transcripts.

2020-03-11 | GSE132948 | GEO

HyperTRIBE uncovers MSI2 increased RNA binding activity and differential regulation in leukemic stem cells [LSK cells]

Project description:Understanding RBPs’ molecular functions as well as their cell-type specific activity requires identification of RBPs’ direct mRNA targets. However, efforts to identify RNA targets of RNA binding proteins in stem cells have been hindered by limited cell numbers. Here we adapted the HyperTRIBE method using an RBP fused to a Drosophila RNA editing enzyme (ADAR) to allow for global mapping of mRNA targets of the RBP MSI2 in rare mammalian adult stem cells. We applied this method to identify MSI2 RNA binding targets in subcompartments of mouse HSPCs including long-term HSCs (LT-HSCs), short-term HSCs (ST-HSCs), multipotent progenitors MPP2 and MPP4. MSI2 fusion with the catalytic domain of the Hyperactive ADAR mutant (MSI2-ADA) or with the dead catalytic mutant (MSI2-DCD) were overexpressed in sorted LSK cells, which were transplanted into mice. After 7 weeks, mouse HSPCs were sorted into 4 populations for RNA-seq. As ADAR converts A to I (G), the fusion leaves a "finger-print" where MSI2 binds. MSI2-DCD and empty vector controls were used to normalize the background editing. We were able to identify MSI2 RNA binding targets in hematopoietic stem and progenitor cells for the first time. Furthermore, we show differential RNA binding activity (by target transcripts and editing frequency) of MSI2 in different subcompartments of HSPCs.

2020-03-11 | GSE132947 | GEO

HyperTRIBE uncovers MSI2 increased RNA binding activity and differential regulation in leukemic stem cells [LSK cells]

Project description:HyperTRIBE uncovers MSI2 increased RNA binding activity and differential regulation in leukemic stem cells [LSK cells]

| PRJNA549510 | ENA

HyperTRIBE uncovers MSI2 increased RNA binding activity and differential regulation in leukemic stem cells [Molm13_ADA_RRM_controls]

2020-03-11 | GSE146770 | GEO

HyperTRIBE uncovers MSI2 increased RNA binding activity and differential regulation in leukemic stem cells [MOLM-13]

2020-03-11 | GSE132896 | GEO

HyperTRIBE uncovers MSI2 increased RNA binding activity and differential regulation in leukemic stem cells

Project description:HyperTRIBE uncovers MSI2 increased RNA binding activity and differential regulation in leukemic stem cells

| PRJNA549512 | ENA

HyperTRIBE uncovers MSI2 increased RNA binding activity and differential regulation in leukemic stem cells [Molm13_ADA_RRM_controls]

Project description:HyperTRIBE uncovers MSI2 increased RNA binding activity and differential regulation in leukemic stem cells [Molm13_ADA_RRM_controls]

| PRJNA611929 | ENA

Msi2 sustains the MLL leukemia stem cell regulatory program

Project description:Leukemia stem cells (LSCs) are found in most aggressive myeloid diseases and contribute to therapeutic resistance. Genetic and epigenetic alterations cause a dysregulated developmental program in leukemia. The MSI2 RNA binding protein has been previously shown to predict poor survival in leukemia. We demonstrate that the conditional deletion of Msi2 results in delayed leukemogenesis, reduced disease burden and a loss of LSC function. Gene expression profiling of the Msi2 ablated LSCs demonstrates a loss of the HSC/LSC and an increase in the differentiation program. The gene signature from the Msi2 deleted LSCs correlates with survival in AML patients. MSI2’s maintains the MLL self-renewal program by interacting with and retaining efficient translation of Hoxa9, Myc and Ikzf2. We further demonstrate that shRNA depletion of the MLL target gene Ikzf2 also contributes to MLL leukemia cell survival. Our data provides evidence that MSI2 controls efficient translation of the oncogenic LSC self-renewal program and a rationale for clinically targeting MSI2 in myeloid leukemia. RNA-Seq was performed on sorted c-Kit high leukemic cells from 2 Msi2 -/- and 2 Msi2 f/f mice.

2015-01-15 | E-GEOD-64545 | biostudies-arrayexpress

HyperTRIBE uncovers MSI2 increased RNA binding activity and differential regulation in leukemic stem cells [MOLM-13]

Project description:HyperTRIBE uncovers MSI2 increased RNA binding activity and differential regulation in leukemic stem cells [MOLM-13]

| PRJNA549412 | ENA

Msi2 sustains the MLL leukemia stem cell regulatory program

2015-01-15 | GSE64545 | GEO