Abstract
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.
Keywords
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Article info
Publication history
Accepted:
September 10,
2004
Received in revised form:
July 22,
2004
Received:
April 13,
2004
Identification
Copyright
© 2004 Elsevier B.V. Published by Elsevier Inc. All rights reserved.
