Histone modifications in Rett syndrome lymphocytes: a preliminary evaluation

Brain Dev. 2005 Aug;27(5):331-9. doi: 10.1016/j.braindev.2004.09.005.


Most cases of Rett syndrome (RTT) are associated with mutations in the coding region of the transcriptional regulator MeCP2. This gene appears to repress gene expression through chromatin conformational changes secondary to histone modifications, mainly histone deacetylation of core histones H3 and H4. There is limited and contradictory information about histone modifications in RTT tissues. The present study intended to provide a preliminary characterization of histone acetylation (AcH3, AcH4) and methylation (MeH3) in RTT, with emphasis on non-selected peripheral cells and molecular-neurologic correlations. We compared 17 females with RTT, 11 of them with MeCP2 mutations, with 10 gender-matched controls in terms of lymphocyte lysate immunoblotting-based levels. We found that immunoreactivities for MeCP2 and AcH3/AcH4 are variable in both control and RTT subjects. Despite this variability, RTT subjects with nonsense mutations showed the expected reduction in C-terminal MeCP2 immunoreactivity. Regardless of MeCP2 levels, both subjects with (RTTPos) and without (RTTNeg) mutations had decreased levels of AcH3. The latter reductions were mainly driven by decreases in levels of H3 acetylated at lysine residue 14 (AcH3K14) and independent of parallel, but milder, decreases in immunoreactivity for MeH3 lysine residues (MeH3K4/MeH3K9). Within our study sample, reductions in AcH3 were correlated with severity of head growth deceleration in the RTTPos group. This contrasted with the lack of significant association between location of MeCP2 mutation and severity of the RTT neurologic phenotype. We concluded that there were distinctive profiles of histone acetylation/methylation in RTT peripheral cells, which reflect pathogenetic mechanisms common to subjects with clinical features of this disorder, regardless of mutation status, and that these patterns may be relevant to neurologic dysfunction in RTT.

Publication types

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

MeSH terms

  • Acetylation
  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Chromosomal Proteins, Non-Histone / genetics*
  • Chromosomal Proteins, Non-Histone / metabolism
  • DNA Mutational Analysis
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Female
  • Histones / genetics*
  • Histones / metabolism
  • Humans
  • Lymphocytes / pathology*
  • Methyl-CpG-Binding Protein 2
  • Methylation
  • Polymerase Chain Reaction
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Rett Syndrome / genetics*


  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Histones
  • MECP2 protein, human
  • Methyl-CpG-Binding Protein 2
  • Repressor Proteins