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Brain DNA methylomic analysis of frontotemporal lobar degeneration reveals OTUD4 in shared dysregulated signatures across pathological subtypes
Frontotemporal lobar degeneration (FTLD) is an umbrella term describing the neuropathology of a clinically, genetically and pathologically heterogeneous group of diseases, including frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). Among the major FTLD pathological subgroups, F...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Springer Berlin Heidelberg
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10261190/ https://www.ncbi.nlm.nih.gov/pubmed/37149835 http://dx.doi.org/10.1007/s00401-023-02583-z |
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author | Fodder, Katherine Murthy, Megha Rizzu, Patrizia Toomey, Christina E. Hasan, Rahat Humphrey, Jack Raj, Towfique Lunnon, Katie Mill, Jonathan Heutink, Peter Lashley, Tammaryn Bettencourt, Conceição |
author_facet | Fodder, Katherine Murthy, Megha Rizzu, Patrizia Toomey, Christina E. Hasan, Rahat Humphrey, Jack Raj, Towfique Lunnon, Katie Mill, Jonathan Heutink, Peter Lashley, Tammaryn Bettencourt, Conceição |
author_sort | Fodder, Katherine |
collection | PubMed |
description | Frontotemporal lobar degeneration (FTLD) is an umbrella term describing the neuropathology of a clinically, genetically and pathologically heterogeneous group of diseases, including frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). Among the major FTLD pathological subgroups, FTLD with TDP-43 positive inclusions (FTLD-TDP) and FTLD with tau-positive inclusions (FTLD-tau) are the most common, representing about 90% of the cases. Although alterations in DNA methylation have been consistently associated with neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, little is known for FTLD and its heterogeneous subgroups and subtypes. The main goal of this study was to investigate DNA methylation variation in FTLD-TDP and FTLD-tau. We used frontal cortex genome-wide DNA methylation profiles from three FTLD cohorts (142 FTLD cases and 92 controls), generated using the Illumina 450K or EPIC microarrays. We performed epigenome-wide association studies (EWAS) for each cohort followed by meta-analysis to identify shared differentially methylated loci across FTLD subgroups/subtypes. In addition, we used weighted gene correlation network analysis to identify co-methylation signatures associated with FTLD and other disease-related traits. Wherever possible, we also incorporated relevant gene/protein expression data. After accounting for a conservative Bonferroni multiple testing correction, the EWAS meta-analysis revealed two differentially methylated loci in FTLD, one annotated to OTUD4 (5’UTR-shore) and the other to NFATC1 (gene body-island). Of these loci, OTUD4 showed consistent upregulation of mRNA and protein expression in FTLD. In addition, in the three independent co-methylation networks, OTUD4-containing modules were enriched for EWAS meta-analysis top loci and were strongly associated with the FTLD status. These co-methylation modules were enriched for genes implicated in the ubiquitin system, RNA/stress granule formation and glutamatergic synaptic signalling. Altogether, our findings identified novel FTLD-associated loci, and support a role for DNA methylation as a mechanism involved in the dysregulation of biological processes relevant to FTLD, highlighting novel potential avenues for therapeutic development. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00401-023-02583-z. |
format | Online Article Text |
id | pubmed-10261190 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-102611902023-06-15 Brain DNA methylomic analysis of frontotemporal lobar degeneration reveals OTUD4 in shared dysregulated signatures across pathological subtypes Fodder, Katherine Murthy, Megha Rizzu, Patrizia Toomey, Christina E. Hasan, Rahat Humphrey, Jack Raj, Towfique Lunnon, Katie Mill, Jonathan Heutink, Peter Lashley, Tammaryn Bettencourt, Conceição Acta Neuropathol Original Paper Frontotemporal lobar degeneration (FTLD) is an umbrella term describing the neuropathology of a clinically, genetically and pathologically heterogeneous group of diseases, including frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). Among the major FTLD pathological subgroups, FTLD with TDP-43 positive inclusions (FTLD-TDP) and FTLD with tau-positive inclusions (FTLD-tau) are the most common, representing about 90% of the cases. Although alterations in DNA methylation have been consistently associated with neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, little is known for FTLD and its heterogeneous subgroups and subtypes. The main goal of this study was to investigate DNA methylation variation in FTLD-TDP and FTLD-tau. We used frontal cortex genome-wide DNA methylation profiles from three FTLD cohorts (142 FTLD cases and 92 controls), generated using the Illumina 450K or EPIC microarrays. We performed epigenome-wide association studies (EWAS) for each cohort followed by meta-analysis to identify shared differentially methylated loci across FTLD subgroups/subtypes. In addition, we used weighted gene correlation network analysis to identify co-methylation signatures associated with FTLD and other disease-related traits. Wherever possible, we also incorporated relevant gene/protein expression data. After accounting for a conservative Bonferroni multiple testing correction, the EWAS meta-analysis revealed two differentially methylated loci in FTLD, one annotated to OTUD4 (5’UTR-shore) and the other to NFATC1 (gene body-island). Of these loci, OTUD4 showed consistent upregulation of mRNA and protein expression in FTLD. In addition, in the three independent co-methylation networks, OTUD4-containing modules were enriched for EWAS meta-analysis top loci and were strongly associated with the FTLD status. These co-methylation modules were enriched for genes implicated in the ubiquitin system, RNA/stress granule formation and glutamatergic synaptic signalling. Altogether, our findings identified novel FTLD-associated loci, and support a role for DNA methylation as a mechanism involved in the dysregulation of biological processes relevant to FTLD, highlighting novel potential avenues for therapeutic development. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00401-023-02583-z. Springer Berlin Heidelberg 2023-05-07 2023 /pmc/articles/PMC10261190/ /pubmed/37149835 http://dx.doi.org/10.1007/s00401-023-02583-z Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Original Paper Fodder, Katherine Murthy, Megha Rizzu, Patrizia Toomey, Christina E. Hasan, Rahat Humphrey, Jack Raj, Towfique Lunnon, Katie Mill, Jonathan Heutink, Peter Lashley, Tammaryn Bettencourt, Conceição Brain DNA methylomic analysis of frontotemporal lobar degeneration reveals OTUD4 in shared dysregulated signatures across pathological subtypes |
title | Brain DNA methylomic analysis of frontotemporal lobar degeneration reveals OTUD4 in shared dysregulated signatures across pathological subtypes |
title_full | Brain DNA methylomic analysis of frontotemporal lobar degeneration reveals OTUD4 in shared dysregulated signatures across pathological subtypes |
title_fullStr | Brain DNA methylomic analysis of frontotemporal lobar degeneration reveals OTUD4 in shared dysregulated signatures across pathological subtypes |
title_full_unstemmed | Brain DNA methylomic analysis of frontotemporal lobar degeneration reveals OTUD4 in shared dysregulated signatures across pathological subtypes |
title_short | Brain DNA methylomic analysis of frontotemporal lobar degeneration reveals OTUD4 in shared dysregulated signatures across pathological subtypes |
title_sort | brain dna methylomic analysis of frontotemporal lobar degeneration reveals otud4 in shared dysregulated signatures across pathological subtypes |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10261190/ https://www.ncbi.nlm.nih.gov/pubmed/37149835 http://dx.doi.org/10.1007/s00401-023-02583-z |
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