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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Abbreviations
- ATRX:
-
alpha thalassemia/mental retardation X linked
- CDX2:
-
caudal type homeobox 2
- ChIP:
-
chromatin immunoprecipitation
- CREB:
-
cAMP response element-binding
- Daxx:
-
death-domain associated protein
- Dnmt3:
-
DNA methyltransferase
- dXNP:
-
drosopila homolog of XNP/ATRX
- GATA2:
-
transcription factors GATA2
- GMR:
-
glass multimer repeat
- HD:
-
Huntington's disease
- H3K9me3:
-
trimethylation of H3K9
- Htt :
-
Huntingtin
- HP1α:
-
heterochromatin protein 1
- MeCP2:
-
methyl-CpG-binding protein 2
- mtHtt:
-
mutant huntingtin
- PML-NBs:
-
promyelocytic leukemia nuclear bodies
- SP1:
-
specificity protein1
- SWI/SNF:
-
switch/sucrose non-fermentable
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Acknowledgements
We thank Dr. Marcy MacDonald for STHdhQ7/7 and STHdhQ111/111 cells and Soung Chan Kim for their technical assistance. This study was supported by NIH NS 067283-01A1 (HR), WCU Neurocytomics Program Grant (800-20080848) (HR), and SRC Grant (2010-0029-403) (HR) from NRF.
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Lee, J., Hong, Y., Jeon, G. et al. ATRX induction by mutant huntingtin via Cdx2 modulates heterochromatin condensation and pathology in Huntington's disease. Cell Death Differ 19, 1109–1116 (2012). https://doi.org/10.1038/cdd.2011.196
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DOI: https://doi.org/10.1038/cdd.2011.196
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