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

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

doi:10.1038/s41467-020-15814-8

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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	2026
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-15814-8
State	Published - 1 Dec 2020
Externally published	Yes

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Nguyen, D. T. T., Lu, Y., Chu, K. L., Yang, X., Park, S. M., Choo, Z. N., Chin, C. R., Prieto, C., Schurer, A., Barin, E., Savino, A. M., Gourkanti, S., Patel, P., Vu, L. P., Leslie, C. S., & Kharas, M. G. (2020). HyperTRIBE uncovers increased MUSASHI-2 RNA binding activity and differential regulation in leukemic stem cells. Nature Communications, 11(1), Article 2026. https://doi.org/10.1038/s41467-020-15814-8

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

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{\textquoteright}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.",

author = "Nguyen, {Diu T.T.} and Yuheng Lu and Chu, {Karen L.} and Xuejing Yang and Park, {Sun Mi} and Choo, {Zi Ning} and Chin, {Christopher R.} and Camila Prieto and Alexandra Schurer and Ersilia Barin and Savino, {Angela M.} and Saroj Gourkanti and Payal Patel and Vu, {Ly P.} and Leslie, {Christina S.} and Kharas, {Michael G.}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-15814-8",

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Nguyen, DTT, Lu, Y, Chu, KL, Yang, X, Park, SM, Choo, ZN, Chin, CR, Prieto, C, Schurer, A, Barin, E, Savino, AM, Gourkanti, S, Patel, P, Vu, LP, Leslie, CS & Kharas, MG 2020, 'HyperTRIBE uncovers increased MUSASHI-2 RNA binding activity and differential regulation in leukemic stem cells', Nature Communications, vol. 11, no. 1, 2026. https://doi.org/10.1038/s41467-020-15814-8

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T1 - HyperTRIBE uncovers increased MUSASHI-2 RNA binding activity and differential regulation in leukemic stem cells

AU - Nguyen, Diu T.T.

AU - Lu, Yuheng

AU - Chu, Karen L.

AU - Yang, Xuejing

AU - Park, Sun Mi

AU - Choo, Zi Ning

AU - Chin, Christopher R.

AU - Prieto, Camila

AU - Schurer, Alexandra

AU - Barin, Ersilia

AU - Savino, Angela M.

AU - Gourkanti, Saroj

AU - Patel, Payal

AU - Vu, Ly P.

AU - Leslie, Christina S.

AU - Kharas, Michael G.

PY - 2020/12/1

Y1 - 2020/12/1

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AB - 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.

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

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