Epigenetics at the Epicenter of Modern Medicine Andrew P. Feinberg, MD, MPH
JAMA. 2008;299(11):1345-1350.
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Epigenetics, the study of non-DNA sequence–related heredity, is at the epicenter of modern medicine because it can help to explain the relationship between an individual’s genetic background, the environment, aging, and disease. It can do so because the epigenetic state varies among tissues and during a lifetime, whereas the DNA sequence remains essentially the same. As cells adapt to a changing internal and external environment, epigenetic mechanisms can remember these changes in the normal programming and reprogramming of gene activity. The common disease genetic and epigenetic (CDGE) model provides an epidemiologic framework that can incorporate epigenetic with genetic variation in the context of age-related susceptibility to disease. Under CDGE, the epigenetic program can modify the effects of deleterious genes or may be influenced by an adverse environment. Thus, including epigenetics into epidemiologic studies of human disease may help explain the relationship between the genome and the environment and may provide new clues to modifying these effects in disease prevention and therapy.
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Although epigenetics is considered a relatively new area of medicine, the term is more than 60 years old. Waddington first used the term epigenetics to describe what is now called developmental biology, the idea that phenotype, or the morphologic and functional properties of an organism, arises sequentially under a program defined by the genome under the influence of the organism’s environment.1 The modern definition of epigenetics is modifications of the DNA or associated proteins, other than DNA sequence variation, that carry information content during cell division.2 The best understood example of epigenetic modification is DNA methylation, a covalent addition of a methyl (CH3) group to the nucleotide cytosine. DNA methylation is maintained during cell division in mammals only at dinucleotide C-G (CpG), by virtue of the enzyme DNA methyltransferase I. This occurs because during semiconservative DNA replication, a methylated CpG on the parent DNA strand is partnered with a newly synthesized unmethylated CpG on the daughter strand. DNA methyltransferase I searches out this hemimethylated DNA and places a new methyl group on the daughter CpG.2 An important environmental connection to epigenetics is that the source of methyl groups in this reaction is methionine, an essential amino acid, that is converted to a biologically active methyl donor state through a well-understood pathway that involves folic acid (Figure 1).3
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A second well-studied example of epigenetic change is chromatin modification, specifically, covalent modifications of the histone proteins that make up the nucleosomes around which the DNA double helix is coiled, approximately 2 turns of 200 base pairs, including the linker DNA between each nucleosome. These chemical modifications also include methylation but in this case involve the amino acids arginine or lysine, as well as phosphorylation of serine, acetylation of lysine, and ubiquitinylation of lysine.4 Unlike DNA methylation, the mechanism of maintaining chromatin modifications during cell division is not well understood because no enzyme has yet been identified that recognizes chromatin modifications from the parent cell and reproduces them in the daughter cell.5 Other examples of epigenetic information are the density of nucleosome packing along the DNA, the complex of DNA and nucleosomes with specific proteins that recognize methylated DNA or modified histones, and the higher-order topologic organization of all these elements into complex structures that are only beginning to be recognized in the laboratory.4
What is the effect of these epigenetic changes? The simplest answer is that they regulate gene expression. For example, DNA methylation has traditionally been thought to be found with silenced genes. More than 100 specific chromatin modifications have been discovered, some of which exist in association with actively transcribed genes and others with silenced genes.4 The relaxation of condensed nucleosomes is important for gene activity, and a key insight published more than 10 years ago was that proteins that cooperate with transcription factors in activating or silencing genes act by acetylating or deacetylating histones, respectively.6–7 A more subtle change is that epigenetic modifications as a group may define a higher-order structure within the nucleus. Recent studies using new methods, such as chromatin conformation capture to identify long-distance DNA interactions, have revealed that groups of genes may change their physical relationship with one another, depending on their transcriptional state.8–9 Similarly, important differences in tissue-specific gene expression are controlled by enhancer sequences on the DNA, and the physical relationship between these enhancers and the promoters, ie, the elements to which the transcriptional machinery binds to activate gene expression, is controlled in part by the methylation of insulator sequences and the resultant folding of gene regions into loops of various sizes, depending on the state of the cell.10
Modern Epigenetics Is at the Heart of Developmental Biology
Perhaps the most important aspect of epigenetics is that the modern definition and Waddington’s definition have converged because the epigenetic state of an organism has a lifecycle, whereas the DNA sequence does not (Figure 2). Epigenetic marks distinguish most of the important developmental properties of tissues from one another. For example, stem cell biology has now achieved the point at which differentiated somatic cells can be restored to a pluripotent state, ie, induced progenitor stem cells.11 But clearly, the DNA in these cells has not changed, and without interference from the investigator, the pluripotency of DNA or lack of such capacity is relatively stable, ie, heritable during cell division. Thus, an epigenetic program must underlie these state changes.
