MEDICALPROGRESS

EPIGENETICS IS HERE TO STAY

JUDITH G. HALL, MD

T he last decade has seen remarkable advances in genetics, but in many ways the advances show us what we do not know.The sequencing of the human genome led to recognition that we need to understand how proteins work, and that has ledto a recognition that there is a lot that goes on in the cell that is not just the consequence of the sequence of the DNA. The

term that has been used to describe heritable states that do not depend on the DNA sequence is ‘‘epigenetics.’’ The conceptincludes heritable and reversible modifications of chromosomes and DNA, these modifications modulate chromosome structureand gene function and thus affect the phenotype—the structural and functional features of the organism. These modifications areof interest because they are a window into the control and regulation of gene expression and thus are very relevant to tissuespecificity and the timing of expression. Furthermore, epigenetic changes have become of interest because when they do notfunction properly at a cellular level, cancer and other bad things can happen.1 The ‘‘epigenome’’ is the combination of all the sitesin the genome (ie, the DNA sequences) in which there is this kind of control exerted by modification of the DNA sequence (bothchemical and physical). An epimutation is a mutation that interferes with normal epigenetic (control) function.

Historically, Lamark (1744–1829) suggested that there might be inheritance of acquired characteristics or traits. He becamea laughing stock in his lifetime because he suggested that acquired characteristics (such as when a giraffe stretched its neck) couldbe transmitted to offspring (the next generation of giraffes would have longer necks). The first time the term ‘‘epigenetics’’ wasused is probably during the 1940s by Waddington. He used it to describe the control of genes during development that gives riseto the phenotypes that are observed. McClintock’s work on ‘‘jumping genes’’ in corn is also relevant because the transposableelements can lead to changes in gene and epigenetic expression.

Tissue variation in terms of the specific genes that are expressed is produced by epigenetic control, because the same genes(DNA sequences) are present in every cell, but tissue phenotype variation can be dramatically different, as we all know. Genomicimprinting has been recognized as the phenomenon by which there is expression of an allele (one of the pair of genes) inheritedfrom one parent but not from the allele inherited of the other parent. It is also a form of epigenetics. X-inactivation uses RNAtranscripts to silence much of the genetic material on one of the X chromosomes in mammalian females, and this too is a formof epigenetics.

To understand how epigenetic control works, it is important to realize that DNA is folded in a very complex way within thecell, and that complex packaging structures have something to do with control of gene expression as well. Each nucleated cell hasabout 2 yards of DNA that has to be folded and condensed so that it can fit into the nucleus of the cell. That folding andcondensing is done by wrapping DNA around proteins called histones. What has been recognized in the last few years is thatsecondary chemical changes occur to both the DNA and the histones and these have a lot to do with whether or not a gene will beexpressed. In the case of DNA, the modification involves methylation (attaching a carbon group to certain cytosines). In the caseof histones, it involves methylation, acetylation, phosphorylation, and ubiquination, all of which are potentially reversibleinteractions. These DNA and histone modifications are mediated by enzymes, some of which are tissue specific. In DNA, themodified sites (CpG sequences) also seem to be prone to mutation.2

In the human genome, there are DNA sequences called CpG islands. A CpG island ismade up of length of DNA more than 500 base pairs long that has a high GC (guanine/cytosine) content. These CpG islands are usually outside genes but seem to have a lot to dowith gene transcription or silencing. These sites can be identified using a moleculartechnique that determines whether the DNA is methylated. Consequently, it is possible todetermine in a specific tissue (at a specific time) whether a gene is actively expressing.

