Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Genome-wide analysis of Musashi-2 targets reveals novel functions in governing epithelial cell migration

ABSTRACT: The Musashi-2 (Msi2) RNA-binding protein maintains stem cell self-renewal and promotes oncogenesis by enhancing cell proliferation in hematopoietic and gastrointestinal tissues. However, it is unclear how Msi2 recognizes and regulates mRNA targets in vivo and whether Msi2 primarily controls cell growth in all cell types. Here we identified Msi2 targets with HITSCLIP and revealed that Msi2 primarily recognizes mRNA 3UTRs at sites enriched in multiple copies of UAG motifs in epithelial progenitor cells. RNA-seq and ribosome profiling demonstrated that Msi2 promotes targeted mRNA decay without affecting translation efficiency. Unexpectedly, the most prominent Msi2 targets identified are key regulators that govern cell motility with a high enrichment in focal adhesion and extracellular matrix-receptor interaction, in addition to regulators of cell growth and survival. Loss of Msi2 stimulates epithelial cellmigration, increases the number of focal adhesion and also compromises cell growth. These findings provide new insights into the molecular mechanisms of Msi2’s recognition and repression of targets and uncover a key function of Msi2 in restricting epithelial cell migration.

ORGANISM(S): Mus musculus

PROVIDER: GSE71333 | GEO | 2016/04/01

SECONDARY ACCESSION(S): PRJNA290912

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Genome-wide analysis of Musashi-2 targets reveals novel functions in governing epithelial cell migration

Project description:The Musashi-2 (Msi2) RNA-binding protein maintains stem cell self-renewal and promotes oncogenesis by enhancing cell proliferation in hematopoietic and gastrointestinal tissues. However, it is unclear how Msi2 recognizes and regulates mRNA targets in vivo and whether Msi2 primarily controls cell growth in all cell types. Here we identified Msi2 targets with HITSCLIP and revealed that Msi2 primarily recognizes mRNA 3UTRs at sites enriched in multiple copies of UAG motifs in epithelial progenitor cells. RNA-seq and ribosome profiling demonstrated that Msi2 promotes targeted mRNA decay without affecting translation efficiency. Unexpectedly, the most prominent Msi2 targets identified are key regulators that govern cell motility with a high enrichment in focal adhesion and extracellular matrix-receptor interaction, in addition to regulators of cell growth and survival. Loss of Msi2 stimulates epithelial cellmigration, increases the number of focal adhesion and also compromises cell growth. These findings provide new insights into the molecular mechanisms of Msi2âs recognition and repression of targets and uncover a key function of Msi2 in restricting epithelial cell migration. Identification of direct Musashi-2 targets in keratinocytes through the use of RNA-Seq, Ribosome-Profiling, and Msi2-HITS-CLIP

2016-04-01 | E-GEOD-71333 | biostudies-arrayexpress

A novel regulatory axis of MSI2-AGO2/miR-30a-3p-CGRRF1 drives cancer chemoresistance by upregulating the KRAS/ERK pathway

Project description:The KRAS/ERK pathway is crucial in cancer progression and chemotherapy resistance, yet its upstream regulatory mechanism remains elusive. We identified MSI2 as a new promoter of chemotherapy resistance in cancers. MSI2 directly binds to a specific class of mature miRNAs by recognizing the 'UAG' motif and interacts with the essential effector AGO2, highlighting MSI2 as a novel regulatory factor within the miRNA pathway. Specifically, MSI2 recruits UAG-miRNA miR-30a-3p to facilitate its loading onto AGO2, efficiently inhibiting the expression of CGRRF1. Further analysis reveals that CGRRF1 functions as a new ubiquitin E3 ligase for KRAS, mediating the ubiquitination and proteasome degradation of KRAS. Consequently, a novel regulatory axis involving MSI2-AGO2/miR-30a-3p-CGRRF1 positively regulates the KRAS/ERK pathway. Remarkably, platinum-based chemotherapy drugs significantly enhance the levels of phosphorylated ERK1/2 (p-ERK1/2) in cancer cells, and the EGFR inhibitor Gefitinib also increases p-ERK1/2 levels in Gefitinib-resistant cancer cells. Combining small-molecule inhibitors targeting MSI2, such as Ro 08-2750, efficiently alleviated chemoresistance in tumor cells exposed to Platinum and Gefitinib. These findings suggest that MSI2 could be a novel therapeutic target for developing strategies to counteract cancer resistance to treatment.

2024-11-27 | GSE262884 | 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 [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 [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

The microRNA-200 family mediates hair follicle development through coordinated regulation of cell adhesion and polarity

Project description:The microRNA-200 family is highly expressed in epithelial cells and frequently lost in metastatic cancer. Although the tumor-suppressing roles of this family are well documented and directly linked to the inhibition of mesenchymal genes, their targets and functions in normal epithelial tissues remain unclear. Furthermore, how the two sub-families of the five-microRNA family distinguished by a single nucleotide within the seed region regulate their targets is unclear. Here we show that the microRNA-200 family governs hair morphogenesis and fine-tunes stem cell specification by regulating cell adhesion, polarity and signaling pathways. By directly ligating microRNAs to their targeted mRNA regions, we identify numerous targets involved in the regulation of actin cytoskeleton, focal adhesion, cell cycle and Hippo/Yap signaling in a miRNA:mRNA pair-specific manner. The two sub-families bind to largely distinct target sites although many genes are regulated by both sub-families for a greater degree of regulation. Using inducible and knockout mouse models, we show that the microRNA-200 family enhances cell adhesion, inhibits migration and reduces cell division, contributing to precise stem cell specification. Our findings demonstrate that combinatorial targeting of many genes is critical for microRNA functions and provide new insights into microRNA-200s’ functions in normal epithelial tissues.

2018-03-16 | GSE102291 | GEO

Liver Epithelial Focal Adhesion Kinase Modulates Fibrogenesis and Hedgehog Signaling

Project description:Liver Epithelial Focal Adhesion Kinase Modulates Fibrogenesis and Hedgehog Signaling

| PRJNA660335 | ENA

HyperTRIBE uncovers MSI2 RNA binding activity and the effect of Ro, GSK-591 and combination in Z-138 cells

Project description:Identifying MSI2 RNA-direct binding targets in B-cell lymphoma and evaluating how MSI2 binding activity can be affected by the inhibition of PRMT5 using GSK-591 and the MSI2 inhibitor, Ro and the combination of the two agents.

2022-08-17 | GSE194362 | GEO

Mus musculus

Project description:Focal Adhesion Kinase Dependent Expression

| PRJNA187977 | ENA