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一种综合的多组学方法确定了与阿尔茨海默病相关的表观遗传改变。

An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer's disease.

机构信息

Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

出版信息

Nat Genet. 2020 Oct;52(10):1024-1035. doi: 10.1038/s41588-020-0696-0. Epub 2020 Sep 28.

DOI:10.1038/s41588-020-0696-0
PMID:32989324
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8098004/
Abstract

Protein aggregation is the hallmark of neurodegeneration, but the molecular mechanisms underlying late-onset Alzheimer's disease (AD) are unclear. Here we integrated transcriptomic, proteomic and epigenomic analyses of postmortem human brains to identify molecular pathways involved in AD. RNA sequencing analysis revealed upregulation of transcription- and chromatin-related genes, including the histone acetyltransferases for H3K27ac and H3K9ac. An unbiased proteomic screening singled out H3K27ac and H3K9ac as the main enrichments specific to AD. In turn, epigenomic profiling revealed gains in the histone H3 modifications H3K27ac and H3K9ac linked to transcription, chromatin and disease pathways in AD. Increasing genome-wide H3K27ac and H3K9ac in a fly model of AD exacerbated amyloid-β42-driven neurodegeneration. Together, these findings suggest that AD involves a reconfiguration of the epigenome, wherein H3K27ac and H3K9ac affect disease pathways by dysregulating transcription- and chromatin-gene feedback loops. The identification of this process highlights potential epigenetic strategies for early-stage disease treatment.

摘要

蛋白质聚集是神经退行性变的标志，但晚发性阿尔茨海默病 (AD) 的分子机制尚不清楚。在这里，我们整合了对死后人脑的转录组、蛋白质组和表观基因组分析，以鉴定 AD 相关的分子途径。RNA 测序分析显示转录和染色质相关基因上调，包括 H3K27ac 和 H3K9ac 的组蛋白乙酰转移酶。一个无偏见的蛋白质组筛选突出了 H3K27ac 和 H3K9ac 作为 AD 特有的主要富集物。反过来，表观基因组分析显示 AD 中与转录、染色质和疾病途径相关的组蛋白 H3 修饰 H3K27ac 和 H3K9ac 增加。在 AD 的果蝇模型中增加全基因组范围内的 H3K27ac 和 H3K9ac 会加剧淀粉样蛋白-β42 驱动的神经退行性变。总之，这些发现表明 AD 涉及表观基因组的重新配置，其中 H3K27ac 和 H3K9ac 通过扰乱转录和染色质-基因反馈回路来影响疾病途径。该过程的鉴定突出了潜在的表观遗传策略，用于早期疾病治疗。

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