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Epigenetics

Genetics is the DNA code for what a cell can transcribe into specific types of RNA or translate into specific proteins. However, just because there are over 20 000 genes in the human genome, it does not mean that every gene is expressed, even in the brain. Epigenetics is a parallel system that determines whether any given gene is actually made into its specific RNA and protein, or if it is instead ignored or silenced. If the genome is a lexicon of all protein "words," then the epigenome is a "story" resulting from arranging the "words" into a coherent tale. The genomic lexicon of all potential proteins is the same in every one of the 10+ billion neurons in the brain, and indeed is the same in all of the 200+ types of cells in the body. So, the plot of how a normal neuron becomes a malfunctioning neuron in a psychiatric disorder, as well as how a neuron becomes a neuron instead of a liver cell, is the selection of which specific genes are expressed or silenced. In addition, malfunctioning neurons are impacted by inherited genes that have abnormal nucleotide sequences, which if expressed contribute to mental disorders. Thus, the story of the brain depends not only on which genes are inherited but also on whether any abnormal genes are expressed or even whether normal genes are expressed when they should be silent or silenced when they should be expressed. Neurotransmission, genes themselves, drugs, and the environment all regulate which genes are expressed or silenced, and thus all affect whether the story of the brain is a compelling narrative such as learning and memory, a regrettable tragedy such as drug abuse, stress reactions, and psychiatric disorders, or therapeutic improvement of a psychiatric disorder by medications or psychotherapy.

What are the molecular mechanisms of epigenetics?

Epigenetic mechanisms turn genes on and off by modifying the structure of chromatin in the cell nucleus ( ). The character of a cell is fundamentally determined by its chromatin, aFigure 1-30 substance composed of nucleosomes ( ). Nucleosomes are an octet of proteins calledFigure 1-30 histones around which DNA is wrapped ( ). Epigenetic control over whether a gene is readFigure 1-30 (i.e., expressed) or is not read (i.e., silenced), is achieved by modifying the structure of chromatin. Chemical modifications that can do this include not only methylation, but also acetylation, phosphorylation, and other processes that are regulated by neurotransmission, drugs, and the environment ( ). For example, when DNA or histones are methylated, this compacts theFigure 1-30 chromatin and acts to close off access of molecular transcription factors to the promoter regions of DNA, with the consequence that the gene in this region is silenced, and not expressed, so no RNA or protein is manufactured ( ). Silenced DNA means molecular features that are not part of aFigure 1-30 given cell’s personality.

Histones are methylated by enzymes called histone methyl-transferases, and this is reversed by enzymes called histone demethylases ( ). Methylation of histones can silence genes,Figure 1-30 whereas demethylation of histones can activate genes. DNA can also be methylated, and this also silences genes. Demethylation of DNA reverses this. Methylation of DNA is regulated by DNA methyl-transferase (DNMT) enzymes, and demethylation of DNA by DNA demethylase enzymes (

). There are many forms of methyl-transferase enzymes, and they all tag their substratesFigure 1-30 with methyl groups donated from methylfolate via S-adenosyl-methionine (SAMe) ( ).L- Figure 1-30 When neurotransmission, drugs, or the environment affect methylation, this regulates whether genes are epigenetically silenced or expressed.

Methylation of DNA can eventually lead to deacetylation of histones as well, by activating enzymes called histone deacetylases (HDACs). Deacetylation of histones also has a silencing action on gene expression ( ). Methylation and deacetylation compress chromatin, as though a molecularFigure 1-30 gate has been closed. This prevents transcription factors from accessing the promoter regions that activate genes; thus, the genes are silenced and not transcribed into RNA or translated into proteins ( ). On the other hand, demethylation and acetylation do just the oppostite: theyFigure 1-30 decompress chromatin as though a molecular gate has been opened, and thus transcription factors can get to the promoter regions of genes and activate them ( ). Activated genes thusFigure 1-30 become part of the molecular personality of a given cell.

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Figure 1-30. . Molecular gates are opened by acetylation and/or demethylationGene activation and silencing of histones, allowing transcription factors access to genes, thus activating them. Molecular gates are closed by deacetylation and/or methylation provided by the methyl donor SAMe derived from methylfolate. This preventsL- access of transcription factors to genes, thus silencing them. Ac, acetyl; Me, methyl; DNMT, DNA methyl-transferase; TF, transcription factor; SAMe, S-adenosyl-methionine; L-MF, methylfolate.L-

How epigenetics maintains or changes the status quo

Some enzymes try to maintain the status quo of a cell, such as DNMT1 (DNA methyl-transferase 1), which maintains the methylation of specific areas of DNA and keeps various genes quiet for a lifetime. That is, this process keeps a neuron a neuron and a liver cell a liver cell, including when a cell divides into another one. Presumably, methylation is maintained at genes that one cell does not need, even though another cell type might.

It used to be thought that, once a cell differentiated, the epigenetic pattern of gene activation and gene silencing remained stable for the lifetime of that cell. Now, however, it is known that there are various circumstances in which epigenetics may change in mature, differentiated neurons. Although the initial epigenetic pattern of a neuron is indeed set during neurodevelopment to give each neuron its own lifelong "personality," it now appears that the storyline of some neurons is that they respond to their narrative experiences throughout life with a changing character arc, thus causing de novo alterations in their epigenome. Depending upon what happens to a neuron (such as child abuse, adult stress, dietary deficiencies, productive new encounters, psychotherapy, drugs of abuse, or psychotropic therapeutic medications), it now seems that previously silenced genes can become activated and/or previously active genes can become silenced ( ). When this happens,Figure 1-30 both favorable and unfavorable developments can occur in the character of neurons. Favorable epigenetic mechanisms may be triggered in order for one to learn (e.g., spatial memory formation) or to experience the therapeutic actions of psychopharmacologic agents. On the other hand,

unfavorable epigenetic mechanisms may be triggered in order for one to become addicted to drugs of abuse or to experience various forms of "abnormal learning," such as when one develops fear conditioning, an anxiety disorder, or a chronic pain condition.

How these epigenetic mechanisms arrive at the scene of the crime remains a compelling neurobiological and psychiatric mystery. Nevertheless, a legion of scientific detectives is working on these cases and is beginning to show how epigenetic mechanisms are mediators of psychiatric disorders. There is also the possibility that epigenetic mechanisms can be harnessed to treat addictions, extinguish fear, and prevent the development of chronic pain states. It may even be possible to prevent disease progression of psychiatric disorders such as schizophrenia by identifying high-risk individuals before the "plot thickens" and the disorder is irreversibly established and relentlessly marches on to an unwanted destiny.

One of the mechanisms for changing the status quo of epigenomic patterns in a mature cell is via de novo DNA methylation by a type of DNMT enzyme known as DNMT2 or DNMT3 ( ).Figure 1-30 These enzymes target neuronal genes for silencing that were previously active in a mature neuron. Of course, deacetylation of histones near previously active genes would do the same thing, namely silence them, and this is mediated by the enzymes called histone deacetylases (HDACs). In reverse, demethylation or acetylation both activate genes that were previously silent. The real question is, how does a neuron know which genes among its thousands to silence or activate in response to the environment, including stress, drugs, and diet? How might this go wrong when a psychiatric disorder develops? This part of the story remains a twisted mystery, but some very interesting detective work has already been done by various investigators who hope to understand how some neuronal stories evolve into psychiatric tragedies. These investigations may set the stage for rewriting the narrative of various psychiatric disorders by therapeutically altering the epigenetics of key neuronal characters so that the story has a happy ending.