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Mutant GGGGCC RNA prevents YY1 from binding to Fuzzy promoter which stimulates Wnt/β-catenin pathway in C9ALS/FTD

Author

Listed:
  • Zhefan Stephen Chen

    (The Chinese University of Hong Kong
    University of Oxford)

  • Mingxi Ou

    (The Chinese University of Hong Kong)

  • Stephanie Taylor

    (University of Oxford)

  • Ruxandra Dafinca

    (University of Oxford
    University of Oxford, Dorothy Crowfoot Hodgkin Building)

  • Shaohong Isaac Peng

    (The Chinese University of Hong Kong)

  • Kevin Talbot

    (University of Oxford
    University of Oxford, Dorothy Crowfoot Hodgkin Building)

  • Ho Yin Edwin Chan

    (The Chinese University of Hong Kong
    The Chinese University of Hong Kong)

Abstract

The GGGGCC hexanucleotide repeat expansion mutation in the chromosome 9 open reading frame 72 (C9orf72) gene is a major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). In this study, we demonstrate that the zinc finger (ZF) transcriptional regulator Yin Yang 1 (YY1) binds to the promoter region of the planar cell polarity gene Fuzzy to regulate its transcription. We show that YY1 interacts with GGGGCC repeat RNA via its ZF and that this interaction compromises the binding of YY1 to the FuzzyYY1 promoter sites, resulting in the downregulation of Fuzzy transcription. The decrease in Fuzzy protein expression in turn activates the canonical Wnt/β-catenin pathway and induces synaptic deficits in C9ALS/FTD neurons. Our findings demonstrate a C9orf72 GGGGCC RNA-initiated perturbation of YY1–Fuzzy transcriptional control that implicates aberrant Wnt/β-catenin signalling in C9ALS/FTD-associated neurodegeneration. This pathogenic cascade provides a potential new target for disease-modifying therapy.

Suggested Citation

  • Zhefan Stephen Chen & Mingxi Ou & Stephanie Taylor & Ruxandra Dafinca & Shaohong Isaac Peng & Kevin Talbot & Ho Yin Edwin Chan, 2023. "Mutant GGGGCC RNA prevents YY1 from binding to Fuzzy promoter which stimulates Wnt/β-catenin pathway in C9ALS/FTD," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44215-w
    DOI: 10.1038/s41467-023-44215-w
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    References listed on IDEAS

    as
    1. Ankur Jain & Ronald D. Vale, 2017. "RNA phase transitions in repeat expansion disorders," Nature, Nature, vol. 546(7657), pages 243-247, June.
    2. Deborah Y. Kwon & Bing Xu & Peng Hu & Ying-Tao Zhao & Jonathan A. Beagan & Jonathan H. Nofziger & Yue Cui & Jennifer E. Phillips-Cremins & Julie A. Blendy & Hao Wu & Zhaolan Zhou, 2022. "Neuronal Yin Yang1 in the prefrontal cortex regulates transcriptional and behavioral responses to chronic stress in mice," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Aaron R. Haeusler & Christopher J. Donnelly & Goran Periz & Eric A. J. Simko & Patrick G. Shaw & Min-Sik Kim & Nicholas J. Maragakis & Juan C. Troncoso & Akhilesh Pandey & Rita Sattler & Jeffrey D. Ro, 2014. "C9orf72 nucleotide repeat structures initiate molecular cascades of disease," Nature, Nature, vol. 507(7491), pages 195-200, March.
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