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Small molecule regulators of microRNAs identified by high-throughput screen coupled with high-throughput sequencing

Author

Listed:
  • Lien D. Nguyen

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Zhiyun Wei

    (Brigham and Women’s Hospital and Harvard Medical School
    Tongji University)

  • M. Catarina Silva

    (Massachusetts General Hospital and Harvard Medical School)

  • Sergio Barberán-Soler

    (RealSeq Biosciences)

  • Jiarui Zhang

    (Boston University School of Medicine)

  • Rosalia Rabinovsky

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Christina R. Muratore

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Jonathan M. S. Stricker

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Colin Hortman

    (RealSeq Biosciences)

  • Tracy L. Young-Pearse

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Stephen J. Haggarty

    (Massachusetts General Hospital and Harvard Medical School)

  • Anna M. Krichevsky

    (Brigham and Women’s Hospital and Harvard Medical School)

Abstract

MicroRNAs (miRNAs) regulate fundamental biological processes by silencing mRNA targets and are dysregulated in many diseases. Therefore, miRNA replacement or inhibition can be harnessed as potential therapeutics. However, existing strategies for miRNA modulation using oligonucleotides and gene therapies are challenging, especially for neurological diseases, and none have yet gained clinical approval. We explore a different approach by screening a biodiverse library of small molecule compounds for their ability to modulate hundreds of miRNAs in human induced pluripotent stem cell-derived neurons. We demonstrate the utility of the screen by identifying cardiac glycosides as potent inducers of miR-132, a key neuroprotective miRNA downregulated in Alzheimer’s disease and other tauopathies. Coordinately, cardiac glycosides downregulate known miR-132 targets, including Tau, and protect rodent and human neurons against various toxic insults. More generally, our dataset of 1370 drug-like compounds and their effects on the miRNome provides a valuable resource for further miRNA-based drug discovery.

Suggested Citation

  • Lien D. Nguyen & Zhiyun Wei & M. Catarina Silva & Sergio Barberán-Soler & Jiarui Zhang & Rosalia Rabinovsky & Christina R. Muratore & Jonathan M. S. Stricker & Colin Hortman & Tracy L. Young-Pearse & , 2023. "Small molecule regulators of microRNAs identified by high-throughput screen coupled with high-throughput sequencing," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43293-0
    DOI: 10.1038/s41467-023-43293-0
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    References listed on IDEAS

    as
    1. Benjamin Readhead & Brigham J. Hartley & Brian J. Eastwood & David A. Collier & David Evans & Richard Farias & Ching He & Gabriel Hoffman & Pamela Sklar & Joel T. Dudley & Eric E. Schadt & Radoslav Sa, 2018. "Expression-based drug screening of neural progenitor cells from individuals with schizophrenia," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    2. M. Catarina Silva & Ghata A. Nandi & Sharon Tentarelli & Ian K. Gurrell & Tanguy Jamier & Diane Lucente & Bradford C. Dickerson & Dean G. Brown & Nicholas J. Brandon & Stephen J. Haggarty, 2020. "Prolonged tau clearance and stress vulnerability rescue by pharmacological activation of autophagy in tauopathy neurons," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
    3. Xiaolan Liu & Xufeng Cen & Ronghai Wu & Ziyan Chen & Yanqi Xie & Fengqi Wang & Bing Shan & Linghui Zeng & Jichun Zhou & Bojian Xie & Yangjun Cai & Jinyan Huang & Yingjiqiong Liang & Youqian Wu & Chao , 2023. "ARIH1 activates STING-mediated T-cell activation and sensitizes tumors to immune checkpoint blockade," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. Benjamin Readhead & Brigham J. Hartley & Brian J. Eastwood & David A. Collier & David Evans & Richard Farias & Ching He & Gabriel Hoffman & Pamela Sklar & Joel T. Dudley & Eric E. Schadt & Radoslav Sa, 2018. "Author Correction: Expression-based drug screening of neural progenitor cells from individuals with schizophrenia," Nature Communications, Nature, vol. 9(1), pages 1-1, December.
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