Selective loss of 5hmC links to A-T Purkinje cell vulnerability

• 作 者: De-WeiJian[1]Qian-QuanChen[2]Jia-LiLi[2]
• 机 构: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan
• 出 处: 第三届灵长类动物模型学术论坛
• 发表日期: 2014年期

　　The neurodegenerative disease known as ataxia-telangiectasia(A-T)is caused by the absence of the ATM(A-T mutated)protein.A long-standing mystery surrounding A-T is why cerebellar Purkinje cells(PCs)appear uniquely vulnerable to ATM-deficiency.Here,we present that 5-hydroxymethylcytosine(5hmC),a newly recognized epigenetic marker found at high levels in neurons,is substantially reduced in human A-T and Atm-/-mouse cerebellar PCs.TET1,an enzyme that converts 5mC to 5hmC,responds to DNA damage.Manipulation of TET1 activity directly affects neuronal cell cycle reentry and cell death after the induction of DNA damage.Quantitative,genome-wide analysis of 5hmC of samples from human cerebellum showed that in ATM-deficiency there is a remarkable genome-wide reduction of 5hmC enrichment at both proximal and distal regulatory elements.These results reveal a role of TET1-mediated 5hmC in DNA damage response,and provide insights into the basis of a PC-specific DNA demethylation alteration in ATM-deficiency.