ATRX induction by mutant huntingtin via Cdx2 modulates heterochromatin condensation and pathology in Huntington's disease.
Cell Death Differ
; 19(7): 1109-16, 2012 Jul.
Article
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| MEDLINE
| ID: mdl-22240898
ABSTRACT
Aberrant chromatin remodeling is involved in the pathogenesis of Huntington's disease (HD) but the mechanism is not known. Herein, we report that mutant huntingtin (mtHtt) induces the transcription of alpha thalassemia/mental retardation X linked (ATRX), an ATPase/helicase and SWI/SNF-like chromatin remodeling protein via Cdx-2 activation. ATRX expression was elevated in both a cell line model and transgenic model of HD, and Cdx-2 occupancy of the ATRX promoter was increased in HD. Induction of ATRX expanded the size of promyelocytic leukemia nuclear body (PML-NB) and increased trimethylation of H3K9 (H3K9me3) and condensation of pericentromeric heterochromatin, while knockdown of ATRX decreased PML-NB and H3K9me3 levels. Knockdown of ATRX/dXNP improved the hatch rate of fly embryos expressing mtHtt (Q127). ATRX/dXNP overexpression exacerbated eye degeneration of eye-specific mtHtt (Q127) expressing flies. Our findings suggest that transcriptional alteration of ATRX by mtHtt is involved in pericentromeric heterochromatin condensation and contributes to the pathogenesis of HD.
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Base de datos:
MEDLINE
Asunto principal:
Proteínas Nucleares
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Heterocromatina
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ADN Helicasas
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Proteínas de Homeodominio
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Proteínas del Tejido Nervioso
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Cell Death Differ
Año:
2012
Tipo del documento:
Article
País de afiliación:
Estados Unidos