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

Zhefan Stephen Chen, Mingxi Ou, Stephanie Taylor, Ruxandra Dafinca, Shaohong Isaac Peng, Kevin Talbot () and Ho Yin Edwin Chan ()
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Zhefan Stephen Chen: The Chinese University of Hong Kong
Mingxi Ou: The Chinese University of Hong Kong
Stephanie Taylor: University of Oxford
Ruxandra Dafinca: University of Oxford
Shaohong Isaac Peng: The Chinese University of Hong Kong
Kevin Talbot: University of Oxford
Ho Yin Edwin Chan: The Chinese University of Hong Kong

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-44215-w

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