Dysregulation of the Epigenetic Landscape of Normal Aging in Alzheimer's Disease

Overview

Journal Nat Neurosci

Date 2018 Mar 7

PMID 29507413

Citations 159

Authors

Raffaella Nativio

Greg Donahue

Amit Berson

Yemin Lan

Alexandre Amlie-Wolf

Ferit Tuzer

Jon B Toledo

Sager J Gosai

Brian D Gregory

Claudio Torres

John Q Trojanowski

Li-San Wang

F Brad Johnson

Nancy M Bonini

Shelley L Berger

Affiliations

Soon will be listed here.

Abstract

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.

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References

Toledo J, Zetterberg H, Van Harten A, Glodzik L, Martinez-Lage P, Bocchio-Chiavetto L . Alzheimer's disease cerebrospinal fluid biomarker in cognitively normal subjects. Brain. 2015; 138(Pt 9):2701-15. PMC: 4643624. DOI: 10.1093/brain/awv199. View

Sen P, Shah P, Nativio R, Berger S . Epigenetic Mechanisms of Longevity and Aging. Cell. 2016; 166(4):822-839. PMC: 5821249. DOI: 10.1016/j.cell.2016.07.050. View

Kawahara T, Michishita E, Adler A, Damian M, Berber E, Lin M . SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell. 2009; 136(1):62-74. PMC: 2757125. DOI: 10.1016/j.cell.2008.10.052. View

Graff J, Tsai L . Histone acetylation: molecular mnemonics on the chromatin. Nat Rev Neurosci. 2013; 14(2):97-111. DOI: 10.1038/nrn3427. View

Huang H, Matevossian A, Jiang Y, Akbarian S . Chromatin immunoprecipitation in postmortem brain. J Neurosci Methods. 2006; 156(1-2):284-92. DOI: 10.1016/j.jneumeth.2006.02.018. View

Stadler F, Kolb G, Rubusch L, Baker S, Jones E, Akbarian S . Histone methylation at gene promoters is associated with developmental regulation and region-specific expression of ionotropic and metabotropic glutamate receptors in human brain. J Neurochem. 2005; 94(2):324-36. DOI: 10.1111/j.1471-4159.2005.03190.x. View

Nagy C, Maheu M, Lopez J, Vaillancourt K, Cruceanu C, Gross J . Effects of postmortem interval on biomolecule integrity in the brain. J Neuropathol Exp Neurol. 2015; 74(5):459-69. DOI: 10.1097/NEN.0000000000000190. View

Bennett D, Yu L, Yang J, Srivastava G, Aubin C, De Jager P . Epigenomics of Alzheimer's disease. Transl Res. 2014; 165(1):200-20. PMC: 4233194. DOI: 10.1016/j.trsl.2014.05.006. View

Cheung I, Shulha H, Jiang Y, Matevossian A, Wang J, Weng Z . Developmental regulation and individual differences of neuronal H3K4me3 epigenomes in the prefrontal cortex. Proc Natl Acad Sci U S A. 2010; 107(19):8824-9. PMC: 2889328. DOI: 10.1073/pnas.1001702107. View

10.

Zhou Z, Yuan Q, Mash D, Goldman D . Substance-specific and shared transcription and epigenetic changes in the human hippocampus chronically exposed to cocaine and alcohol. Proc Natl Acad Sci U S A. 2011; 108(16):6626-31. PMC: 3081016. DOI: 10.1073/pnas.1018514108. View

11.

Shogren-Knaak M, Ishii H, Sun J, Pazin M, Davie J, Peterson C . Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science. 2006; 311(5762):844-7. DOI: 10.1126/science.1124000. View

12.

Akhtar A, Becker P . Activation of transcription through histone H4 acetylation by MOF, an acetyltransferase essential for dosage compensation in Drosophila. Mol Cell. 2000; 5(2):367-75. DOI: 10.1016/s1097-2765(00)80431-1. View

13.

Sammons M, Zhu J, Drake A, Berger S . TP53 engagement with the genome occurs in distinct local chromatin environments via pioneer factor activity. Genome Res. 2014; 25(2):179-88. PMC: 4315292. DOI: 10.1101/gr.181883.114. View

14.

Sharma G, So S, Gupta A, Kumar R, Cayrou C, Avvakumov N . MOF and histone H4 acetylation at lysine 16 are critical for DNA damage response and double-strand break repair. Mol Cell Biol. 2010; 30(14):3582-95. PMC: 2897562. DOI: 10.1128/MCB.01476-09. View

15.

Dang W, Steffen K, Perry R, Dorsey J, Johnson F, Shilatifard A . Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature. 2009; 459(7248):802-7. PMC: 2702157. DOI: 10.1038/nature08085. View

16.

Kozak M, Chavez A, Dang W, Berger S, Ashok A, Guo X . Inactivation of the Sas2 histone acetyltransferase delays senescence driven by telomere dysfunction. EMBO J. 2009; 29(1):158-70. PMC: 2808364. DOI: 10.1038/emboj.2009.314. View

17.

Rai T, Cole J, Nelson D, Dikovskaya D, Faller W, Vizioli M . HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia. Genes Dev. 2014; 28(24):2712-25. PMC: 4265675. DOI: 10.1101/gad.247528.114. View

18.

Taylor G, Eskeland R, Hekimoglu-Balkan B, Pradeepa M, Bickmore W . H4K16 acetylation marks active genes and enhancers of embryonic stem cells, but does not alter chromatin compaction. Genome Res. 2013; 23(12):2053-65. PMC: 3847775. DOI: 10.1101/gr.155028.113. View

19.

Blalock E, Buechel H, Popovic J, Geddes J, Landfield P . Microarray analyses of laser-captured hippocampus reveal distinct gray and white matter signatures associated with incipient Alzheimer's disease. J Chem Neuroanat. 2011; 42(2):118-26. PMC: 3163806. DOI: 10.1016/j.jchemneu.2011.06.007. View

20.

Lu T, Pan Y, Kao S, Li C, Kohane I, Chan J . Gene regulation and DNA damage in the ageing human brain. Nature. 2004; 429(6994):883-91. DOI: 10.1038/nature02661. View