Mthsetigosef

WOtnccbtuuqwfgqp

1

from the associationOF PROFESSIONAL INTEREST

Epigenetics: What It Is and How It Can AffectDietetics Practice

Gail P. A. Kauwell, PhD, RD

spaqpgpotftsdglm

etmtcqsb6spemciamcgvwiaogmtcfcM

aqta

fsgptvttwtafmpnatboqronbgc(smhcEoteh

iagthp

ost food and nutrition profes-sionals know that our geneticcode, the sequence of nucleo-

ides in our DNA, can influenceealth status. But there is anotheret of instructions that affects genexpression, and this set of instruc-ions can be altered by diet. Epigenet-cs, the study of heritable changes inene function that occur independentf a change in DNA sequence, repre-ents a new frontier in biomedical sci-nce that has important implicationsor dietetics practice.

HAT MAKES US DIFFERENT?ne of the factors that accounts for

he diversity among people is our ge-otype. With the exception of identi-al twins, the specific sequence of nu-leotides (ie, sugar, phosphate andase—adenine, cytosine, guanine, orhymine) comprising our DNA isnique to each of us. This geneticniqueness is partly a result of se-uence variations in our DNA inhich one nucleotide is substituted

or another at specific locations in ourenome. In some cases, these se-uence variations or single nucleotideolymorphisms (SNPs) affect the

G. P. A. Kauwell is a professor,Food Science and Human Nutri-tion Department, University ofFlorida, Gainesville, FL.

Address correspondence to: GailP. A. Kauwell, PhD, RD, Food Sci-ence and Human Nutrition Depart-ment, University of Florida, POBox 110370, Newell Dr, Bldg 475,Gainesville, FL 32611-0370.E-mail: gpk@ifas.ufl.eduCopyright © 2008 by the AmericanDietetic Association.0002-8223/08/10806-0021$34.00/0

Mdoi: 10.1016/j.jada.2008.03.003

056 Journal of the AMERICAN DIETETIC ASSOCIATI

tructure and function of the generoduct, which subsequently mightlter nutrient metabolism and re-uirements. SNPs occurring in non-rotein coding regions of DNA (ie, re-ions that do not typically code forroteins) can also affect events thatccur at the molecular level. SNPs inhese regions can affect transcriptionactor binding to the promoter region ofhe gene, which can alter gene expres-ion, or they can affect gene splicing (ie,ifferential inclusion or exclusion of re-ions of the pre-mRNA transcript)eading to different forms of mature

RNA.An example of a nutritionally rel-

vant SNP is one associated withhe gene that encodes the enzymeethylenetetrahydrofolate reduc-

ase (MTHFR). Inheritance of aommon variation in the DNA se-uence of the MTHFR gene (ie, sub-titution of cytosine with thymine atase pair 677 of the gene; MTHFR77C¡T) results in a coding changeuch that valine replaces alanine atosition 222 in the gene product (ie,nzyme). While this may seem like ainor change, inheriting one or two

opies of this MTHFR gene variants associated with reduced enzymectivity (1). Furthermore, the ho-ozygous variant genotype (ie, two

opies of the altered version of theene) is associated with mildly ele-ated plasma homocysteine and,hen coupled with low folate status,

s a modest risk factor for coronaryrtery disease (2). Thus, SNPs thatccur within the coding region of aene are partly responsible for whatakes us different and, depending on

he circumstances, can increase, de-rease, or have no effect on the riskor common chronic diseases andonditions. Fortunately, reducedTHFR activity associated with the

THFR 677C¡T polymorphism is h

ON © 2008

ttenuated when folate status is ade-uate (2), providing one example ofhe importance of learning morebout nutrient�gene interactions.While our genome dictates the code

or the countless proteins that can beynthesized by our bodies, our epi-enome (ie, pattern of methyl, acetyl,hosphate, or chemical groups boundo DNA and associated proteins) pro-ides an extra layer of instructionshat influences gene activity. This ex-ra layer of instructions affectshether or not various genes are

ranscribed (ie, turned “on” or “off”),nd ultimately can affect cellularunction and metabolism. Environ-ental factors, such as food and sup-

