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多组学方法揭示了与阿尔茨海默病相关的表观遗传改变
2020-09-29 16:20

美国宾夕法尼亚大学Shelley L. Berger和 Nancy M. Bonini课题组合作的最新研究表明,多组学相结合的方法可鉴别与阿尔茨海默氏病(AD)相关的表观遗传学改变。2020年9月28日,《自然—遗传学》发表了这一成果。

在本研究中,研究人员整合了人类死后大脑的转录组学、蛋白质组学和表观基因组学分析,以鉴别参与AD的分子途径。 RNA测序分析揭示了转录和染色质相关基因的上调,包括参与H3K27ac和H3K9ac修饰的组蛋白乙酰转移酶。

无偏倚的蛋白质组学筛选表明H3K27ac和H3K9ac是AD特有的富集成分。反之,表观基因组学分析揭示了与AD转录、染色质和疾病途径相关H3K27ac和H3K9ac修饰的增加。在AD Fly模型中全基因组范围内H3K27ac和H3K9ac的增加加剧了淀粉样蛋白β42驱动的神经变性。

总之,这些发现表明AD患者存在表观基因组重编程,其中H3K27ac和H3K9ac通过失调转录和染色质基因反馈回路来影响疾病进展。该研究为早期治疗AD提供了潜在的表观遗传策略。

据悉,蛋白质聚集是神经退行性病变的标志,但迟发性阿尔茨海默氏病的分子机制尚不清楚。

附:英文原文

Title: An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer’s disease

Author: Raffaella Nativio, Yemin Lan, Greg Donahue, Simone Sidoli, Amit Berson, Ananth R. Srinivasan, Oksana Shcherbakova, Alexandre Amlie-Wolf, Ji Nie, Xiaolong Cui, Chuan He, Li-San Wang, Benjamin A. Garcia, John Q. Trojanowski, Nancy M. Bonini, Shelley L. Berger

Issue&Volume: 2020-09-28

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.

DOI: 10.1038/s41588-020-0696-0

Source: https://www.nature.com/articles/s41588-020-0696-0

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Online/在线发表

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