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Trans effects of chromosome aneuploidies on DNA methylation patterns in human Down syndrome and mouse models
BACKGROUND: Trisomy 21 causes Down syndrome (DS), but the mechanisms by which the extra chromosome leads to deficient intellectual and immune function are not well understood. RESULTS: Here, we profile CpG methylation in DS and control cerebral and cerebellar cortex of adults and cerebrum of fetuses...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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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/PMC4659173/ https://www.ncbi.nlm.nih.gov/pubmed/26607552 http://dx.doi.org/10.1186/s13059-015-0827-6 |
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author | Mendioroz, Maite Do, Catherine Jiang, Xiaoling Liu, Chunhong Darbary, Huferesh K. Lang, Charles F. Lin, John Thomas, Anna Abu-Amero, Sayeda Stanier, Philip Temkin, Alexis Yale, Alexander Liu, Meng-Min Li, Yang Salas, Martha Kerkel, Kristi Capone, George Silverman, Wayne Yu, Y. Eugene Moore, Gudrun Wegiel, Jerzy Tycko, Benjamin |
author_facet | Mendioroz, Maite Do, Catherine Jiang, Xiaoling Liu, Chunhong Darbary, Huferesh K. Lang, Charles F. Lin, John Thomas, Anna Abu-Amero, Sayeda Stanier, Philip Temkin, Alexis Yale, Alexander Liu, Meng-Min Li, Yang Salas, Martha Kerkel, Kristi Capone, George Silverman, Wayne Yu, Y. Eugene Moore, Gudrun Wegiel, Jerzy Tycko, Benjamin |
author_sort | Mendioroz, Maite |
collection | PubMed |
description | BACKGROUND: Trisomy 21 causes Down syndrome (DS), but the mechanisms by which the extra chromosome leads to deficient intellectual and immune function are not well understood. RESULTS: Here, we profile CpG methylation in DS and control cerebral and cerebellar cortex of adults and cerebrum of fetuses. We purify neuronal and non-neuronal nuclei and T lymphocytes and find biologically relevant genes with DS-specific methylation (DS-DM) in each of these cell types. Some genes show brain-specific DS-DM, while others show stronger DS-DM in T cells. Both 5-methyl-cytosine and 5-hydroxy-methyl-cytosine contribute to the DS-DM. Thirty percent of genes with DS-DM in adult brain cells also show DS-DM in fetal brains, indicating early onset of these epigenetic changes, and we find early maturation of methylation patterns in DS brain and lymphocytes. Some, but not all, of the DS-DM genes show differential expression. DS-DM preferentially affected CpGs in or near specific transcription factor binding sites (TFBSs), implicating a mechanism involving altered TFBS occupancy. Methyl-seq of brain DNA from mouse models with sub-chromosomal duplications mimicking DS reveals partial but significant overlaps with human DS-DM and shows that multiple chromosome 21 genes contribute to the downstream epigenetic effects. CONCLUSIONS: These data point to novel biological mechanisms in DS and have general implications for trans effects of chromosomal duplications and aneuploidies on epigenetic patterning. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13059-015-0827-6) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4659173 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-46591732015-11-26 Trans effects of chromosome aneuploidies on DNA methylation patterns in human Down syndrome and mouse models Mendioroz, Maite Do, Catherine Jiang, Xiaoling Liu, Chunhong Darbary, Huferesh K. Lang, Charles F. Lin, John Thomas, Anna Abu-Amero, Sayeda Stanier, Philip Temkin, Alexis Yale, Alexander Liu, Meng-Min Li, Yang Salas, Martha Kerkel, Kristi Capone, George Silverman, Wayne Yu, Y. Eugene Moore, Gudrun Wegiel, Jerzy Tycko, Benjamin Genome Biol Research BACKGROUND: Trisomy 21 causes Down syndrome (DS), but the mechanisms by which the extra chromosome leads to deficient intellectual and immune function are not well understood. RESULTS: Here, we profile CpG methylation in DS and control cerebral and cerebellar cortex of adults and cerebrum of fetuses. We purify neuronal and non-neuronal nuclei and T lymphocytes and find biologically relevant genes with DS-specific methylation (DS-DM) in each of these cell types. Some genes show brain-specific DS-DM, while others show stronger DS-DM in T cells. Both 5-methyl-cytosine and 5-hydroxy-methyl-cytosine contribute to the DS-DM. Thirty percent of genes with DS-DM in adult brain cells also show DS-DM in fetal brains, indicating early onset of these epigenetic changes, and we find early maturation of methylation patterns in DS brain and lymphocytes. Some, but not all, of the DS-DM genes show differential expression. DS-DM preferentially affected CpGs in or near specific transcription factor binding sites (TFBSs), implicating a mechanism involving altered TFBS occupancy. Methyl-seq of brain DNA from mouse models with sub-chromosomal duplications mimicking DS reveals partial but significant overlaps with human DS-DM and shows that multiple chromosome 21 genes contribute to the downstream epigenetic effects. CONCLUSIONS: These data point to novel biological mechanisms in DS and have general implications for trans effects of chromosomal duplications and aneuploidies on epigenetic patterning. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13059-015-0827-6) contains supplementary material, which is available to authorized users. BioMed Central 2015-11-25 2015 /pmc/articles/PMC4659173/ /pubmed/26607552 http://dx.doi.org/10.1186/s13059-015-0827-6 Text en © Mendioroz et al. 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 Mendioroz, Maite Do, Catherine Jiang, Xiaoling Liu, Chunhong Darbary, Huferesh K. Lang, Charles F. Lin, John Thomas, Anna Abu-Amero, Sayeda Stanier, Philip Temkin, Alexis Yale, Alexander Liu, Meng-Min Li, Yang Salas, Martha Kerkel, Kristi Capone, George Silverman, Wayne Yu, Y. Eugene Moore, Gudrun Wegiel, Jerzy Tycko, Benjamin Trans effects of chromosome aneuploidies on DNA methylation patterns in human Down syndrome and mouse models |
title | Trans effects of chromosome aneuploidies on DNA methylation patterns in human Down syndrome and mouse models |
title_full | Trans effects of chromosome aneuploidies on DNA methylation patterns in human Down syndrome and mouse models |
title_fullStr | Trans effects of chromosome aneuploidies on DNA methylation patterns in human Down syndrome and mouse models |
title_full_unstemmed | Trans effects of chromosome aneuploidies on DNA methylation patterns in human Down syndrome and mouse models |
title_short | Trans effects of chromosome aneuploidies on DNA methylation patterns in human Down syndrome and mouse models |
title_sort | trans effects of chromosome aneuploidies on dna methylation patterns in human down syndrome and mouse models |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659173/ https://www.ncbi.nlm.nih.gov/pubmed/26607552 http://dx.doi.org/10.1186/s13059-015-0827-6 |
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