lement intake, can alter the epige-etic state of the genome, therebyffecting gene expression (ie, pheno-ype) independent of the sequence ofase pairs in our genetic code. Inther words, the same exact DNA se-uence for a particular gene may giveise to different outcomes, dependingn its epigenotype and, unlike the ge-etic code, which Gosden and Fein-erg liken to “indelible ink,” the epi-enetic code can be altered “like aode written in pencil in the margins”3). By controlling gene activation andilencing, diet-induced epigeneticodification of the human genome

as the potential to influence risk forertain cancers and chronic diseases.ventually, it may be possible to rec-mmend specific nutrition interven-ions aimed at modifying the epig-nomic profile in ways that optimizeealth and reduce disease risk.One way in which gene expression

s modulated is through DNA methyl-tion—the degree to which methylroups are present or absent from cer-ain regions of our genes. In general,ypomethylated sites allow gene ex-ression to be activated. In contrast,

ypermethylated sites generally in-

by the American Dietetic Association

tilbwpDiBogoftem

gtgictpyafwaolDDwa

tTammitnDggtcsac

EISfswstB

slfftaftsyvcpsbpmdatbocosmepoo

cgasmbmlIpthhtwso

mctacmwpdcfk

EAttgctnFsmntityhasatwlhvpi

TEChIhlgntttmtoeoagpaaimgeceti

OF PROFESSIONAL INTEREST

erfere with gene expression. Depend-ng on the circumstances, hypomethy-ation or hypermethylation can beeneficial or harmful—it depends onhich genes are turned on, at whatoint in time, and in which tissues.NA methylation can be affected by

ntake of folate, vitamins B-12 and-6, choline, and methionine becausef the role these nutrients play in theeneration of methyl groups throughne carbon metabolism. Other dietaryactors, such as genistein, coumes-erol, and polyphenols (4) also influ-nce DNA methylation, although theechanism of action is unknown.In addition to DNA methylation, epi-

enetic modification can be achievedhrough histone modification andenomic imprinting. DNA is packagedn our cells by coiling around positivelyharged proteins called histones. His-ones can be modified by a number ofrocesses, including methylation, acet-lation, phosphorylation, ribosylation,nd biotinylation. Histone modifiers af-ect how tightly the DNA strand israpped around the histones. For ex-mple, histone acetylation (ie, additionf acetyl groups) causes the DNA tooosen, allowing access to genes.eacetylation of histones causes theNA strand to be folded more tightly,hich can make nearby genes unavail-ble for gene expression.Genomic imprinting is another way

hat gene expression is regulated.his can occur through DNA methyl-tion or histone modification. Theseodifications allow the genes to “re-ember” whether they were inher-

ted from the mother or the father sohat only the paternally or mater-ally inherited allele is expressed.isorders arising from imprintedene mutations or dysregulation ofene expression that may be familiaro food and nutrition professionals in-lude Prader-Willi and Angelmanyndromes. Some imprinted geneslso have been linked to certain can-ers.

PIGENETIC RESEARCH FINDINGS ANDMPLICATIONStudies of mice have shown that dif-

erences in maternal nutrition re-ulted in epigenetic modificationsith sustained impacts on the off-

pring, some of which have the poten-ial to alter chronic disease risk.

ased on findings from earlier re- c

earch conducted by Wolff and col-eagues (5), Waterland and Jirtle (6)ed a methyl-supplemented diet (ie,olate, vitamin B-12, choline, and be-aine) before and during pregnancynd lactation to genetically identicalemale mice bred to genetically iden-ical males that carry an altered ver-ion of a dominant gene (ie, viableellow agouti allele or Avy). The Avy

ariant of the agouti gene affects coatolor and is associated with a predis-osition to cancer, diabetes, and obe-ity. Researchers found that despiteeing genetically identical, a greaterroportion of the Avy offspring whoseothers consumed the methyl-rich

iet had heavily mottled and pseudo-gouti (ie, brown) coats compared tohe unsupplemented dams who gaveirth to a higher proportion of Avy

ffspring with yellow coats. Coatolor was correlated with the degreef methylation of the agouti geneupporting the concept that hyper-ethylation of the gene through the

