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Transcriptional Regulation in Schizophrenia 113Additional Means of TranscriptionalRegulation in SchizophreniaRNA interference (RNAi) is a recently described phenomenon that is anothermeans by which gene expression can be regulated. mRNA usually exists in thecytoplasm as single-stranded RNA. The unpaired nucleotides of the mRNA canthen interact with the ribosomal complex to translate the message and synthesizeprotein. However, like DNA, mRNA can exist in double-stranded form (dsRNA).RNA interference machinery in the cell finds dsRNA, cuts it with an enzyme knownas Dicer, separates the two strands of mRNA, and then proceeds to destroy othersingle-stranded RNA with that same sequence. Like mRNA, microRNAs (miRNA)are another type of RNA transcribed from genomic DNA. However, these smallermiRNAs fold back on themselves generating a double-stranded hairpin shape. TheRNA interference machinery then detects these dsRNAs, breaks them apart, anddestroys mRNAs with the same sequence as the miRNA, thus reducing the expressionof many mRNAs. Recent studies have identified 66 brain specific miRNAsand identified a subset of 19 miRNAs expressed during neuronal differentiation(Sempere et al., 2004). The demonstration of a temporal expression wave ofselect miRNAs during mouse brain development (Miska et al., 2004) may providenew insight on our understanding of transcriptional regulation during developmentand may provide clues as to which transcripts may be modified inschizophrenia.Methylation of DNA is another means by which transcription can be regulated.DNA methylation is a process by which a methyl group is added to specific basepairs of DNA after replication. Of the four types of base pairs, methylation occursonly at the cytosine-guanine pairing (CG). Once the methyl group is addedto the base pair, the DNA is unrecognizable to enzymes in the nucleus, particularlyenzymes that initiate transcription. Repetitive runs of CG doublets in the DNAsequence are referred to as “CpG islands” and are important sites of methylationin the genome. In general, genes are methylated in tissues in which they are notexpressed and are unmethylated in tissues in which they are active. Methylationat specific sites, such as promoter elements, is likely important for suppression oftranscription. Interestingly, DNA-methyltransferase 1 (DNMT1), a protein thatcontributes to the hypermethylation of promoter CpG islands is upregulated inthe cortex of schizophrenics—preferentially expressed in interneurons secretingGABA (Veldic et al., 2004; Veldic et al., 2005). Reelin, a protein that is importantto neuronal development, is decreased in the brains of schizophrenic patients.Interestingly, DNMT1–induced hypermethylation decreases reelin expression inmouse primary cortical cultures and may mediate the decreased reelin expressionobserved in the schizophrenic brain (Chen et al., 2002; Noh et al., 2005). Furtherstudies are warranted to assess hypermethylation as a mechanism for transcriptionalregulation in schizophrenia.