机构：[1]Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province 215004, P.R. China,[2]Institute of Neuroscience, Soochow University, Suzhou City, Jiangsu Province 215123, P.R. China,[3]Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, P.R. China,[4]Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA,[5]Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu, P.R. China,[6]Department of Neurology, Suzhou Kowloon Hospital, Suzhou City, Jiangsu Province 215021, P.R. China[7]Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
Epigenetic modifications such as cytosine methylation and histone modification are linked to the pathology of ischemic brain injury. Recent research has implicated 5-hydroxymethylcytosine (5hmC), a DNA base derived from 5-methylcytosine (5mC) via oxidation by ten-eleven translocation (Tet) enzymes, in DNA methylation-related plasticity. Here we show that 5hmC abundance was increased after ischemic injury, and Tet2 was responsible for this increase; furthermore, inhibiting Tet2 expression abolished the increase of 5hmC caused by ischemic injury. The decrease in 5hmC modifications from inhibiting Tet2 activity was accompanied by increased infarct volume after ischemic injury. Genome-wide profiling of 5hmC revealed differentially hydroxymethylated regions (DhMRs) associated with ischemic injury, and DhMRs were enriched among the genes involved in cell junction, neuronal morphogenesis and neurodevelopment. In particular, we found that 5hmC modifications at the promoter region of brain-derived neurotrophic factor (BDNF) increased, which was accompanied by increased BDNF mRNA, whereas the inhibition of Tet2 reduced BDNF mRNA and protein expression. Finally, we show that the abundance of 5hmC in blood samples from patients with acute ischemic stroke was also significantly increased. Together, these data suggest that 5hmC modification could serve as both a potential biomarker and a therapeutic target for the treatment of ischemic stroke.
基金：
This study was supported by grants from the National Natural
Science Foundation of China (81071095, 81120108011 and
81361128010 to X.X.), Ministry of Science and Technology of
China (2013CB945400 to M.S.), National Institutes of Health
(NS079625 to P.J.), Canadian Institutes of Health Research (CIHR,
CCI-132567 to J.K.) and the Priority Academic Program Development
of Jiangsu Higher Education Institutions of China.
第一作者机构：[1]Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province 215004, P.R. China,[2]Institute of Neuroscience, Soochow University, Suzhou City, Jiangsu Province 215123, P.R. China,
共同第一作者：
通讯作者：
通讯机构：[1]Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province 215004, P.R. China,[4]Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA,
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