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

Diu T. T. Nguyen, Yuheng Lu, Eren 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 and Michael G. Kharas ()
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Diu T. T. Nguyen: Memorial Sloan Kettering Cancer Center
Yuheng Lu: Memorial Sloan Kettering Cancer Center
Eren L. Chu: Memorial Sloan Kettering Cancer Center
Xuejing Yang: Memorial Sloan Kettering Cancer Center
Sun-Mi Park: Memorial Sloan Kettering Cancer Center
Zi-Ning Choo: Weill Cornell School of Medical Sciences
Christopher R. Chin: Weill Cornell School of Medical Sciences
Camila Prieto: Memorial Sloan Kettering Cancer Center
Alexandra Schurer: Memorial Sloan Kettering Cancer Center
Ersilia Barin: Memorial Sloan Kettering Cancer Center
Angela M. Savino: Memorial Sloan Kettering Cancer Center
Saroj Gourkanti: Memorial Sloan Kettering Cancer Center
Payal Patel: Weill Cornell School of Medical Sciences
Ly P. Vu: British Columbia Cancer Research Centre
Christina S. Leslie: Memorial Sloan Kettering Cancer Center
Michael G. Kharas: Memorial Sloan Kettering Cancer Center

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-15814-8

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