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Similarly, reprogramming of somatic cells and cancer cells by nuclear transplantation shows that information successfully transmitted during cell division for years or even decades can be erased and reprogrammed epigenetically.12 This difference between stem and somatic cells extends to individual cell types. After all, how can a liver cell know to divide to form 2 liver cells rather than brain cells or heart cells, without some embedded epigenetic memory? Recently, it was shown that stem cells carry “bivalent” chromatin marks, ie, both on and off, on some genes, which then commit to one or the other state in differentiated tissues.13 Understanding the epigenetic correlate of tissue-specific differentiation is one of the great challenges of modern developmental biology.
Epigenetics of Disease: Disruption of Normal Phenotypic Plasticity
The first example of a human disease with an epigenetic mechanism was cancer. In 1983, widespread loss of DNA methylation was observed in colorectal cancers compared with matched normal mucosa from the same patients.14 This hypomethylation has been shown to lead to abnormal activation of genes in cancer, as well as genetic instability and chromosomal rearrangements.2 Subsequently, hypermethylation of gene promoters was reported for a number of tumor suppressor genes in cancer.15–17 Epigenetic activation and silencing of genes in cancer turn genes on that should be off and vice versa. In fact, each type of normal epigenetic mark described earlier is altered in cancers, including abnormal histone modifications; excess of chromatin factors such as trithorax group proteins that promote gene expression, such as ALL1 in acute lymphocytic leukemia; and polycomb group proteins that repress gene expression, such as EZH2 in metastatic cancers.2
Single gene disorders of the epigenetic machinery also impair normal gene expression. For example, Rett syndrome, which involves progressive loss of developmental milestones caused by abnormal gene expression in the brain, is caused by lack of a normal MeCP2 protein that recognizes methylated DNA and thus helps to repress gene expression.18 Immunodeficiency, centromeric instability, and facial anomalies syndrome is caused by loss of DNMT3B, a DNA de novo DNA methyltransferase that adds methyl groups to CpGs where they were not present before.19 Affected cells abnormally express genes involved in immune function, neural function, and development.19
The unifying theme of epigenetic disease is disruption of normal phenotypic plasticity. Just as epigenetic change is at the heart of normal development, so also do disruptions in epigenetic modification disturb normal developmental programs. Thus, single gene disorders such as Rett syndrome show abnormal brain reprogramming in development, and complex traits such as cancer involve disruptions of the normal commitment of differentiating cells in tumors to specific patterns of active and repressed genes.20
Age-Related Disease and the Common Disease Genetic and Epigenetic Hypothesis
Clinical medicine deals more with delaying and mitigating the effects of aging than reversing and eliminating disease, particularly as the baby boom generation grows older, because all organ systems function more poorly with time among individuals and among tissues within individuals. Dan L. Longo, MD, scientific director of the National Institute on Aging, defines aging as a loss of phenotypic plasticity over time (written communication, February 8, 2008). This loss of responsiveness to stress also exacerbates the effects of underlying genetic variant–associated disease, accounting at least in part for the age dependence of common disorders such as heart disease, diabetes, and acquired intellectual impairment. But what accounts for this loss of responsiveness? Could lack of responsiveness interact at the level of the DNA with disease-predisposing genetic variation?
Fallin, Bjornsson, and Feinberg21 have proposed a model that could provide an epigenetic explanation to these questions. The common disease genetic and epigenetic (CDGE) model overlies the genetic variant hypothesis of disease, with an epigenetic component interacting with it. This could occur in several ways, first by environmental factors modifying epigenetic marks on the DNA or chromatin. DNA methylation depends on dietary methionine and folate, both of which are affected by nutritional state. Studies in mice have shown that reduction of dietary methionine can affect coat color by altering DNA methylation of the agouti gene.22 Simply feeding rats a low-methionine diet causes them to develop liver cancer at high frequency through hypomethylation of their DNA.23 Continue reading Epigenetics at the epicenter of modern medicine
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