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Whole-genome analysis of 5-hydroxymethylcytosine and 5-methylcytosine at base resolution in the human brain

BACKGROUND: 5-methylcytosine (mC) can be oxidized by the tet methylcytosine dioxygenase (Tet) family of enzymes to 5-hydroxymethylcytosine (hmC), which is an intermediate of mC demethylation and may also be a stable epigenetic modification that influences chromatin structure. hmC is particularly abu...

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Autores principales: Wen, Lu, Li, Xianlong, Yan, Liying, Tan, Yuexi, Li, Rong, Zhao, Yangyu, Wang, Yan, Xie, Jingcheng, Zhang, Yan, Song, Chunxiao, Yu, Miao, Liu, Xiaomeng, Zhu, Ping, Li, Xiaoyu, Hou, Yu, Guo, Hongshan, Wu, Xinglong, He, Chuan, Li, Ruiqiang, Tang, Fuchou, Qiao, Jie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4053808/
https://www.ncbi.nlm.nih.gov/pubmed/24594098
http://dx.doi.org/10.1186/gb-2014-15-3-r49
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author Wen, Lu
Li, Xianlong
Yan, Liying
Tan, Yuexi
Li, Rong
Zhao, Yangyu
Wang, Yan
Xie, Jingcheng
Zhang, Yan
Song, Chunxiao
Yu, Miao
Liu, Xiaomeng
Zhu, Ping
Li, Xiaoyu
Hou, Yu
Guo, Hongshan
Wu, Xinglong
He, Chuan
Li, Ruiqiang
Tang, Fuchou
Qiao, Jie
author_facet Wen, Lu
Li, Xianlong
Yan, Liying
Tan, Yuexi
Li, Rong
Zhao, Yangyu
Wang, Yan
Xie, Jingcheng
Zhang, Yan
Song, Chunxiao
Yu, Miao
Liu, Xiaomeng
Zhu, Ping
Li, Xiaoyu
Hou, Yu
Guo, Hongshan
Wu, Xinglong
He, Chuan
Li, Ruiqiang
Tang, Fuchou
Qiao, Jie
author_sort Wen, Lu
collection PubMed
description BACKGROUND: 5-methylcytosine (mC) can be oxidized by the tet methylcytosine dioxygenase (Tet) family of enzymes to 5-hydroxymethylcytosine (hmC), which is an intermediate of mC demethylation and may also be a stable epigenetic modification that influences chromatin structure. hmC is particularly abundant in mammalian brains but its function is currently unknown. A high-resolution hydroxymethylome map is required to fully understand the function of hmC in the human brain. RESULTS: We present genome-wide and single-base resolution maps of hmC and mC in the human brain by combined application of Tet-assisted bisulfite sequencing and bisulfite sequencing. We demonstrate that hmCs increase markedly from the fetal to the adult stage, and in the adult brain, 13% of all CpGs are highly hydroxymethylated with strong enrichment at genic regions and distal regulatory elements. Notably, hmC peaks are identified at the 5′splicing sites at the exon-intron boundary, suggesting a mechanistic link between hmC and splicing. We report a surprising transcription-correlated hmC bias toward the sense strand and an mC bias toward the antisense strand of gene bodies. Furthermore, hmC is negatively correlated with H3K27me3-marked and H3K9me3-marked repressive genomic regions, and is more enriched at poised enhancers than active enhancers. CONCLUSIONS: We provide single-base resolution hmC and mC maps in the human brain and our data imply novel roles of hmC in regulating splicing and gene expression. Hydroxymethylation is the main modification status for a large portion of CpGs situated at poised enhancers and actively transcribed regions, suggesting its roles in epigenetic tuning at these regions.
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spelling pubmed-40538082014-06-12 Whole-genome analysis of 5-hydroxymethylcytosine and 5-methylcytosine at base resolution in the human brain Wen, Lu Li, Xianlong Yan, Liying Tan, Yuexi Li, Rong Zhao, Yangyu Wang, Yan Xie, Jingcheng Zhang, Yan Song, Chunxiao Yu, Miao Liu, Xiaomeng Zhu, Ping Li, Xiaoyu Hou, Yu Guo, Hongshan Wu, Xinglong He, Chuan Li, Ruiqiang Tang, Fuchou Qiao, Jie Genome Biol Research BACKGROUND: 5-methylcytosine (mC) can be oxidized by the tet methylcytosine dioxygenase (Tet) family of enzymes to 5-hydroxymethylcytosine (hmC), which is an intermediate of mC demethylation and may also be a stable epigenetic modification that influences chromatin structure. hmC is particularly abundant in mammalian brains but its function is currently unknown. A high-resolution hydroxymethylome map is required to fully understand the function of hmC in the human brain. RESULTS: We present genome-wide and single-base resolution maps of hmC and mC in the human brain by combined application of Tet-assisted bisulfite sequencing and bisulfite sequencing. We demonstrate that hmCs increase markedly from the fetal to the adult stage, and in the adult brain, 13% of all CpGs are highly hydroxymethylated with strong enrichment at genic regions and distal regulatory elements. Notably, hmC peaks are identified at the 5′splicing sites at the exon-intron boundary, suggesting a mechanistic link between hmC and splicing. We report a surprising transcription-correlated hmC bias toward the sense strand and an mC bias toward the antisense strand of gene bodies. Furthermore, hmC is negatively correlated with H3K27me3-marked and H3K9me3-marked repressive genomic regions, and is more enriched at poised enhancers than active enhancers. CONCLUSIONS: We provide single-base resolution hmC and mC maps in the human brain and our data imply novel roles of hmC in regulating splicing and gene expression. Hydroxymethylation is the main modification status for a large portion of CpGs situated at poised enhancers and actively transcribed regions, suggesting its roles in epigenetic tuning at these regions. BioMed Central 2014 2014-03-04 /pmc/articles/PMC4053808/ /pubmed/24594098 http://dx.doi.org/10.1186/gb-2014-15-3-r49 Text en Copyright © 2014 Wen et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Wen, Lu
Li, Xianlong
Yan, Liying
Tan, Yuexi
Li, Rong
Zhao, Yangyu
Wang, Yan
Xie, Jingcheng
Zhang, Yan
Song, Chunxiao
Yu, Miao
Liu, Xiaomeng
Zhu, Ping
Li, Xiaoyu
Hou, Yu
Guo, Hongshan
Wu, Xinglong
He, Chuan
Li, Ruiqiang
Tang, Fuchou
Qiao, Jie
Whole-genome analysis of 5-hydroxymethylcytosine and 5-methylcytosine at base resolution in the human brain
title Whole-genome analysis of 5-hydroxymethylcytosine and 5-methylcytosine at base resolution in the human brain
title_full Whole-genome analysis of 5-hydroxymethylcytosine and 5-methylcytosine at base resolution in the human brain
title_fullStr Whole-genome analysis of 5-hydroxymethylcytosine and 5-methylcytosine at base resolution in the human brain
title_full_unstemmed Whole-genome analysis of 5-hydroxymethylcytosine and 5-methylcytosine at base resolution in the human brain
title_short Whole-genome analysis of 5-hydroxymethylcytosine and 5-methylcytosine at base resolution in the human brain
title_sort whole-genome analysis of 5-hydroxymethylcytosine and 5-methylcytosine at base resolution in the human brain
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4053808/
https://www.ncbi.nlm.nih.gov/pubmed/24594098
http://dx.doi.org/10.1186/gb-2014-15-3-r49
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