Studies of the X-chromosome have led to the recognition that RNA antisensetranscripts (RNA that uses the complementary base pairs, but ‘‘reads’’ in the oppositedirection) hybridize, because of their complementary double-helix structure, to the DNAand through this mechanism turn the DNA off (permanently) for all subsequent celldivisions.3 Most recently, it has been recognized that if enough RNA is made to createdouble strands of RNA, it is a signal to the cells to cut up the RNA, and that then createssingle antistrands of RNA that can turn the active gene off.4 The cells’ use of RNA tocontrol gene expression seems to be a complex feedback system with multiple levels of

From the Departments of MedicalGenetics and Pediatrics, UBC andChildren’s and Women’s Health Cen-tre of British Columbia, Vancouver,British Columbia, Canada.

Reprint requests: Judith G. Hall, De-partment of Pediatrics, British Colum-bia’s Children’s Hospital, 4480 Oak St,Vancouver, BC, Canada. E-mail: jhall@cw.bc.ca.

J Pediatr 2005;147:427-8.0022-3476/$ - see front matter

Copyrightª 2005 Elsevier Inc. All rightsreserved.

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control. But, in addition, there are many very small RNAs inthe cell that interfere with DNA expression and tie things upall the time.5 Again, this is called ‘‘epigenetic’’ because it doesnot change the basic DNA sequence of the cells.

The ‘‘take home’’ message about epigenetics is that themechanisms by which cells ‘‘turn on and off’’ gene expressionare beginning to be unraveled, but it is very complex! DNAmethylation, histone modification, and RNA-associated si-lencing of DNA are important actors.

All of this sounds terribly technical, but the reason it isso exciting and important is that by understanding the way itworks, it may be possible to create forms of therapy in whichsmall RNAs are introduced into the cell or methylation of theDNA is enhanced in such a way to accomplish the expressionof the genes that are desirable or to turn off those genes thatare undesirable.6

Pediatricians know that folic acid is important in theprevention of birth defects. It is not at all clear how folic aciddoes this, but it may have something to do with turning on andoff genes at critical points in development because folic acidplays a major role in methylation.

Interestingly, epigenetic effects are very time and tissuespecific in developmental processes. For instance, when aprimordial germ cell begins to develop, the methylation ofgenes that had been present is lost, but as the germ cell maturesthe DNA become more and more methylated in a parent oforigin way (ie, sperm and ova are different).7 As soon asfertilization occurs, there is loss of DNA methylation againthat is then reestablished during tissue-specific development.This in turn must happen properly for genomic imprinting (anepigenetic phenomenon) to be established normally, withoutwhich a variety of abnormal phenotypes result. The exactcontrol of all of this is not understood yet either, except thatthere are known to be very specific and different DNAmethylation enzymes at different times in development.8

There are animal models that are relevant to the humansituation. For instance, the Agouti mouse is a strain of mice inwhich there is variable color. Agouti mice that are fully yelloware prone to diabetes, obesity, and cancer. The yellow color

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was believed to be a maternally inherited trait in that the moreyellow the mother was, the more yellow babies she had. In fact,if the grandmother was yellow, there would be even moreyellow baby mice—all more prone to disease. There seems tobe no male contribution to this trait. The Agouti yellow coatcolor correlated with the methylation of a transposableelement upstream of the parakin protein gene. Interestingly,if Agouti mice are put on high–folic acid diets, they completelylose their yellow color and the secondary diseases. Methylgroups provided by the folic acid attach to the transposon andsilence it, leading to normal expression of the parakin gene.9,10

Maybe that is the sort of thing that happens in human beings!The mechanisms by which gene expression is controlled

are key to understanding normal development and health, aswell as using molecular mechanisms to prevent and treatdisease and disability. Modifications of the secondary structureof DNA seem to be fundamental and, hence, worthy ofinvestigation and understanding. It does seem as if epigeneticsis going to be a very important concept for pediatricians!

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4. Novina CD, Sharp PA. The RNAi revolution. Nature 2004;430:161-4.

5. He L, Hannon GL. MicroRNAs: Small RNAs with a big role in gene

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6. Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease

and prospects for epigenetic therapy. Nature 2004;429:457-63.

7. Reik W, Walter J. Genomic imprinting: parental influence on the

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The Journal of Pediatrics � October 2005