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Updated: Feb 7, 2026
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Genome-wide Surveillance of Transcription Errors in Eukaryotic Organisms
Published on: September 13, 2018
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C9orf72 hexanucleotide repeat RNA drives transcriptional dysregulation through genome-wide DNA:RNA hybrid
Honghe Liu1, Mingming Liu1, Yang Liu1
1Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
Neuron
|February 5, 2026
Summary
A GGGGCC repeat RNA expansion in C9orf72 causes neurodegenerative diseases by forming DNA:RNA hybrid G-quadruplexes. This structure disrupts gene regulation, leading to neuronal vulnerability and disease.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- C9orf72 hexanucleotide repeat expansion is a leading genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia.
- The precise mechanisms by which repeat RNAs contribute to neurodegeneration are not fully understood.
Purpose of the Study:
- To investigate how GGGGCC repeat RNA interacts with the genome and affects gene expression in patient cells.
- To elucidate the structural basis of RNA-mediated transcriptional interference.
Main Methods:
- Genome-wide chromatin engagement analysis of GGGGCC repeat RNA.
- Biochemical assays, single-molecule imaging, and native bisulfite sequencing.
- Assessment of neuronal vulnerability and gene dysregulation in patient-derived models.
Main Results:
- GGGGCC repeat RNA binds genome-wide, particularly at promoter regions, obstructing RNA polymerase II and transcription factors.
- Repeat RNA forms intrinsic DNA:RNA hybrid G-quadruplexes (HQs) with DNA, causing transcriptional interference.
- Stabilizing HQs increases neuronal vulnerability to stress, while correcting gene dysregulation enhances resistance.
Conclusions:
- GGGGCC repeat RNA forms pathogenic DNA:RNA hybrid G-quadruplexes that disrupt gene regulation.
- This mechanism contributes to neurodegeneration in C9orf72-associated diseases.
- Targeting these structures or restoring gene expression may offer therapeutic strategies.
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