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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.


Diu T T Nguyen, Yuheng Lu, Karen L Chu, Xuejing Yang, Sun-Mi Park, Zi-Ning Choo, Christopher R Chin, Camila Prieto, Alexandra Schurer, Ersilia Barin, Angela M Savino, Saroj Gourkanti, Payal Patel, Ly P Vu, Christina S Leslie, Michael G Kharas. HyperTRIBE uncovers increased MUSASHI-2 RNA binding activity and differential regulation in leukemic stem cells. Nature communications. 2020 Apr 24;11(1):2026

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PMID: 32332729

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