RESUMO
BACKGROUND: A number of neurodevelopmental syndromes are caused by mutations in genes encoding proteins that normally function in epigenetic regulation. Identification of epigenetic alterations occurring in these disorders could shed light on molecular pathways relevant to neurodevelopment. RESULTS: Using a genome-wide approach, we identified genes with significant loss of DNA methylation in blood of males with intellectual disability and mutations in the X-linked KDM5C gene, encoding a histone H3 lysine 4 demethylase, in comparison to age/sex matched controls. Loss of DNA methylation in such individuals is consistent with known interactions between DNA methylation and H3 lysine 4 methylation. Further, loss of DNA methylation at the promoters of the three top candidate genes FBXL5, SCMH1, CACYBP was not observed in more than 900 population controls. We also found that DNA methylation at these three genes in blood correlated with dosage of KDM5C and its Y-linked homologue KDM5D. In addition, parallel sex-specific DNA methylation profiles in brain samples from control males and females were observed at FBXL5 and CACYBP. CONCLUSIONS: We have, for the first time, identified epigenetic alterations in patient samples carrying a mutation in a gene involved in the regulation of histone modifications. These data support the concept that DNA methylation and H3 lysine 4 methylation are functionally interdependent. The data provide new insights into the molecular pathogenesis of intellectual disability. Further, our data suggest that some DNA methylation marks identified in blood can serve as biomarkers of epigenetic status in the brain.
Assuntos
Metilação de DNA , Oxirredutases N-Desmetilantes/genética , Contagem de Células Sanguíneas , Encéfalo/metabolismo , Proteínas de Ligação ao Cálcio/sangue , Proteínas de Ligação ao Cálcio/genética , Cromossomos Humanos X , Cromossomos Humanos Y , Ilhas de CpG , Epigênese Genética , Proteínas F-Box/sangue , Proteínas F-Box/genética , Feminino , Histona Desmetilases , Histonas/genética , Histonas/metabolismo , Humanos , Masculino , Mutação , Proteínas do Grupo Polycomb/sangue , Proteínas do Grupo Polycomb/genética , Regiões Promotoras Genéticas , Complexos Ubiquitina-Proteína Ligase , Ubiquitina-Proteína Ligases/sangue , Ubiquitina-Proteína Ligases/genéticaRESUMO
The action of several peptides and drugs is thought to be primarily dependent on their interactions with specific cell surface G-protein-coupled receptors and ionic transporters such as channels and exchangers. Recent development of 3-D confocal microscopy allowed several laboratories, including ours, to identify and study the localization of receptors, channels, and exchangers at the transcellular level of several cell types. Using this technique, we demonstrated in the nuclei of several types of cells the presence of Ca(2+) channels as well as Na(+)-H(+) exchanger and receptors such as endothelin-1 and angiotensin II receptors. Stimulation of these nuclear membrane G-protein-coupled receptors induced an increase of nuclear Ca(2+). Our results suggest that, similar to the plasma membrane, nuclear membranes possess channels, exchangers and receptors such as those for endothelin-1 and angiotensin II, and that the nucleus seems to be a cell within a cell. This article will emphasize these findings.
