DNA methylation analysis on purified neurons and glia dissects age and Alzheimer's disease-specific changes in the human cortex

被引：139

作者：

Gasparoni, Gilles ^{[1
]}

Bultmann, Sebastian ^{[2
,3
]}

Lutsik, Pavlo ^{[4
]}

Kraus, Theo F. J. ^{[5
]}

Sordon, Sabrina ^{[6
]}

Vlcek, Julia ^{[5
]}

Dietinger, Vanessa ^{[5
]}

Steinmaurer, Martina ^{[5
]}

Haider, Melanie ^{[5
]}

Mulholland, Christopher B. ^{[2
,3
]}

Arzberger, Thomas ^{[5
]}

Roeber, Sigrun ^{[5
]}

Riemenschneider, Matthias ^{[6
]}

Kretzschmar, Hans A. ^{[5
]}

Giese, Armin ^{[5
]}

Leonhardt, Heinrich ^{[2
,3
]}

Walter, Joern ^{[1
]}

机构：

[1] Univ Saarland UdS, Dept Genet, D-66123 Saarbrucken, Germany

[2] LMU, Dept Biol, D-82152 Munich, Germany

[3] LMU, Ctr Integrated Prot Sci, D-82152 Munich, Germany

[4] German Canc Res Ctr, Epigen & Canc Risk Factors, D-69120 Heidelberg, Germany

[5] LMU, Ctr Neuropathol & Prion Res, D-82152 Munich, Germany

[6] Saarland Univ Hosp UKS, Dept Psychiat & Psychotherapy, D-66424 Homburg, Germany

来源：

EPIGENETICS & CHROMATIN | 2018年 / 11卷

关键词：

DNA methylation; Epigenetics; Alzheimer's disease; Neurodegeneration; Aging; Cell sorting; Neuron; Glia; Brain; EWAS; CELL-TYPE HETEROGENEITY; ALPHA CONVERTING-ENZYME; GENOME-WIDE ASSOCIATION; PRECURSOR PROTEIN GENE; HUMAN-BRAIN; CLUSTERIN GENE; CLUSTERIN/APOLIPOPROTEIN-J; CEREBRAL-CORTEX; STEM-CELL; EXPRESSION;

D O I：

10.1186/s13072-018-0211-3

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Background: Epigenome-wide association studies (EWAS) based on human brain samples allow a deep and direct understanding of epigenetic dysregulation in Alzheimer's disease (AD).However, strong variation of cell-type proportions across brain tissue samples represents a significant source of data noise.Here, we report the first EWAS based on sorted neuronal and non-neuronal (mostly glia) nuclei from postmortem human brain tissues. Results: We show that cell sorting strongly enhances the robust detection of disease-related DNA methylation changes even in a relatively small cohort.We identify numerous genes with eell-type-specific methylation signatures and document differential methylation dynamics associated with aging specifically in neurons such as CLU, SYNJ2 and NCOR2 or in glia RAI1,CXXC5 and INPP5A.Further, we found neuron or glia-specific associations with AD Braak stage progression at genes such as MCF2L,ANK1, MAP2, LRRC8B, STK32C and S100B.A comparison of our study with previous tissue-based EWAS validates multiple AD-associated DNA methylation signals and additionally specifies their origin to neuron, e.g., HOXA3 or glia (ANK1). In a meta-analysis, we reveal two novel previously unrecognized methylation changes at the key AD risk genes APP and ADAM17. Conclusions: Our data highlight the complex interplay between disease, age and cell-type-specific methylation changes in AD risk genes thus offering new perspectives for the validation and interpretation of large EWAS results.

引用

页数：19

共 145 条

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