Dynamic dysregulation of retrotransposons in neurodegenerative diseases at the single-cell level

IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Genome research Pub Date : 2024-10-18 DOI:10.1101/gr.279363.124
Wankun Deng, Citu Citu, Andi Liu, Zhongming Zhao
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Abstract

Retrotransposable elements (RTEs) are common mobile genetic elements comprising ∼42% of the human genome. RTEs play critical roles in gene regulation and function, but how they are specifically involved in complex diseases is largely unknown. Here, we investigate the cellular heterogeneity of RTEs using 12 single-cell transcriptome profiles covering three neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease, and multiple sclerosis. We identify cell type marker RTEs in neurons, astrocytes, oligodendrocytes, and oligodendrocyte precursor cells that are related to these diseases. The differential expression analysis reveals the landscape of dysregulated RTE expression, especially L1s, in excitatory neurons of multiple neurodegenerative diseases. Machine learning algorithms for predicting cell disease stage using a combination of RTE and gene expression features suggests dynamic regulation of RTEs in AD. Furthermore, we construct a single-cell atlas of retrotransposable elements in neurodegenerative disease (scARE) using these data sets and features. scARE has six feature analysis modules to explore RTE dynamics in a user-defined condition. To our knowledge, scARE represents the first systematic investigation of RTE dynamics at the single-cell level within the context of neurodegenerative diseases.
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单细胞水平上神经退行性疾病中逆转录转座子的动态失调
可逆转座元件(RTE)是一种常见的移动遗传元件,占人类基因组的 42%。RTEs 在基因调控和功能方面发挥着关键作用,但它们如何具体参与复杂疾病的发生,目前尚不清楚。在这里,我们利用 12 个单细胞转录组图谱研究了 RTE 的细胞异质性,这些图谱涵盖了三种神经退行性疾病:阿尔茨海默病(AD)、帕金森病和多发性硬化症。我们在神经元、星形胶质细胞、少突胶质细胞和少突胶质细胞前体细胞中发现了与这些疾病相关的细胞类型标志物 RTE。差异表达分析揭示了多种神经退行性疾病的兴奋性神经元中 RTE(尤其是 L1s)表达失调的情况。结合 RTE 和基因表达特征预测细胞疾病阶段的机器学习算法表明,RTE 在 AD 中的动态调控。此外,我们还利用这些数据集和特征构建了神经退行性疾病逆转录表达元件单细胞图谱(scARE)。据我们所知,scARE 是首次在神经退行性疾病的背景下对单细胞水平的 RTE 动态进行的系统研究。
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来源期刊
Genome research
Genome research 生物-生化与分子生物学
CiteScore
12.40
自引率
1.40%
发文量
140
审稿时长
6 months
期刊介绍: Launched in 1995, Genome Research is an international, continuously published, peer-reviewed journal that focuses on research that provides novel insights into the genome biology of all organisms, including advances in genomic medicine. Among the topics considered by the journal are genome structure and function, comparative genomics, molecular evolution, genome-scale quantitative and population genetics, proteomics, epigenomics, and systems biology. The journal also features exciting gene discoveries and reports of cutting-edge computational biology and high-throughput methodologies. New data in these areas are published as research papers, or methods and resource reports that provide novel information on technologies or tools that will be of interest to a broad readership. Complete data sets are presented electronically on the journal''s web site where appropriate. The journal also provides Reviews, Perspectives, and Insight/Outlook articles, which present commentary on the latest advances published both here and elsewhere, placing such progress in its broader biological context.
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