Metilacion Del Adn

Yu et al. Molecular Brain 2011, 4:5 http://www.molecularbrain.com/content/4/1/5

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DNA methylation-mediated control of learning and memory
Nam-Kyung Yu1, Sung Hee Baek2, Bong-Kiun Kaang1,3*
Abstract Animals constantly receive and respond to external or internal stimuli, and these experiences are learned and memorized in their brains. In animals, this is a crucialfeature for survival, by making it possible for them to adapt their behavioral patterns to the ever-changing environment. For this learning and memory process, nerve cells in the brain undergo enormous molecular and cellular changes, not only in the input-output-related local subcellular compartments but also in the central nucleus. Interestingly, the DNA methylation pattern, which is normally stable ina terminally differentiated cell and defines the cell type identity, is emerging as an important regulatory mechanism of behavioral plasticity. The elucidation of how this covalent modification of DNA, which is known to be the most stable epigenetic mark, contributes to the complex orchestration of animal behavior is a fascinating new research area. We will overview the current understanding ofthe mechanism of modifying the methyl code on DNA and its impact on learning and memory. Cytosine methylation in mammals In mammals, methylation at symmetric CpG dinucleotides in genomic DNA is important for heritable gene silencing and regulation of gene expression [1]. It is one of the primary epigenetic mechanisms for the regulation of gene transcription along with the various histonemodifications such as methylation, acetylation, SUMOylation, ubiquitination, and phosphorylation. DNA methylation has been shown to play essential roles in genomic imprinting, X chromosome inactivation, and maintenance of genome stability [1,2]. The addition of a methyl group from SAM (S-adenosylL-methionine) substrates to the cytosine is catalyzed by DNA (cytosine-5)-methyltransferases. Three DNAmethyltransferases, DNMT1, DNMT3a, and DNMT3b, have functional enzymatic activity in mammals (Figure 1) [3,4]. DNMT1 has been called a “maintenance methyltransferase” as it has a substrate preference for hemimethylated DNA over unmethylated DNA. DNMT1 interacts with the DNA replication machinery during the S phase of dividing cells so that the methylation pattern is reliably copied to the daughter strand[5]. DNMT3a
* Correspondence: kaang@snu.ac.kr 1 National Creative Research Initiative Center for Memory, Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-747, Korea Full list of author information is available at the end of the article

and DNMT3b are regarded as “de novo methyltransferases” since they can methylate the cytosine of CpGdinucleotides previously unmethylated on both strands, altering the epigenetic information content. They play crucial roles in establishing genomic methylation patterns during cell differentiation [6]. However, this functional distinction is not always obvious since DNMT1 also displays de novo methyltransferase activity, and its substrate preference is limited in a cellular context-dependent manner [3].The three DNMT genes display differential expression profiles in the central nervous system. DNMT1 is highly expressed in neurons from embryogenesis through adulthood [7,8]. DNMT3b expression is observed in neural progenitor tissue only during early embryogenesis. DNMT3a is expressed from late embryogenesis to adulthood with a peak during the early postnatal period, then its level declines butremains detectable in the post-mitotic neurons of the adult brain [9,10]. Aberrant regulation of DNMT expression has been shown to be related to drug abuse [11,12], suicide [13], and psychiatric disorders such as schizophrenia and bipolar disorder [14,15]. Given that the DNMTs exhibit little or no innate sequence specificity beyond the CpG dinucleotide [3], the manner in which these enzymes find a...