One of the key papers in our Special Topics Research
Front Map onEpigenetic
Gene Regulationis "Transposable elements:
targets for early nutritional effects on epigenetic gene
regulation" (Waterland, R.A. and Jirtle, R.L., Mol.
Cell. Biol. 23: 5293-300, August 2003). In
Essential Science IndicatorsSMfrom
Reuters, this paper is currently a Highly
Cited Paper in the field of Molecular Biology &
Genetics, with 306 citations up to April 30, 2009.
This paper was coauthored Dr. Randy Jirtle and Dr. Robert Waterland,
who was a postdoctoral fellow Dr. Jirtle's at the time. Dr. Jirtle's record
in our database includes 56 papers cited a total of 2,466 times between
January 1, 1999 and April 30, 2009. He is the Director of the Epigenetics
and Imprinting Laboratory at Duke University in Durham, NC.
In the interview below,
ScienceWatch.com talks with Dr. Jirtle about this paper and
its influence on the field of epigenetics.
Would you please describe the significance of
your paper and why it is highly cited?
Both animal experiments and human epidemiological studies demonstrate that
maternal nutritional privation during pregnancy is adversely associated
with an offspring’s susceptibility to diseases and neurological
disorders after birth. Our 2003 Molecular and Cellular Biology
paper provided the first experimental evidence that the memory system
linking these two disparate time points in life involves epigenetic
modifications established soon after fertilization1. In so
doing, we opened the mechanistic 'black box' of the developmental origins
of adult disease susceptibility, and firmly placed the word,
epigenetics, in the vernacular of this research field.
Specifically, we showed that dietary supplementation of viable yellow
agouti (Avy) mice during pregnancy with methyl donors (i.e. choline,
betaine, folic acid, and vitamin B12) decreased the incidence of offspring
with a yellow coat color (Figure 1), which is associated concomitantly with
a reduction in their risk of developing
diabetes, and cancer.
Moreover, these phenotypic changes were shown to result from increased
DNA methylation of a transposable element upstream of the
Agouti gene rather than mutation of the gene.
Interestingly, genistein, a weak phytoestrogen found in soy products,
elicits a similar epigenetic effect at the Avy locus even though
it is not a methyl donor2. Both methyl donors and genistein can
also counteract the CpG hypomethylation caused by
bisphenol A, an endocrine disrupting
agent used to make hard clear plastic and epoxy resins3. As
Hippocrates asserted over two millennia ago, food is medicine!
How did you become involved in this research,
and were there any particular successes or obstacles that stand
Our lab became involved in epigenetics research in the early 1990s when we
identified the IGF2R (Insulin-like Growth Factor 2 Receptor) to be
a liver tumor suppressor gene4. IGF2R is also imprinted
in a number of species5, and the paternal-specific allelic
silencing that results in monoallelic expression of this gene is
epigenetically controlled. Thus, IGF2R was the first imprinted
tumor suppressor gene identified.
With this discovery, we realized that cancer could potentially arise by a
single genetic mutation or a lone epigenetic event in an imprinted tumor
suppressor gene. But, could changes in the environment during pregnancy
cause modifications at epigenetically labile loci that increase the risk of
developing cancer and other complex diseases years later? We used the Avy
mouse model described above to address this fundamentally important
Where do you see your research and the
broader field leading in the future?
The number of papers published last year on epigenetics was 16,000—a
40-fold increase since we started research in this field. Therefore,
epigenetics research is growing exponentially. This is due, in part, to the
availability of high-throughput sequencing platforms that have enabled
scientists to ascertain how DNA methylation, histone marks, nucleosome
position, and non-coding RNA species interact at the chromatin level to
control cell differentiation and normal cell function. As these regulatory
systems are more precisely defined, we will increasingly focus our
laboratory research efforts on identifying those genes that are imprinted
in humans, and determining their role in the pathogenesis of human
conditions, e.g., autism, bipolar disorder, cancer, drug
addiction, and schizophrenia.
