Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration

Persistent DNA double-strand breaks (DSBs) in neurons are an early pathological hallmark of neurodegenerative diseases including Alzheimer’s disease (AD), with the potential to disrupt genome integrity. We used single-nucleus RNA-seq in human postmortem prefrontal cortex samples and found that excit...

Full description

Saved in:
Bibliographic Details
Published in:Cell 2023-09, Vol.186 (20), p.4404-4421.e20
Main Authors: Dileep, Vishnu, Boix, Carles A., Mathys, Hansruedi, Marco, Asaf, Welch, Gwyneth M., Meharena, Hiruy S., Loon, Anjanet, Jeloka, Ritika, Peng, Zhuyu, Bennett, David A., Kellis, Manolis, Tsai, Li-Huei
Format: Article
Language:English
Subjects:
3D genome organization
Alzheimer’s disease
DNA double-strand breaks
epigenome
genome rearrangements
genomic mosaicism
neurodegeneration
senescence
structural variations
transcriptome
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Persistent DNA double-strand breaks (DSBs) in neurons are an early pathological hallmark of neurodegenerative diseases including Alzheimer’s disease (AD), with the potential to disrupt genome integrity. We used single-nucleus RNA-seq in human postmortem prefrontal cortex samples and found that excitatory neurons in AD were enriched for somatic mosaic gene fusions. Gene fusions were particularly enriched in excitatory neurons with DNA damage repair and senescence gene signatures. In addition, somatic genome structural variations and gene fusions were enriched in neurons burdened with DSBs in the CK-p25 mouse model of neurodegeneration. Neurons enriched for DSBs also had elevated levels of cohesin along with progressive multiscale disruption of the 3D genome organization aligned with transcriptional changes in synaptic, neuronal development, and histone genes. Overall, this study demonstrates the disruption of genome stability and the 3D genome organization by DSBs in neurons as pathological steps in the progression of neurodegenerative diseases. [Display omitted] •Increased somatic mosaic gene fusions in excitatory neurons in Alzheimer’s disease•DNA double-strand breaks lead to mosaic gene fusions and genome structural variations•Changes in 3D genome organization in neurons enriched for DNA double-strand breaks•3D genome changes align with differential gene expression in neurodegeneration Disruption of genome stability and 3D genome organization by DNA double-strand breaks in neurons are pathological steps in the progression of neurodegeneration.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2023.08.038