xtra supply of methyl groups sup-ressed gene expression. The effectn coat color was sustained through-ut adulthood.Using a similar protocol, Dolinoy and

olleagues (7) examined the effects ofenistein on coat color, DNA methyl-tion, and body weight. The Avy off-pring of genistein-supplementedothers were more likely to have

rown coats and a higher degree ofethylation of the agouti gene and less

ikely to become overweight as adults.nterestingly, a human agouti-relatedeptide that shares sequence similarityo the mouse agouti protein acts on theypothalamus to stimulate eating be-avior in humans (8). Parallels such ashis provide researchers with clues forhat to investigate to better under-

tand the potential effects of nutritionn gene expression.Another example of the effects ofaternal diet on gene expression

omes from research examining micehat have an altered version of thexin gene (ie, axin-fused allele) thatauses tail kinking (9). Providing aethyl-supplemented diet to miceith the axin-fused allele duringregnancy was associated with a re-uction in tail kinks in their offspringompared to the offspring of mothersed the control diet. Reduction in tailinking was associated with in-

reased methylation of the axin gene. r

June 2008 ● Journal

PIGENETICS AND MONOZYGOTIC TWINSfascinating finding demonstrating

he influence of epigenetic modifica-ions comes from the human monozy-otic (MZ) twin study by Fraga andolleagues (10). While every set of MZwins has an identical genotype, phe-otypic discordance often exists.raga and colleagues (10) hypothe-ized that epigenetic differencesight provide an explanation for phe-

otypic discordance. To investigatehis hypothesis, researchers exam-ned the epigenetic patterns of MZwins ranging in age from 3 to 74ears. Young twin pairs tended toave very similar DNA methylationnd histone acetylation patterns, butubstantial disparity in methylationnd acetylation was noted in olderwin pairs. Methylation differencesere greatest in MZ twins who spent

ess of their lifetime together and whoad the most divergent lifestyles, pro-iding additional support for the im-act of environmental factors, includ-ng diet, on gene expression.

RANSGENERATIONAL EPIGENETICFFECTSan epigenetic modifications be in-erited across multiple generations?f so, what does this mean in terms ofuman nutrition? Cropley and col-

eagues (11) provided evidence forerm-line inheritance of grandmater-al diet-induced epigenetic modifica-ion. Using the Avy mouse model,hese researchers showed that whenhe “grandmother” had been fed aethyl-rich diet during pregnancy,

he effects endured through the sec-nd generation (“grandchildren”),ven though the mothers of the sec-nd-generation animals were not fed

methyl-rich diet. This study sug-ests the possibility that dietary ex-osures in previous generations mayffect the status of subsequent gener-tions. Epigenetic transgenerationalnheritance also may occur in hu-

ans, but while the concept of trans-enerational epigenetic effects is anxciting phenomenon that may ac-ount for the incidence of chronic dis-ases such as obesity and diabetes inhe current generation (12), the truempact on human health and disease

isk remains unknown.

of the AMERICAN DIETETIC ASSOCIATION 1057

UAitfwwsmtmbestoeSn

1

2

3

4

5

6

IDtgehtaoshtnsItpivmiitdhpanseo

gmcmmPtntifsptial

tt

●

●

●

●

●

●

Pa

●

●

●

●

●

●

Insisfstbsocgtf

OF PROFESSIONAL INTEREST

1

NANSWERED QUESTIONSnimal and cell model studies exam-

ning the relationship between nutri-ion and epigenetic modifications areascinating and provide researchersith clues of what to look for andhat to study next, but more exten-

ive investigations that validate hu-an applications are needed. Some of

hese studies suggest that epigeneticodifications by dietary factors may

e influenced by timing and/or dose ofxposure, genotype, and physiologicaltatus. In addition, the effect of nutri-ion and other environmental factorsn epigenetic modifications is not nec-ssarily universal in all cells/tissues.pecific examples of questions thateed to be addressed include:

. Which sites in the human genomeare epigenetically labile? Do thenutritional influences on epige-netic modifications observed in an-imal and cell models correlate withwhat occurs in humans in terms ofeffect (ie, beneficial versus harm-ful), location(s), timing, stage ofdevelopment, physiological state,dose, and duration?

