Transcriptional modulator H2A histone family, member Y (H2AFY) marks Huntington disease activity in man and mouse

Proc Natl Acad Sci U S A. 2011 Oct 11;108(41):17141-6. doi: 10.1073/pnas.1104409108. Epub 2011 Oct 3.


Huntington disease (HD) is a progressive neurodegenerative disease that affects 30,000 individuals in North America. Treatments that slow its relentless course are not yet available, and biomarkers that can reliably measure disease activity and therapeutic response are urgently needed to facilitate their development. Here, we interrogated 119 human blood samples for transcripts associated with HD. We found that the dynamic regulator of chromatin plasticity H2A histone family, member Y (H2AFY) is specifically overexpressed in the blood and frontal cortex of patients with HD compared with controls. This association precedes the onset of clinical symptoms, was confirmed in two mouse models, and was independently replicated in cross-sectional and longitudinal clinical studies comprising 142 participants. A histone deacetylase inhibitor that suppresses neurodegeneration in animal models reduces H2AFY levels in a randomized phase II clinical trial. This study identifies the chromatin regulator H2AFY as a potential biomarker associated with disease activity and pharmacodynamic response that may become useful for enabling disease-modifying therapeutics for HD.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Adult
  • Aged
  • Animals
  • Case-Control Studies
  • Cross-Sectional Studies
  • Disease Models, Animal
  • Double-Blind Method
  • Female
  • Frontal Lobe / metabolism
  • Gene Expression
  • Histone Deacetylase Inhibitors / pharmacology
  • Histones / blood
  • Histones / genetics*
  • Histones / metabolism*
  • Humans
  • Huntington Disease / blood
  • Huntington Disease / genetics*
  • Huntington Disease / metabolism*
  • Longitudinal Studies
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Transgenic
  • Middle Aged
  • Nerve Degeneration / drug therapy
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism


  • Histone Deacetylase Inhibitors
  • Histones
  • MACROH2A2 protein, human
  • RNA, Messenger
  • macroH2A histone

Associated data

  • GEO/GSE24250
  • GEO/GSE6613