HyperTRIBE uncovers increased MUSASHI-2 RNA binding activity and differential regulation in leukemic stem cells
Menée in vitro, sur des souris et à l'aide d'une nouvelle méthode destinée à identifier les cibles des protéines de liaison à l'ARN, cette étude met en évidence, par rapport aux cellules souches hématopoïétiques normales et aux cellules progénitrices, une augmentation et une régulation différentielle de l'activité de liaison à l'ARN de la protéine MUSASHI-2 dans les cellules souches leucémiques
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.
Nature Communications , Article en libre accès, 2020