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- Title
Alteration in 5-hydroxymethylcytosine-mediated epigenetic regulation leads to Purkinje cell vulnerability in ATM deficiency.
- Authors
Dewei Jiang; Ying Zhang; Hart, Ronald P.; Jianmin Chen; Herrup, Karl; Jiali Li; Jiang, Dewei; Zhang, Ying; Chen, Jianmin; Li, Jiali
- Abstract
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.
- Subjects
ATAXIA telangiectasia; METHYLCYTOSINE; EPIGENETICS; PURKINJE cells; PSYCHOLOGICAL vulnerability; NEURAL physiology; DIAGNOSIS; PROTEIN metabolism; ANIMAL behavior; ANIMAL experimentation; CELL culture; CEREBELLUM; DNA; GENES; HETEROCYCLIC compounds; MICE; NEURONS; PROTEIN kinases; RESEARCH funding; DNA-binding proteins
- Publication
Brain: A Journal of Neurology, 2015, Vol 138, Issue 12, p3520
- ISSN
0006-8950
- Publication type
journal article
- DOI
10.1093/brain/awv284