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

Vishnu Dileep*, Carles A. Boix, Hansruedi Mathys, Asaf Marco, Gwyneth M. Welch, Hiruy S. Meharena, Anjanet Loon, Ritika Jeloka, Zhuyu Peng, David A. Bennett, Manolis Kellis*, Li Huei Tsai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)4404-4421.e20
JournalCell
Volume186
Issue number20
DOIs
StatePublished - 28 Sep 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023 The Authors

Keywords

  • 3D genome organization
  • Alzheimer's disease
  • DNA double-strand breaks
  • epigenome
  • genome rearrangements
  • genomic mosaicism
  • neurodegeneration
  • senescence
  • structural variations
  • transcriptome

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