Comprehensive analysis of PM20D1 QTL in Alzheimer's disease

Background: Alzheimer’s disease (AD) is a complex disorder caused by a combination of genetic and non-genetic risk factors. In addition, an increasing evidence suggests that epigenetic mechanisms also accompany AD. Genetic and epigenetic factors are not independent, but multiple loci show genetic-ep...

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Autores: Sánchez Mut, Jose Vicente, Glauser, Liliane, Monk, David, Gräff, Johannes
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/173207
Acceso en línea:https://hdl.handle.net/2445/173207
Access Level:acceso abierto
Palabra clave:Malaltia d'Alzheimer
Epigenètica
Alzheimer's disease
Epigenetics
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spelling Comprehensive analysis of PM20D1 QTL in Alzheimer's diseaseSánchez Mut, Jose VicenteGlauser, LilianeMonk, DavidGräff, JohannesMalaltia d'AlzheimerEpigenèticaAlzheimer's diseaseEpigeneticsBackground: Alzheimer’s disease (AD) is a complex disorder caused by a combination of genetic and non-genetic risk factors. In addition, an increasing evidence suggests that epigenetic mechanisms also accompany AD. Genetic and epigenetic factors are not independent, but multiple loci show genetic-epigenetic interactions, the so-called quantitative trait loci (QTLs). Recently, we identified the first QTL association with AD, namely Peptidase M20 Domain Containing 1 (PM20D1). We observed that PM20D1 DNA methylation, RNA expression, and genetic background are correlated and, in turn, associated with AD. We provided mechanistic insights for these correlations and had shown that by genetically increasing and decreasing PM20D1 levels, AD-related pathologies were decreased and accelerated, respectively. However, since the PM20D1 QTL region encompasses also other genes, namely Nuclear Casein Kinase and Cyclin Dependent Kinase Substrate 1 (NUCKS1); RAB7, member RAS oncogene family-like 1 (RAB7L1); and Solute Carrier Family 41 Member 1 (SLC41A1), we investigated whether these genes might also contribute to the described AD association. Results: Here, we report a comprehensive analysis of these QTL genes using a repertoire of in silico methods as well as in vivo and in vitro experimental approaches. First, we analyzed publicly available databases to pinpoint the major QTL correlations. Then, we validated these correlations using a well-characterized set of samples and locus- specific approaches—i.e., Sanger sequencing for the genotype, cloning/sequencing and pyrosequencing for the DNA methylation, and allele-specific and real-time PCR for the RNA expression. Finally, we defined the functional relevance of the observed alterations in the context of AD in vitro. Using this approach, we show that only PM20D1 DNA methylation and expression are significantly correlated with the AD-risk associated background. We find that the expression of SLC41A1 and PM20D1—but not NUCKS1 and RAB7L1—is increased in mouse models and human samples of AD, respectively. However, SLC41A1 and PM20D1 are differentially regulated by AD-related stressors, with only PM20D1 being upregulated by amyloid-β and reactive oxygen species, and with only PM20D1 being neuroprotective when overexpressed in cell and primary cultures. Conclusions: Our findings reinforce PM20D1 as the most likely gene responsible of the previously reported PM20D1 QTL association with AD.BioMed Central2021202120202020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion11 p.application/pdfhttps://hdl.handle.net/2445/173207Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1186/s13148-020-0814-yClinical Epigenetics, 2020, vol. 12https://doi.org/10.1186/s13148-020-0814-ycc by (c) Sánchez Mut, et al., 2020http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1732072026-05-29T05:05:01Z
dc.title.none.fl_str_mv Comprehensive analysis of PM20D1 QTL in Alzheimer's disease
title Comprehensive analysis of PM20D1 QTL in Alzheimer's disease
spellingShingle Comprehensive analysis of PM20D1 QTL in Alzheimer's disease
Sánchez Mut, Jose Vicente
Malaltia d'Alzheimer
Epigenètica
Alzheimer's disease
Epigenetics
title_short Comprehensive analysis of PM20D1 QTL in Alzheimer's disease
title_full Comprehensive analysis of PM20D1 QTL in Alzheimer's disease
title_fullStr Comprehensive analysis of PM20D1 QTL in Alzheimer's disease
title_full_unstemmed Comprehensive analysis of PM20D1 QTL in Alzheimer's disease
title_sort Comprehensive analysis of PM20D1 QTL in Alzheimer's disease
dc.creator.none.fl_str_mv Sánchez Mut, Jose Vicente
Glauser, Liliane
Monk, David
Gräff, Johannes
author Sánchez Mut, Jose Vicente
author_facet Sánchez Mut, Jose Vicente
Glauser, Liliane
Monk, David
Gräff, Johannes
author_role author
author2 Glauser, Liliane
Monk, David
Gräff, Johannes
author2_role author
author
author
dc.subject.none.fl_str_mv Malaltia d'Alzheimer
Epigenètica
Alzheimer's disease
Epigenetics
topic Malaltia d'Alzheimer
Epigenètica
Alzheimer's disease
Epigenetics
description Background: Alzheimer’s disease (AD) is a complex disorder caused by a combination of genetic and non-genetic risk factors. In addition, an increasing evidence suggests that epigenetic mechanisms also accompany AD. Genetic and epigenetic factors are not independent, but multiple loci show genetic-epigenetic interactions, the so-called quantitative trait loci (QTLs). Recently, we identified the first QTL association with AD, namely Peptidase M20 Domain Containing 1 (PM20D1). We observed that PM20D1 DNA methylation, RNA expression, and genetic background are correlated and, in turn, associated with AD. We provided mechanistic insights for these correlations and had shown that by genetically increasing and decreasing PM20D1 levels, AD-related pathologies were decreased and accelerated, respectively. However, since the PM20D1 QTL region encompasses also other genes, namely Nuclear Casein Kinase and Cyclin Dependent Kinase Substrate 1 (NUCKS1); RAB7, member RAS oncogene family-like 1 (RAB7L1); and Solute Carrier Family 41 Member 1 (SLC41A1), we investigated whether these genes might also contribute to the described AD association. Results: Here, we report a comprehensive analysis of these QTL genes using a repertoire of in silico methods as well as in vivo and in vitro experimental approaches. First, we analyzed publicly available databases to pinpoint the major QTL correlations. Then, we validated these correlations using a well-characterized set of samples and locus- specific approaches—i.e., Sanger sequencing for the genotype, cloning/sequencing and pyrosequencing for the DNA methylation, and allele-specific and real-time PCR for the RNA expression. Finally, we defined the functional relevance of the observed alterations in the context of AD in vitro. Using this approach, we show that only PM20D1 DNA methylation and expression are significantly correlated with the AD-risk associated background. We find that the expression of SLC41A1 and PM20D1—but not NUCKS1 and RAB7L1—is increased in mouse models and human samples of AD, respectively. However, SLC41A1 and PM20D1 are differentially regulated by AD-related stressors, with only PM20D1 being upregulated by amyloid-β and reactive oxygen species, and with only PM20D1 being neuroprotective when overexpressed in cell and primary cultures. Conclusions: Our findings reinforce PM20D1 as the most likely gene responsible of the previously reported PM20D1 QTL association with AD.
publishDate 2020
dc.date.none.fl_str_mv 2020
2020
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/173207
url https://hdl.handle.net/2445/173207
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1186/s13148-020-0814-y
Clinical Epigenetics, 2020, vol. 12
https://doi.org/10.1186/s13148-020-0814-y
dc.rights.none.fl_str_mv cc by (c) Sánchez Mut, et al., 2020
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Sánchez Mut, et al., 2020
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 11 p.
application/pdf
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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