. What is the “optimum” epigenomicprofile for an individual, and howmight this change throughout thelifecycle or as a result of environ-mental exposures?

. What is the optimal dose of a nutri-ent, nutrient combination, and/orbioactive food component(s) toachieve the desired epigenomic pro-file? Do epigenetic modificationsonly occur at levels of intakeachieved through supplementation?Could excessive supplementationyield undesirable outcomes?

. What criteria/evidence will be suffi-cient to determine that nutritionalintervention strategies aimed atmodifying gene expression are“market-ready”—in other words,that the intended benefits will berealized and the risk for deleteriouseffects will be minimal?

. Will a nutritional epigenomic/nu-trigenomic approach to health cre-ate greater disparities in healthcare? What can be done to preventwidening the health disparity gap?What are the public health impli-cations?

. What type of oversight and regula-tion will be associated with nu-

tritional epigenomic/nutrigenomic

058 June 2008 Volume 108 Number 6

testing and prescriptions? Who willbe responsible for these functions?

MPLICATIONS FOR DIETETICS PRACTICEespite the hurdles faced by scientists,

he field of nutritional epigenomics/enomics will no doubt continue tovolve and will impact the future ofealth care and dietetics practice. Inhinking about the impact of geneticnd epigenetic research on practice,ne must consider consumers. Are con-umers ready to adopt the concept ofealth care based on information con-ained within their epigenome/ge-ome? Based on a survey commis-ioned by the International Foodnformation Council (2005), more thanwo-thirds of Americans surveyed ex-ressed a favorable opinion toward thedea of using genetic information to de-elop personalized nutrition recom-endations (13). Similarly, 70% were

nterested in learning more about us-ng genetic information to develop nu-rition recommendations aimed at re-ucing disease risk or optimizingealth (13). Interestingly, online com-anies already offer testing servicesnd products tailored for certain ge-etic profiles even though there are in-ufficient data on which to makevidence-based genotype-specific rec-mmendations.Advances in epigenomic and

enomic research are expected toake it possible to recommend spe-

ific dietary interventions aimed atodifying gene expression to opti-ize health and reduce disease risk.rogression to this stage will necessi-ate changes in practice and requireew tools to support dietetics prac-ice. At the same time, some of thessues faced by food and nutrition pro-essionals are likely to remain theame. The following are examples ofrojected changes in dietetics prac-ice, tools needed to support practicen the epigenomic/nutrigenomic era,nd practice-related issues that areikely to remain the same.

Projected changes in dietetics prac-ice and tools needed to support prac-ice:

application of nutritional epig-enomic/nutrigenomic health assess-ments and counseling by practitio-ners with specialty training at first,followed by gradual integration into

all aspects of dietetics practice; o

development of sophisticated soft-ware packages that integrate datafrom the “-omic” sciences (ie,genomics, proteomics, transcrip-tomics, metabolomics) that will beused to assess nutritional epig-enomic/nutrigenomic health statusand to design tailored nutrition pre-scriptions, meal plans, menus andrecipes;expansion of food composition data-bases to include more foods andmore extensive food compositiondata, including bioactive food com-ponents;development of new diagnostic teststo assess status and measure effi-cacy of nutrition prescriptions;paradigm shifts in the design of Di-etary Reference Intakes, with ex-pansion of the variables on whichrecommendations will be based (ie,SNPs, genome stability, diseaseprevention orientation); andexpansion of “food for health” prod-uct lines (ie, functional foods) mar-keted to individuals with specificepigenomic/genomic and biomarkerprofiles.

rojected practice-related issues thatre likely to remain the same:

people will still get sick and sufferinjuries;behavioral issues: nonadherence;propensity to think more is better;disparities in access to nutritionalepigenomic/nutrigenomic healthcare;potential for quackery; misguidedadvice; abuse; extrapolation andapplication of results prematurely;malpractice issues; anddesire to enjoy food and the plea-sures of eating.

n contemplating the future, food andutrition professionals should con-ider the options they have for learn-ng about epigenomics and relatedciences. While it is premature to of-er nutrition-based epigenomic pre-criptions to patients and clients,hese topics are in the news, and itehooves us to move toward under-tanding the concepts and the “statef the science” so that we can providelients and patients with appropriateuidance and responses to their ques-ions. The following are suggestionsor preparing for this emerging area

f practice:

