Abstract
The symptoms of ataxia-telangiectasia (A-T) include a progressive neurodegeneration caused by ATM protein deficiency. We previously found that nuclear accumulation of histone deacetylase-4, HDAC4, contributes to this degeneration; we now report that increased trimethylation of histone H3 on Lys27 (H3K27me3) mediated by polycomb repressive complex 2 (PRC2) is also important in the A-T phenotype. Enhancer of zeste homolog 2 (EZH2), a core catalytic component of PRC2, is a new ATM kinase target, and ATM-mediated phosphorylation of EZH2 on Ser734 reduces protein stability. Thus, PRC2 formation is elevated along with H3K27me3 in ATM deficiency. Chromatin immunoprecipitation and sequencing showed an increase in H3K27me3 'marks' and a dramatic shift in their location. The change of H3K27me3 chromatin-binding pattern is directly related to cell cycle reentry and cell death of ATM-deficient neurons. Lentiviral knockdown of EZH2 rescued Purkinje cell degeneration and behavioral abnormalities in Atm(-/-) mice, demonstrating that EZH2 hyperactivity is another key factor in A-T neurodegeneration.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Ataxia Telangiectasia Mutated Proteins / genetics
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Ataxia Telangiectasia Mutated Proteins / metabolism
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Ataxia Telangiectasia* / complications
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Ataxia Telangiectasia* / genetics
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Ataxia Telangiectasia* / metabolism
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Brain / cytology
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Brain / pathology
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Cell Cycle / drug effects
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Cell Cycle / physiology
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Cells, Cultured
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Chromatin Immunoprecipitation
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Embryo, Mammalian
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Enhancer of Zeste Homolog 2 Protein
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Exploratory Behavior / physiology
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Female
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism*
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Humans
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Male
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Methylation
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Mice
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Mice, Transgenic
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Neurodegenerative Diseases* / etiology
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Neurodegenerative Diseases* / genetics
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Neurodegenerative Diseases* / metabolism
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Neurons / metabolism
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Neurons / pathology
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Phosphorylation / physiology
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Polycomb Repressive Complex 2 / genetics
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Polycomb Repressive Complex 2 / metabolism*
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Young Adult
Substances
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Repressor Proteins
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EZH2 protein, human
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Enhancer of Zeste Homolog 2 Protein
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Polycomb Repressive Complex 2
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Ataxia Telangiectasia Mutated Proteins
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HDAC4 protein, human
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Histone Deacetylases