title: Altering 5-hydroxymethylcytosine modification impacts ischemic brain injury.
abstract: 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.
authors.affiliation: 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, Institute of Neuroscience, Soochow University, Suzhou City, Jiangsu Province 215123, P.R. China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Miao
authors.affiliation: Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, P.R. China.
authors.forename: Yuquan
authors.initials: Y
authors.lastname: He
authors.affiliation: 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.
authors.forename: Ning
authors.initials: N
authors.lastname: Xin
authors.affiliation: Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu, P.R. China.
authors.forename: Miao
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.affiliation: 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, Department of Neurology, Suzhou Kowloon Hospital, Suzhou City, Jiangsu Province 215021, P.R. China and.
authors.forename: Jizhen
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Jiming
authors.initials: J
authors.lastname: Kong
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA, xingshunxu@suda.edu.cn peng.jin@emory.edu.
authors.forename: Peng
authors.initials: P
authors.lastname: Jin
authors.affiliation: 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, Institute of Neuroscience, Soochow University, Suzhou City, Jiangsu Province 215123, P.R. China, xingshunxu@suda.edu.cn peng.jin@emory.edu.
authors.forename: Xingshun
authors.initials: X
authors.lastname: Xu
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism / Q000031:analogs & derivatives; D000818:Animals; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D049308:Dioxygenases; D044127:Epigenesis, Genetic; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; C579455:BDNF protein, human; D003596:Cytosine; D049308:Dioxygenases; C541081:TET2 protein, human