神经元 DNA 双链断裂导致基因组结构变异和神经退行性变中的三维基因组破坏。

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

机构信息

Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.

出版信息

Cell. 2023 Sep 28;186(20):4404-4421.e20. doi: 10.1016/j.cell.2023.08.038.

DOI:10.1016/j.cell.2023.08.038

PMID:37774679

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10697236/

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.

摘要

神经元中持续存在的 DNA 双链断裂（DSBs）是包括阿尔茨海默病（AD）在内的神经退行性疾病的早期病理标志，有可能破坏基因组的完整性。我们使用人类死后前额叶皮层样本的单核 RNA-seq 发现，AD 中的兴奋性神经元中体细胞镶嵌基因融合富集。基因融合在具有 DNA 损伤修复和衰老基因特征的兴奋性神经元中特别丰富。此外，在 CK-p25 神经退行性变小鼠模型中，神经元中 DSBs 负担过重，体细胞基因组结构变异和基因融合也丰富。富含 DSBs 的神经元还具有较高水平的黏连蛋白，以及 3D 基因组组织的多尺度渐进性破坏，与突触、神经元发育和组蛋白基因的转录变化一致。总的来说，这项研究表明，神经元中 DSB 的出现破坏了基因组的稳定性和 3D 基因组组织，这是神经退行性疾病进展中的病理步骤。