What are the implications of your work for
"Despite the immense popularity and
ease of using mice to 'model' human diseases,
it appears they may not be a suitable choice
for studying diseases resulting principally
from the epigenetic deregulation of imprinted
genes, or for assessing human risk from
environmental factors that alter the
epigenome rather than mutate the
The publication of our 2003 Molecular and Cellular Biology paper
demonstrated unequivocally that the risk of developing diseases in later
life can result from environmental interference of normal epigenetic
programming during gestation1. As a consequence, it is clear
that variation not only in the genome, but also the epigenome participates
in complex disease formation.
Genomic imprinting evolved about 180 million years ago in an ancestor
common to placental mammals (Therians), and it resulted in some genes
having the same parental allele always epigenetically silenced6.
Imprinted genes are particularly susceptible to epigenetic deregulation
because the unique imprint marks that control their idiosyncratic
functional haploid state must staunchly be maintained when the epigenome is
normally reset after fertilization7. Thus, imprinted genes are
candidate disease susceptibility loci uniquely vulnerable to
environmentally induced deregulation during early development.
With the use of computer-learning algorithms, we recently predicted the
presence of 600 candidate imprinted genes in mice8; but only 156
in humans9. Not only are humans predicted to have fewer
imprinted genes than mice, but there is also only a 30% overlap between
their imprinted gene repertoires. Despite the immense popularity and ease
of using mice to 'model' human diseases, it appears they may not be a
suitable choice for studying diseases resulting principally from the
epigenetic deregulation of imprinted genes, or for assessing human risk
from environmental factors that alter the epigenome rather than mutate the
Thus, we are entering a new era of biological research—one where it
is becoming increasingly apparent that humans are indeed the best model for
understanding diseases afflicting mankind, as stated so prophetically by
the English poet Alexander Pope in the early 18th century. This important
realization, and the change in the research approach to which it points,
will require scientists from numerous disciplines to collaborate in order
to bring together the biological samples and patients and exposure
information needed to tease out the alterations in our epigenome, which
link environmental exposures during susceptible stages of life to disease
formation years later. The field of medicine could potentially be
revolutionized by this epigenetic perspective of disease
formation—subsequently shifting our healthcare emphasis from therapy
Randy L. Jirtle, Ph.D. Epigenetics and Imprinting Laboratory Duke University Durham, NC, USA
Waterland, R.A., and Jirtle, R.L. Transposable elements: targets for
early nutritional effects on epigenetic gene regulation. Mol Cell
Biol23: 5293-5300, 2003.
Dolinoy, D.C., Weidman, J.R., Waterland, R.A., and Jirtle, R.L.
Maternal genistein alters coat color and protects Avy mouse offspring from
obesity by modifying the fetal epigenome. Environ Health Perspect114: 567-572, 2006.
Dolinoy, D.C., Huang, D., and Jirtle, R.L. Maternal nutrient
supplementation counteracts bisphenol A-induced DNA hypomethylation in
early development. Proc Natl Acad Sci U S A104: 13056-13061, 2007.
De Souza, A.T., Hankins, G.R., Washington, M.K., Orton, T.C., and
Jirtle, R.L. M6P/IGF2R gene is mutated in human hepatocellular carcinomas
with loss of heterozygosity. Nat Genet11: 447-449, 1995.
Barlow, D.P., Stoger, R., Herrmann, B.G., Saito, K., and Schweifer, N.
The mouse insulin-like growth factor type-2 receptor is imprinted and
closely linked to the Tme locus. Nature349: 84-87, 1991.
Effects of nutrition on the epigenome of viable yellow agouti (Avy) mice.
These female one year old Avy mice are isogenic. The mother of the mouse on
the left ate a normal mouse diet while pregnant. In contrast, the mother of
the mouse on the right ate a diet supplemented with methyl donors while
pregnant . The marked differences in the coat color and weight of these
offspring resulted from a dissimilarity in the level of DNA methylation at
the Agouti locus.