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Histone modifications in Rett syndrome lymphocytes: a preliminary evaluation
Walter E Kaufmann1, Mohammed H Jarrar, Judy S Wang
1Kennedy Krieger Institute and Johns Hopkins University School of Medicine, 3901 Greenspring Avenue, Baltimore, MD 21205, USA. kaufmann@kennedykrieger.org
Brain & Development
|July 19, 2005
Summary
Rett syndrome (RTT) shows altered histone acetylation in peripheral cells, regardless of MECP2 mutation status. These changes correlate with head growth deceleration, suggesting a role in RTT pathogenesis.
Area of Science:
- Neuroscience
- Genetics
- Epigenetics
Background:
- Rett syndrome (RTT) is primarily caused by mutations in the MECP2 gene, a transcriptional regulator involved in chromatin structure.
- Histone modifications, particularly acetylation and methylation, are crucial for gene regulation, but their role in RTT tissues is poorly understood.
- Previous studies on histone modifications in RTT have yielded limited and conflicting results.
Purpose of the Study:
- To characterize histone acetylation (AcH3, AcH4) and methylation (MeH3) in peripheral cells of individuals with RTT.
- To explore correlations between these histone modifications and the severity of neurologic and developmental phenotypes in RTT.
- To investigate whether observed histone modification patterns are associated with MECP2 mutation status.
Main Methods:
- Compared histone acetylation and methylation levels in lymphocyte lysates from 17 females with RTT (11 with MECP2 mutations) and 10 age-matched controls using immunoblotting.
- Assessed levels of MeCP2, AcH3, AcH4, AcH3K14, MeH3K4, and MeH3K9.
- Correlated histone modification levels with clinical parameters, including head growth deceleration and neurologic phenotype severity.
Main Results:
- Immunoreactivities for MeCP2, AcH3, and AcH4 varied in both control and RTT groups.
- Individuals with RTT and nonsense MECP2 mutations showed reduced C-terminal MeCP2.
- Both RTT subjects with (RTTPos) and without (RTTNeg) MECP2 mutations exhibited decreased AcH3 levels, primarily due to reduced AcH3K14.
- Milder decreases in MeH3K4 and MeH3K9 were observed.
- Reduced AcH3 levels correlated with more severe head growth deceleration in the RTTPos group.
- No significant association was found between MECP2 mutation location and RTT neurologic phenotype severity.
Conclusions:
- Distinctive histone acetylation and methylation profiles exist in RTT peripheral cells.
- These epigenetic alterations reflect pathogenetic mechanisms relevant to RTT, irrespective of MECP2 mutation status.
- The observed histone modification patterns may contribute to the neurologic dysfunction seen in RTT.