Dysregulation of the epigenetic landscape of normal aging in Alzheimer's disease

被引：210

作者：

Nativio, Raffaella ^{[1
]}

Donahue, Greg ^{[1
]}

Berson, Amit ^{[2
]}

Lan, Yemin ^{[1
]}

Amlie-Wolf, Alexandre ^{[3
]}

Tuzer, Ferit ^{[4
]}

Toledo, Jon B. ^{[3
]}

Gosai, Sager J. ^{[2
]}

Gregory, Brian D. ^{[2
]}

Torres, Claudio ^{[4
]}

Trojanowski, John Q. ^{[3
]}

Wang, Li-San ^{[3
]}

Johnson, F. Brad ^{[3
]}

Bonini, Nancy M. ^{[2
]}

Berger, Shelley L. ^{[1
]}

机构：

[1] Univ Penn, Perelman Sch Med, Dept Cell & Dev Biol, Epigenet Program, Philadelphia, PA 19104 USA

[2] Univ Penn, Dept Biol, Philadelphia, PA 19104 USA

[3] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA USA

[4] Drexel Univ, Coll Med, Dept Pathol, Philadelphia, PA 19104 USA

来源：

NATURE NEUROSCIENCE | 2018年 / 21卷 / 04期

关键词：

HISTONE H4 ACETYLATION; DNA-DAMAGE; GENE-EXPRESSION; LYSINE; 16; DEVELOPMENTAL REGULATION; SENESCENCE; ACTIVATION; PROTEIN; BRAIN; TRANSCRIPTION;

D O I：

10.1038/s41593-018-0101-9

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Aging is the strongest risk factor for Alzheimer's disease (AD), although the underlying mechanisms remain unclear. The chromatin state, in particular through the mark H4K16ac, has been implicated in aging and thus may play a pivotal role in age-associated neurodegeneration. Here we compare the genome-wide enrichment of H4K16ac in the lateral temporal lobe of AD individuals against both younger and elderly cognitively normal controls. We found that while normal aging leads to H4K16ac enrichment, AD entails dramatic losses of H4K16ac in the proximity of genes linked to aging and AD. Our analysis highlights the presence of three classes of AD-related changes with distinctive functional roles. Furthermore, we discovered an association between the genomic locations of significant H4K16ac changes with genetic variants identified in prior AD genome-wide association studies and with expression quantitative trait loci. Our results establish the basis for an epigenetic link between aging and AD.

引用

页码：497 / +

页数：11

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