Alteration in 5-hydroxymethylcytosine-mediated epigenetic regulation leads to Purkinje cell vulnerability in ATM deficiency.
Brain
; 138(Pt 12): 3520-36, 2015 Dec.
Article
em En
| MEDLINE
| ID: mdl-26510954
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.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Células de Purkinje
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Ataxia Telangiectasia
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Citosina
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Epigênese Genética
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Proteínas Mutadas de Ataxia Telangiectasia
Limite:
Animals
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Humans
Idioma:
En
Revista:
Brain
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
China