DNA methylation signature of human hippocampus in Alzheimer\u2019s disease is linked to neurogenesis

Miren Altuna,Ivonne Jericó,Carmen Echavarri,Luisa Di Stefano,Maite Mendioroz,Idoia Blanco-Luquin,Rosa Larumbe,Amaya Urdánoz-Casado,Álvaro Perdones,Alberto Labarga,María V Zelaya,Miren Roldán,Iván Méndez-López,Julie M J Lepesant,Javier Sánchez-Ruiz De Gordoa

doi:10.1186/s13148-019-0672-7

Abstract

BackgroundDrawing the epigenome landscape of Alzheimer’s disease (AD) still remains a challenge. To characterize the epigenetic molecular basis of the human hippocampus in AD, we profiled genome-wide DNA methylation levels in hippocampal samples from a cohort of pure AD patients and controls by using the Illumina 450K methylation arrays.ResultsUp to 118 AD-related differentially methylated positions (DMPs) were identified in the AD hippocampus, and extended mapping of specific regions was obtained by bisulfite cloning sequencing. AD-related DMPs were significantly correlated with phosphorylated tau burden. Functional analysis highlighted that AD-related DMPs were enriched in poised promoters that were not generally maintained in committed neural progenitor cells, as shown by ChiP-qPCR experiments. Interestingly, AD-related DMPs preferentially involved neurodevelopmental and neurogenesis-related genes. Finally, InterPro ontology analysis revealed enrichment in homeobox-containing transcription factors in the set of AD-related DMPs.ConclusionsThese results suggest that altered DNA methylation in the AD hippocampus occurs at specific regulatory regions crucial for neural differentiation supporting the notion that adult hippocampal neurogenesis may play a role in AD through epigenetic mechanisms.Graphical abstract

Highlights

Drawing the epigenome landscape of Alzheimer’s disease (AD) still remains a challenge
We report on novel gene-specific DNA methylation changes, recurrent across multiple affected subjects, which occur in the AD hippocampus
To avoid spurious molecular findings related to multiprotein deposits, only AD cases with pure deposits of p-tau and β-amyloid were eligible for the study and controls were free of any protein aggregates

Summary

Introduction

Drawing the epigenome landscape of Alzheimer’s disease (AD) still remains a challenge. To characterize the epigenetic molecular basis of the human hippocampus in AD, we profiled genome-wide DNA methylation levels in hippocampal samples from a cohort of pure AD patients and controls by using the Illumina 450K methylation arrays. Alzheimer’s disease (AD) is the leading cause of age-related dementia and one of the major global challenges of our time [1]. DNA methylation is known to be altered in complex diseases including AD. A number of gene-specific differences in DNA methylation have been reported so far [4,5,6,7,8]. Genome-wide approaches have uncovered additional gene-specific methylation differences across different brain regions in AD [9, 10].

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