Alteration in 5-hydroxymethylcytosine-mediated epigenetic regulation leads to Purkinje cell vulnerability in ATM deficiency
文献类型：期刊论文
| 作者 | Jiang DW1,2; Zhang Y1; Hart RP3; Chen JM3; Herrup K4; Li JL[*]1 |
| 刊名 | BRAIN
 |
| 出版日期 | 2015 |
| 卷号 | 138期号:X页码:3520-3536 |
| 关键词 | DNA demethylation Purkinje cell vulnerability ataxia-telangiectasia 5-hydroxymethylcytosine TET1 |
| 通讯作者 | lijiali@mail.kiz.ac.cn |
| 合作状况 | 其它 |
| 英文摘要 | A long-standing mystery surrounding ataxia-telangiectasia is why it is mainly cerebellar neurons, Purkinje cells in particular, that appear vulnerable to ATM deficiency. Here we present data showing that 5-hydroxymethylcytosine (5hmC), a newly recognized epigenetic marker found at high levels in neurons, is substantially reduced in human ataxia-telangiectasia and Atm(-/-) mouse cerebellar Purkinje cells. We further show that TET1, an enzyme that converts 5-methylcytosine (5mC) to 5hmC, responds to DNA damage and manipulation of TET1 activity directly affects the DNA damage signalling and ATM-deficient neuronal cell cycle re-entry and death. Quantitative genome-wide analysis of 5hmC-containing sequences shows that in ATM deficiency there is a cerebellum- and Purkinje cell-specific shift in 5hmC enrichment in both regulatory elements and repeated sequences. Finally, we verify that TET1-mediated 5hmC production is linked to the degenerative process of Purkinje cells and behavioural deficits in Atm(-/-) mice. Taken together, the selective loss of 5hmC plays a critical role in driving Purkinje cell vulnerability in ATM deficiency. |
| 收录类别 | SCI |
| 资助信息 | This work was supported by the Chinese Academy of Sciences (Y406541141 and 1100050210) to J.L. and the National Science Foundation of China (NSFC 81471313) to J.L. as well as the National Key Basic Research Program of China (2015CB755600). The support of the A-T Children’s Project to K.H. and R.P.H. is gratefully acknowledged. This work was also supported by grants from the NIH (NS20591 and NS71022) and the National Key Basic Research Program of China (2013CB530900) as well as The Hong Kong University of Science and Technology and the Hong Kong Research Grants Council, HKSAR (GRF660813) to K.H. NIH support was also provided (R21 DA032984) to R.P.H. |
| 语种 | 英语 |
| 源URL | [http://159.226.149.26:8080/handle/152453/9495]  |
| 专题 | 昆明动物研究所_表观遗传与神经退行性疾病 昆明动物研究所_动物模型与人类重大疾病机理重点实验室 |
| 作者单位 | 1.Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China 2.Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650223, China 3.Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, USA 4.Division of Life Science and the State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong |
| 推荐引用方式 GB/T 7714 | Jiang DW,Zhang Y,Hart RP,et al. Alteration in 5-hydroxymethylcytosine-mediated epigenetic regulation leads to Purkinje cell vulnerability in ATM deficiency[J]. BRAIN,2015,138(X):3520-3536. |
| APA | Jiang DW,Zhang Y,Hart RP,Chen JM,Herrup K,&Li JL[*].(2015).Alteration in 5-hydroxymethylcytosine-mediated epigenetic regulation leads to Purkinje cell vulnerability in ATM deficiency.BRAIN,138(X),3520-3536. |
| MLA | Jiang DW,et al."Alteration in 5-hydroxymethylcytosine-mediated epigenetic regulation leads to Purkinje cell vulnerability in ATM deficiency".BRAIN 138.X(2015):3520-3536. |
入库方式： OAI收割
来源：昆明动物研究所
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