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

Lu Wen1, Xianlong Li1, Liying Yan12, Yuexi Tan1, Rong Li12, Yangyu Zhao12, Yan Wang12, Jingcheng Xie3, Yan Zhang12, Chunxiao Song4, Miao Yu4, Xiaomeng Liu1, Ping Zhu1, Xiaoyu Li6, Yu Hou1, Hongshan Guo1, Xinglong Wu1, Chuan He4*, Ruiqiang Li16*, Fuchou Tang15* and Jie Qiao12*

Author Affiliations

1 Biodynamic Optical Imaging Center & Center for Reproductive Medicine, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, P. R. China

2 Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, P. R. China

3 Department of Neurosurgery, Peking University Third Hospital, Beijing 100191, China

4 Department of Chemistry & Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, USA

5 Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, P. R. China

6 Peking-Tsinghua Center for Life Sciences, College of Life Sciences, Peking University, Beijing 100871, P. R. China

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Genome Biology 2014, 15:R49  doi:10.1186/gb-2014-15-3-r49

Published: 4 March 2014

Abstract

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.