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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE132949 | GEO | 2020/03/11

REPOSITORIES: GEO

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HyperTRIBE uncovers increased MUSASHI-2 RNA binding activity and differential regulation in leukemic stem cells.

Project description:The cell-context dependency for RNA binding proteins (RBPs) mediated control of stem cell fate remains to be defined. Here we adapt the HyperTRIBE method using an RBP fused to a Drosophila RNA editing enzyme (ADAR) to globally map the mRNA targets of the RBP MSI2 in mammalian adult normal and malignant stem cells. We reveal a unique MUSASHI-2 (MSI2) mRNA binding network in hematopoietic stem cells that changes during transition to multipotent progenitors. Additionally, we discover a significant increase in RNA binding activity of MSI2 in leukemic stem cells compared with normal hematopoietic stem and progenitor cells, resulting in selective regulation of MSI2's oncogenic targets. This provides a basis for MSI2 increased dependency in leukemia cells compared to normal cells. Moreover, our study provides a way to measure RBP function in rare cells and suggests that RBPs can achieve differential binding activity during cell state transition independent of gene expression.

| S-EPMC7181745 | biostudies-literature

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 [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 [MOLM-13]

2020-03-11 | GSE132896 | GEO

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

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

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

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 [LSC and LSK]

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

| PRJNA549511 | ENA