PM20D1 is a quantitative trait locus associated with Alzheimer's disease
Por:
Sanchez-Mut JV, Heyn H, Silva BA, Dixsaut L, Garcia-Esparcia P, Vidal E, Sayols S, Glauser L, Monteagudo-Sánchez A, Perez-Tur J, Ferrer I, Monk D, Schneider B, Esteller M and Gräff J
Publicada:
1 may 2018
Resumen:
The chances to develop Alzheimer's disease (AD) result from a combination of genetic and non-genetic risk factors(1), the latter likely being mediated by epigenetic mechanisms(2). In the past, genome-wide association studies (GWAS) have identified an important number of risk loci associated with AD pathology(3), but a causal relationship remains difficult to establish. In contrast, locus-specific or epigenome-wide association studies (EWAS) have revealed site-specific epigenetic alterations, which provide mechanistic insights for a particular risk gene but often lack the statistical power of GWAS(4). Here, combining both approaches, we report a previously unidentified association of the peptidase M20-domain-containing protein 1 (PM20D1) with AD. We find that PM20D1 is a methylation and expression quantitative trait locus coupled to an AD-risk associated haplotype, which displays enhancer-like characteristics and contacts the PM20D1 promoter via a haplotype-dependent, CCCTC-binding-factor-mediated chromatin loop. Furthermore, PM20D1 is increased following AD-related neurotoxic insults at symptomatic stages in the APP/PS1 mouse model of AD and in human patients with AD who are carriers of the non-risk haplotype. In line, genetically increasing or decreasing the expression of PM20D1 reduces and aggravates AD-related pathologies, respectively. These findings suggest that in a particular genetic background, PM20D1 contributes to neuroprotection against AD.
Filiaciones:
Sanchez-Mut JV:
Laboratory of Neuroepigenetics, Brain Mind Institute, Faculty of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Heyn H:
Centro Nacional de Análisis Genómico (CNAG), Center for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
Universitat Pompeu Fabra (UPF), Barcelona, Spain
Silva BA:
Laboratory of Neuroepigenetics, Brain Mind Institute, Faculty of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Dixsaut L:
Laboratory of Neuroepigenetics, Brain Mind Institute, Faculty of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Garcia-Esparcia P:
Department of Pathology and Experimental Therapeutics, University of Barcelona, Institut d'Investigació Biomedica de Bellvitge (IDIBELL), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain
Vidal E:
Center for Genomic Regulation, Barcelona Institute for Science and Technology, Barcelona, Spain
Sayols S:
Bioinformatics Core Facility, Institute of Molecular Biology, Mainz, Germany
Glauser L:
Laboratory of Neuroepigenetics, Brain Mind Institute, Faculty of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Monteagudo-Sánchez A:
Genomic Imprinting and Cancer Group, Cancer Epigenetics and Biology Program, Institut d'Investigació Biomedica de Bellvitge, Barcelona, Spain
:
Institut de Biomedicina de València-CSIC, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Investigación Sanitaria 'La Fe', València, Spain
Ferrer I:
Department of Pathology and Experimental Therapeutics, University of Barcelona, Institut d'Investigació Biomedica de Bellvitge (IDIBELL), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain
Monk D:
Genomic Imprinting and Cancer Group, Cancer Epigenetics and Biology Program, Institut d'Investigació Biomedica de Bellvitge, Barcelona, Spain
Schneider B:
Neurodegenerative Studies Laboratory, Brain Mind Institute, Faculty of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Esteller M:
Cancer Epigenetics Group, Cancer Epigenetics and Biology Program, Institut d'Investigació Biomedica de Bellvitge, Barcelona, Spain
Gräff J:
Laboratory of Neuroepigenetics, Brain Mind Institute, Faculty of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
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