纽约基因组中心朱晨旭研究组在研究中取得进展。他们报道了单细胞平行分析DNA损伤和转录组揭示选择性基因组脆弱性。2025年3月24日，国际知名学术期刊《自然—方法学》发表了这一成果。

为了解决这些挑战，小组开发了Paired-Damage-seq，用于联合分析单细胞中氧化和单链DNA损伤与基因表达。小组将这种方法应用于培养的HeLa细胞和无主脑，作为概念的证明。他们的研究结果表明，损伤形成与表观遗传变化之间存在关联。氧化DNA损伤热点的分布呈现细胞类型特异性模式；这种选择性基因组脆弱性反过来可以预测导致疾病风险的细胞类型和失调的分子程序。

据悉，维持基因组的完整性对多细胞生物的分子程序至关重要。在整个生命周期中，各种内源性因素和环境因素对基因组构成持续的威胁，从而导致DNA损伤。了解DNA损伤的功能后果需要研究它们的首选基因组分布和对基因调控程序的影响。然而，这种分析受到器官内复杂的细胞类型组成和由于损伤形成的随机性而产生的高背景水平的阻碍。

附：英文原文

Title: Single-cell parallel analysis of DNA damage and transcriptome reveals selective genome vulnerability

Author: Bai, Dongsheng, Cao, Zhenkun, Attada, Nivedita, Song, Jinghui, Zhu, Chenxu

Issue&Volume: 2025-03-24

Abstract: Maintenance of genome integrity is paramount to molecular programs in multicellular organisms. Throughout the lifespan, various endogenous and environmental factors pose persistent threats to the genome, which can result in DNA damage. Understanding the functional consequences of DNA damage requires investigating their preferred genomic distributions and influences on gene regulatory programs. However, such analysis is hindered by both the complex cell-type compositions within organs and the high background levels due to the stochasticity of damage formation. To address these challenges, we developed Paired-Damage-seq for joint analysis of oxidative and single-stranded DNA damage with gene expression in single cells. We applied this approach to cultured HeLa cells and the mouse brain as a proof of concept. Our results indicated the associations between damage formation and epigenetic changes. The distribution of oxidative DNA damage hotspots exhibits cell-type-specific patterns; this selective genome vulnerability, in turn, can predict cell types and dysregulated molecular programs that contribute to disease risks.

DOI: 10.1038/s41592-025-02632-3

Source: https://www.nature.com/articles/s41592-025-02632-3