期刊
CELL DEATH AND DIFFERENTIATION
卷 19, 期 7, 页码 1109-1116出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2011.196
关键词
ATRX; huntingtin; heterochromatin condensation; Huntington's disease; Cdx-2
资金
- NIH [NS 067283-01A1]
- WCU [800-20080848]
- SRC from NRF [2010-0029-403]
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. Cell Death and Differentiation (2012) 19, 1109-1116; doi: 10.1038/cdd.2011.196; published online 13 January 2012
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