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Histone post-translational modifications in frontal cortex from human donors with Alzheimer’s disease
BACKGROUND: Alzheimer’s disease (AD) is the sixth leading cause of death and the most costly disease in the US. Despite the enormous impact of AD, there are no treatments that delay onset or stop disease progression currently on the market. This is partly due to the complexity of the disease and the...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4591557/ https://www.ncbi.nlm.nih.gov/pubmed/26435705 http://dx.doi.org/10.1186/s12014-015-9098-1 |
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author | Anderson, Kyle W. Turko, Illarion V. |
author_facet | Anderson, Kyle W. Turko, Illarion V. |
author_sort | Anderson, Kyle W. |
collection | PubMed |
description | BACKGROUND: Alzheimer’s disease (AD) is the sixth leading cause of death and the most costly disease in the US. Despite the enormous impact of AD, there are no treatments that delay onset or stop disease progression currently on the market. This is partly due to the complexity of the disease and the largely unknown pathogenesis of sporadic AD, which accounts for the vast majority of cases. Epigenetics has been implicated as a critical component to AD pathology and a potential “hot spot” for treatments. Histone post-translational modifications (PTMs) are a key element in epigenetic regulation of gene expression and are known to be associated with the pathology of numerous diseases. Investigation of histone PTMs can help elucidate AD pathology and identify targets for therapies. RESULTS: A multiple reaction monitoring mass spectrometry assay was used to measure changes in abundance of several histone PTMs in frontal cortex from human donors affected with AD (n = 6) and age-matched, normal donors (n = 6). Of the changes observed, notable decreases in methylation of H2B residue K108 by 25 % and H4 residue R55 by 35 % were measured and are likely associated with hydrogen bonding networks important for nucleosome stability. Additionally, a 91 % increase in ubiquitination of K120 on H2B was measured as well as an apparent loss in acetylation of the region near the N-terminus of H4. Our method of quantification was also determined to be precise and robust, signifying measured changes were representative of true biological differences between donors and sample groups. CONCLUSION: We are the first to report changes in methylation of H2B K108, methylation of H4 R55, and ubiquitination of H2B K120 in frontal cortex from human donors with AD. These notable PTM changes may be of great importance in elucidating the epigenetic mechanism of AD as it relates to disease pathology. Beyond the structural and functional impacts of the changes we have measured, the sites of altered PTMs may be used to identify enzymes responsible for their modulation, which could be used as prospective drug targets for highly specific AD therapies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12014-015-9098-1) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4591557 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-45915572015-10-03 Histone post-translational modifications in frontal cortex from human donors with Alzheimer’s disease Anderson, Kyle W. Turko, Illarion V. Clin Proteomics Research BACKGROUND: Alzheimer’s disease (AD) is the sixth leading cause of death and the most costly disease in the US. Despite the enormous impact of AD, there are no treatments that delay onset or stop disease progression currently on the market. This is partly due to the complexity of the disease and the largely unknown pathogenesis of sporadic AD, which accounts for the vast majority of cases. Epigenetics has been implicated as a critical component to AD pathology and a potential “hot spot” for treatments. Histone post-translational modifications (PTMs) are a key element in epigenetic regulation of gene expression and are known to be associated with the pathology of numerous diseases. Investigation of histone PTMs can help elucidate AD pathology and identify targets for therapies. RESULTS: A multiple reaction monitoring mass spectrometry assay was used to measure changes in abundance of several histone PTMs in frontal cortex from human donors affected with AD (n = 6) and age-matched, normal donors (n = 6). Of the changes observed, notable decreases in methylation of H2B residue K108 by 25 % and H4 residue R55 by 35 % were measured and are likely associated with hydrogen bonding networks important for nucleosome stability. Additionally, a 91 % increase in ubiquitination of K120 on H2B was measured as well as an apparent loss in acetylation of the region near the N-terminus of H4. Our method of quantification was also determined to be precise and robust, signifying measured changes were representative of true biological differences between donors and sample groups. CONCLUSION: We are the first to report changes in methylation of H2B K108, methylation of H4 R55, and ubiquitination of H2B K120 in frontal cortex from human donors with AD. These notable PTM changes may be of great importance in elucidating the epigenetic mechanism of AD as it relates to disease pathology. Beyond the structural and functional impacts of the changes we have measured, the sites of altered PTMs may be used to identify enzymes responsible for their modulation, which could be used as prospective drug targets for highly specific AD therapies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12014-015-9098-1) contains supplementary material, which is available to authorized users. BioMed Central 2015-10-01 /pmc/articles/PMC4591557/ /pubmed/26435705 http://dx.doi.org/10.1186/s12014-015-9098-1 Text en © Anderson and Turko. 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Anderson, Kyle W. Turko, Illarion V. Histone post-translational modifications in frontal cortex from human donors with Alzheimer’s disease |
title | Histone post-translational modifications in frontal cortex from human donors with Alzheimer’s disease |
title_full | Histone post-translational modifications in frontal cortex from human donors with Alzheimer’s disease |
title_fullStr | Histone post-translational modifications in frontal cortex from human donors with Alzheimer’s disease |
title_full_unstemmed | Histone post-translational modifications in frontal cortex from human donors with Alzheimer’s disease |
title_short | Histone post-translational modifications in frontal cortex from human donors with Alzheimer’s disease |
title_sort | histone post-translational modifications in frontal cortex from human donors with alzheimer’s disease |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4591557/ https://www.ncbi.nlm.nih.gov/pubmed/26435705 http://dx.doi.org/10.1186/s12014-015-9098-1 |
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