●

●

●

●

●

●

R

1

1

1

1

OF PROFESSIONAL INTEREST

develop professional learning plansthat include activities related toepigenetics and nutritional genom-ics;expand knowledge and skill state-ments for dietetics programs to in-crease future practitioners’ under-standing of genetics, nutritionalepigenomics/genomics, and relatedareas;strengthen the ability to criticallyevaluate research, read the litera-ture, and attend continuing educa-tion programs/courses to learnmore about epigenetics and relatedtopics;continue to develop strong counsel-ing and nutrition educationskills—be the best at translatingnutritional epigenomic/genomic in-formation for the public;expand the interdisciplinary teamto include geneticists, molecular bi-ologists, and bioinformatics ex-perts; andlearn more about nonnutrient con-stituents of foods and their pro-posed or known functions/actions.

eferences1. Frosst P, Blom HJ, Milos R, Goyette P, Shep-

pard CA, Matthews RG, Boers GJ, den Hei-jer M, Kluijtmans LA, van den Heuvel LP,Rozen R. A candidate genetic risk factor forvascular disease: A common mutation inmethylenetetrahydrofolate reductase. NatGenet. 1995;10:111-113.

2. Klerk M, Verhoef P, Clarke R, Blom HJ, KokFJ, Schouten EG, MTHFR Studies Collabo-ration Group. MTHFR 677C¡T polymor-phism and risk of coronary heart disease: Ameta-analysis. JAMA. 2002;288:2023-2031.

3. Gosden RG, Feinberg AP. Genetics and epi-genetics—Nature’s pen-and-pencil set.N Engl J Med. 2007;356:731-733.

4. Trujillo E, Davis C, Milner J. Nutrigenom-ics, proteomics, metabolomics, and the prac-tice of dietetics. J Am Diet Assoc. 2006;106:403-413.

5. Wolff GL, Kodell RL, Moore SR, Cooney CA.Maternal epigenetics and methyl supple-ments affect agouti gene expression in Avy/amice. FASEB J. 1998;11:949-957.

6. Waterland RA, Jirtle RL. Transposable ele-ments: Targets for early nutritional effectson epigenetic gene regulation. Mol Cell Biol.2003;23:5293-5300.

7. Dolinoy DC, Weidman JR, Waterland RA,Jirtle RL. Maternal genistein alters coatcolor and protects Avy mouse offspring fromobesity by modifying the fetal epigenome.Environ Health Perspect. 2006;114:567-572.

8. Waterland RA. Does nutrition during in-fancy and early childhood contribute to laterobesity via metabolic imprinting of epige-netic gene regulatory mechanisms? NestleNutr Workshop Ser Pediatr Program. 2005;56:157-174.

9. Waterland RA, Dolinoy DC, Lin JR, SmithCA, Shi X, Tahiliani KG. Maternal methyl

supplements increase offspring DNA meth-ylation at Axin Fused. Genesis. 2006;44:401-406.

0. Fraga MF, Ballestar E, Paz MF, Ropero S,Setien F, Ballestar ML, Heine-Suner D,Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C,Carlsson E, Poulsen P, Vaag A, Stephan Z,Spector TD, Wu YZ, Plass C, Esteller M.Epigenetic differences arise during the life-time of monozygotic twins. Proc Natl AcadSci USA. 2005;102:10604-10609.

1. Cropley JE, Suter CM, Beckman KB, MartinDI. Germ-line epigenetic modification of themurine Avy allele by nutritional supplemen-tation. Proc Natl Acad Sci USA. 2006;103:17308-17312.

2. Cooney CA. Germ cells carry the epigeneticbenefits of grandmother’s diet. Proc NatlAcad Sci USA. 2006;103:17071-17072.

3. International Food Information Council.2005 Consumer Attitudes toward Func-tional Foods/Foods for Health ExecutiveSummary. July 2006. http://www.ific.org/research/upload/2005funcfoodsresearch.pdf.Accessed September 2, 2007.

June 2008 ● Journal of the AMERICAN DIETETIC ASSOCIATION 1059