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Aberrant changes in gene function are believed to be involved in a wide spectrum of human disease including behavioral, cognitive and neurodegenerative pathologies. Most of the attention in last few decades have focused on changes in gene sequence as a cause of gene dysfunction leading to disease and mental health disorders. Germ line mutations or other alterations in the sequence of DNA that associate with different behavioral and neurological pathologies have been identified. However, sequence alterations explain only a small fraction of the cases. In addition there is evidence for “gene–environment” interactions in the brain suggesting mechanisms that alter gene function and the phenotype through environmental exposure. Genes are programmed by “epigenetic” mechanisms such as chromatin structure, chromatin modification and DNA methylation. These mechanisms confer on similar sequences different identities during cellular differentiation. Epigenetic differences are proposed to be involved in differentiating gene function in response to different environmental contexts and could result in alterations in functional gene networks that lead to brain disease. Epigenetic markers could serve important biomarkers in brain and behavioral diseases. Moreover, epigenetic processes are potentially reversible pointing to epigenetic therapeutics in psychotherapy. [ABSTRACT FROM AUTHOR]

Abstract: The genome is programmed by the epigenome, which is comprised of chromatin and a covalent modification of DNA by methylation. Epigenetic patterns are sculpted during development to shape the diversity of gene expression programs in the different cell types of the organism. The epigenome of the developing fetus is especially sensitive to maternal nutrition, and exposure to environmental toxins as well as psychological stress. It is postulated here that not only chemicals but also exposure of the young pup to social behavior, such as maternal care, could affect the epigenome. Since epigenetic programming defines the state of expression of genes, epigenetic differences could have the same consequences as genetic polymorphisms. We will propose here a mechanism linking maternal behavior and epigenetic programming and we will discuss the prospect that similar epigenetic variations generated during early life play a role in generating inter-individual differences in human behavior. We speculate that exposures to different environmental toxins, which affect the epigenetic machinery might alter long-established epigenetic programs in the brain. [Copyright &y& Elsevier]

Abstract: The methyl-CpG binding domain protein MBD3 has been shown to be essential for embryonic development and differentiation, and to act by suppressing gene expression through the recruitment of co-repressor complexes. We have recently shown that MBD3 is also involved in maintaining the demethylated and active state of rRNA genes, and that depletion of MBD3 results in hypermethylation of rRNA promoters. The possibility that MBD3 could also trigger DNA demethylation of RNA polymerase II-transcribed genes has not been addressed. In this study we used a gain-of-function approach to examine whether MBD3 expression alters DNA methylation states in a living cell and whether it has specific targets for DNA methylation or demethylation in the genome. We used a combination of methylated DNA immunoprecipitation (mDIP) and hybridization to a human promoter tiling microarray to examine the landscape of DNA methylation patterns in response to MBD3 overexpression. We demonstrate that MBD3 induces genomic DNA demethylation and that it has specific targets in the genome with which it associates. Demethylation is localized to promoter regions with intermediate CpG density, and promoters with predicted transcription factor binding sites for NF-Y were significantly affected. These data demonstrate a causal relationship between MBD3 and DNA demethylation of genomic targets in cells. [Copyright &y& Elsevier]