From TF to Chromatin

In recent years, our level of analyzing transcriptional mechanisms in the brain has been extended to ► chroma-tin structure, where the covalent modification (e.g., acet-ylation or methylation) of ► histone proteins, around which DNA is wound in the cell nucleus, and methylation of the DNA itself, have profound effects on the ability of genes to be expressed. ► Chromatin exists in a continuum from a permanently inhibited (closed) state to a constitu-tively active (open) state (Fig. 2). Genes in closed chro-matin are not expressed because they are not accessible to the cell's transcriptional machinery, whereas other genes exist in permissive chromatin where the genes are accessible to transcriptional machinery. This explains, for example, why CREB cannot induce neural gene targets in peripheral tissues where the genes exist in silenced chro-matin, but can in nerve cells where the genes exist in permissive chromatin. TFs induce genes in permissive chromatin by recruiting to those genes many types of co-activator proteins. TFs recruit ► histone acetyltrans-ferases, enzymes that acetylate histones; such acetylation further opens the chromatin. TFs also recruit so-called SWI-SNF factors, proteins that provide the molecular motor for histones to move across a strand of DNA as it is being actively transcribed.

This knowledge of chromatin biology has now begun to inform our understanding of gene expression regulation in the brain and, in particular, its role in learning and memory. First, changes in histone acetylation and DNA

Learning & Memory: Molecular Mechanisms. Fig. 2. Differential states of chromatin. Chromatin exists in a continuum of states from being open (i.e., active, allowing gene expression) to condensed (i.e., inactive, repressing gene expression). Changes across this continuum are mediated in part by modifications to core histone proteins. Histone acetylation (A) is associated with chromatin relaxation and the binding of TFs and coactivators, such as HATs (histone acetyl transferases) and SWI-SNF proteins that mediate the movement of histone complexes along a strand of DNA. Histone methylation (M) results in condensed chromatin and transcriptional repression (REP). Methylation of the DNA itself also results in condensed, repressed chromatin. (From McClung CA, Nestler EJ (2008) Neuroplasticity mediated by altered gene expression. Neuropsychopharmacology 33:3-17.)

methylation have been shown to occur in hippocampus in parallel to aversive learning. These findings are striking because they emphasize the degree to which fundamental mechanisms of gene regulation are affected during the course of normal synaptic transmission - on a time scale of hours. Similar changes in chromatin have been demonstrated in striatum in response to drugs of abuse. Second, it has been possible to directly implicate mechanisms of chromatin regulation in aversive learning and drug addiction by demonstrating that direct manipulations of his-tone or DNA modifications has profound effects on behavior. Inhibitors of ► histone deacetylases (enzymes that remove acetyl groups from histones and thereby inhibit gene expression) or of DNA methyltransferases (enzymes that add methyl groups to DNA and thereby inhibit gene expression) promote hippocampal-dependent memory as well as the rewarding effects of drugs of abuse. In contrast, overexpression of these inhibitory enzymes in specific brain regions exerts the opposite effects.

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