ATRX induction by mutant huntingtin via Cdx2 modulates heterochromatin condensation and pathology in Huntington's disease

Cell Death Differ. 2012 Jul;19(7):1109-16. doi: 10.1038/cdd.2011.196. Epub 2012 Jan 13.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • CDX2 Transcription Factor
  • Cell Line
  • DNA Helicases / antagonists & inhibitors
  • DNA Helicases / genetics
  • DNA Helicases / metabolism*
  • Drosophila
  • Drosophila Proteins / antagonists & inhibitors
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Heterochromatin / metabolism*
  • Histones / metabolism
  • Homeodomain Proteins / metabolism*
  • Humans
  • Huntingtin Protein
  • Huntington Disease / metabolism
  • Huntington Disease / pathology
  • Male
  • Methylation
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Promoter Regions, Genetic
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • X-linked Nuclear Protein

Substances

  • CDX2 Transcription Factor
  • CDX2 protein, human
  • Drosophila Proteins
  • HTT protein, human
  • Heterochromatin
  • Histones
  • Homeodomain Proteins
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • RNA, Small Interfering
  • XNP protein, Drosophila
  • DNA Helicases
  • ATRX protein, human
  • X-linked Nuclear Protein