Targeting H3K4 trimethylation in Huntington disease

Proc Natl Acad Sci U S A. 2013 Aug 6;110(32):E3027-36. doi: 10.1073/pnas.1311323110. Epub 2013 Jul 19.

Abstract

Transcriptional dysregulation is an early feature of Huntington disease (HD). We observed gene-specific changes in histone H3 lysine 4 trimethylation (H3K4me3) at transcriptionally repressed promoters in R6/2 mouse and human HD brain. Genome-wide analysis showed a chromatin signature for this mark. Reducing the levels of the H3K4 demethylase SMCX/Jarid1c in primary neurons reversed down-regulation of key neuronal genes caused by mutant Huntingtin expression. Finally, reduction of SMCX/Jarid1c in primary neurons from BACHD mice or the single Jarid1 in a Drosophila HD model was protective. Therefore, targeting this epigenetic signature may be an effective strategy to ameliorate the consequences of HD.

Keywords: neurodegeneration; polyglutamine.

Publication types

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

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Blotting, Western
  • Brain / metabolism*
  • Brain / pathology
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cells, Cultured
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism
  • Female
  • Gene Expression Profiling
  • Histone Demethylases
  • Histones / metabolism*
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics
  • Huntington Disease / metabolism*
  • Lysine / metabolism*
  • Male
  • Methylation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / cytology
  • Neurons / metabolism
  • Oxidoreductases, N-Demethylating / genetics
  • Oxidoreductases, N-Demethylating / metabolism
  • Promoter Regions, Genetic / genetics
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Brain-Derived Neurotrophic Factor
  • HTT protein, human
  • Histones
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Histone Demethylases
  • Kdm5c protein, mouse
  • Oxidoreductases, N-Demethylating
  • Lysine

Associated data

  • GEO/GSE48960
  • GEO/GSE48962
  • GEO/GSE48963