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

doi:10.1016/j.cell.2023.08.038

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 journal › Article › peer-review

29 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 language	English
Pages (from-to)	4404-4421.e20
Journal	Cell
Volume	186
Issue number	20
DOIs	https://doi.org/10.1016/j.cell.2023.08.038
State	Published - 28 Sep 2023
Externally published	Yes

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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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10.1016/j.cell.2023.08.038

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

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.",

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AU - Boix, Carles A.

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AU - Marco, Asaf

AU - Welch, Gwyneth M.

AU - Meharena, Hiruy S.

AU - Loon, Anjanet

AU - Jeloka, Ritika

AU - Peng, Zhuyu

AU - Bennett, David A.

AU - Kellis, Manolis

AU - Tsai, Li Huei

PY - 2023/9/28

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N2 - 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.

AB - 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.

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

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