Alteration in 5-hydroxymethylcytosine-mediated epigenetic regulation leads to Purkinje cell vulnerability in ATM deficiency.
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.
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.
Dewei
D
Jiang
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.
Ying
Y
Zhang
3 Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, USA.
Ronald P
RP
Hart
3 Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, USA.
Jianmin
J
Chen
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.
Karl
K
Herrup
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 lijiali@mail.kiz.ac.cn.
Jiali
J
Li
D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000818:Animals; D001260:Ataxia Telangiectasia / Q000235:genetics* / Q000473:pathology*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000172:deficiency* / Q000235:genetics; D001522:Behavior, Animal / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D044127:Epigenesis, Genetic; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011689:Purkinje Cells / Q000378:metabolism* / Q000473:pathology*
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C540839:TET1 protein, mouse; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse
5-hydroxymethylcytosine; DNA demethylation; Purkinje cell vulnerability; TET1; ataxia-telangiectasia