TY - JOUR
T1 - Histone modifications in Rett syndrome lymphocytes
T2 - A preliminary evaluation
AU - Kaufmann, Walter E.
AU - Jarrar, Mohammed H.
AU - Wang, Judy S.
AU - Lee, Ye Jin M.
AU - Reddy, Sriram
AU - Bibat, Genila
AU - Naidu, Sakkubai
N1 - Funding Information:
We thank J. Christodoulou for supplying MeCP2 antibodies, M. Johnston and S. Baylin for advice and encouragement throughout the project, and T. Jansen for editorial assistance. We are also grateful to the families of our research participants, and in particular to our subjects with Rett syndrome. This work was supported by NIH grants HD24448 and HD24061, and the FRAXA Research Foundation.
PY - 2005/8
Y1 - 2005/8
N2 - 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.
AB - 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.
KW - Acetylation
KW - Histone
KW - MeCP2
KW - Neurologic impairment
KW - Rett syndrome
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U2 - 10.1016/j.braindev.2004.09.005
DO - 10.1016/j.braindev.2004.09.005
M3 - Article
C2 - 16023547
AN - SCOPUS:22244478317
VL - 27
SP - 331
EP - 339
JO - Brain and Development
JF - Brain and Development
SN - 0387-7604
IS - 5
ER -