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Early Epigenetic Influence

Random chance, plus small differences in uterine environments, give rise to divergent epigenetic patterns in identical twins.

By | July 16, 2012

image: Early Epigenetic Influence Wikimedia Commons, Glow

Scientists are still teasing out the contributions of genetic and environmental factors to epigenetic marks on the genome. Differences in DNA methylation patterns have been linked to various disease occurrences in genetically identical twins, for example, suggesting an environmental impact. And a new study, out this week (July 15) in Genome Research, extends the influence of the environment in to the uterus by demonstrating that differences between identical twins in methylation are detectable at birth. Surprisingly, methylation patterns between some twins differ more than between unrelated individuals, also suggesting a role for random chance in the development of the epigenome.

“We already know that twins behave differently and look different, and it’s probably due to epigenetics,” said Jeffrey Craig, who led the study with Richard Saffery, both at the University of Melbourne.

Because of their identical genomes, monozygotic twins allow scientists to identify epigenetic differences that may serve as markers for disease. But it wasn’t known when differences in epigenetic patterns emerged between twins, Tadafumi Kato, who studies the molecular basis of bipolar disorder at RIKEN Brain Science Institute in Japan but was not involved in the current study, wrote in an email to The Scientist.

In order to look more closely at epigenetic differences between twins, Craig and Saffery took tissue samples when the children were born and for several months after birth, following epigenetic changes over time. They compared sets of identical twins and fraternal twins, a classic experimental setup used to separate environmental from genetic effects. They then used a chip array to examine DNA methylation at over 27,000 sites in the human genome in each of three tissues: placenta, umbilical cord vascular endothelial cells, and cord blood mononuclear cells. The researchers also compared the newborns’ methylation patterns to those of unrelated infants.

Although DNA methylation patterns tended to be more similar for identical twins, “we were very surprised by the range” of differences, said Craig, “The distribution of monozygotic twins overlapped unrelated newborns, and some twins were more different than unrelated pairs.

The scientists also found that identical twins that shared a placenta—arguably coming as close as possible to sharing similar environments—had epigenetic patterns that differed more than identical twins that didn’t share a placenta, but did share a uterus. This finding highlights “that sharing the same intrauterine environment does not contribute to having more similar DNA methylation patterns,” Esteban Ballestar, who studies the epigenetics of disease at the University of Barcelona, wrote in an email. “Their results would rather suggest that stochastic events could be more relevant in establishing differences between DNA methylation patterns in individuals,” added Ballestar, who was not involved in the work.

Thus, it seems that random changes and environmental factors together influence epigenetic patterns more than twins’ shared genetics. Indeed, when Craig and his colleagues statistically examined how much genetics, environmental factors, and random chance contributed to epigenetic methylation patterns, they found that slight differences in shared intrauterine environments, such as placenta size or where the umbilical cord attaches, and random changes accounted for more of the variance in epigenetic patterns than the underlying DNA sequence.  As the children aged, their methylation patterns didn’t continue to diverge, however, suggesting that environmental signals  may have less of an influence on epigenetics later in life—a finding that contradicts some earlier studies.

Knowing that low birth weight has been linked to later ill health, the scientists looked more closely at the genes showing differing patterns of methylation. They found that discordantly methylated genes in sets of twins with differing birth weights were often genes encoding proteins involved in metabolism and growth, which suggests to Craig that these pathways can be “nudged” off track early by deleterious patterns of methylation even before birth.

“It’s still a very pilot experiment,” noted Arturas Petronis at the University of Toronto, who pointed out that the 27,000 sites the researchers examined represent only about 0.1 percent of possible methylation sites in the genome. More comprehensive studies will determine how well these findings apply to the whole genome, said Petronis, who did not participate in the study.

In the meantime, Craig and his colleagues are hoping to discover what subtle environmental differences within the uterus can prompt such large epigenetic differences in twins. Placement of the umbilical cord, which can regulate the number nutrients passed from mom to her babies, and even what route they take, could play a role, Craig hypothesized. More importantly, he added, if scientists can identify early epigenetic markers of disease, it may be possible to proactively use epigenetic drugs, such as those already in cancer trials, to “nudge” their methylation patterns back on a healthy track.

L. Gordon, et al., “Neonatal DNA methylation profile in human twins is specified by a complex interplay between intrauterine environmental and genetic factors, subject to tissue-specific influence,” Genome Research, doi: 10.1101/gr.136598.111, 2012.

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Comments

Avatar of: N K Mishra

N K Mishra

Posts: 1457

July 17, 2012

This aspect has been overlooked in case of monozygotic twins. The fact that there can be differential methylation in them leading to certain differences need to be stressed. The use of epigenetic drugs to alter methylation pattern in them might usher a new chapter in the treatment of certain diseases.

Avatar of: James Kohl

James Kohl

Posts: 53

July 17, 2012

In the "Molecular epigenetics" section of our 1996 Hormones and Behavior paper we detailed what was known about genomic or parental imprinting and linked it to sexual differentiation of the brain as well as to differences in sexual orientation. We now see evidence that the epigenetic effects of chemical exchange in placental mammals alters  in utero stochastic changes in twins. These changes must be driven by receptor-mediated events that alter genetically predisposed intracellular signalling and result in differences in gene expression in monozygotic twins. Should we expect to see any mention of why the molecular epigenetic link to sexual orientation that varies in monozygotic twins has been ignored, or expect it to continue to be ignored?
Isn't it important to understand the epigenetics of sexual differentiation, since many disease processes are unequally represented in males and females? See, for example, From fertilization to adult sexual behavior: http://www.ncbi.nlm.nih.gov/pu...

Avatar of: funnythat

funnythat

Posts: 2

July 17, 2012

My understanding is that there is now some reservation about the precise role of DNA methylation in gene regulation. So the rather stochastic patterns of DNA methylation observed may not have huge significance for the expression of the genetic material. It would be important to correlate these findings with transcriptomics studies.

Avatar of: JohnDoe45698765

JohnDoe45698765

Posts: 7

July 21, 2012

Unfortunately, the researchers make a major error by assuming that monozygotic twins that share the same umbilicus are in fact treated the same in utero.  It is well known that monoamniotic-monoamniotic twins have a higher incidence of twin to twin transfusion syndrome when compared to monochorionic-diamniotic.  Dichorionic-diamniotic twins generally do not suffer from twin-to-twin-transfusion syndrome.
This clearly illustrates that sharing a placenta is not "arguably coming as close as possible to sharing similar environments" as one fetus usually gets "the lions share" of nutrients, oxygen and even toxins than the other.  I would be willing to bet that a study of twins that have twin-to-twin-transfusion syndrome would show even greater epigenetic differences than normal identical twins.

Avatar of: JohnDoe45698765

JohnDoe45698765

Posts: 7

July 21, 2012

Unfortunately, the researchers make a major error by assuming that monozygotic twins that share the same umbilicus are in fact treated the same in utero. It is well known that monoamniotic-monoamniotic twins have a higher incidence of twin to twin transfusion syndrome when compared to monochorionic-diamniotic. Dichorionic-diamniotic twins generally do not suffer from twin-to-twin-transfusion syndrome.
This clearly illustrates that sharing a placenta is not "arguably coming as close as possible to sharing similar environments" as one fetus usually gets "the lions share" of nutrients, oxygen and even toxins than the other. I would be willing to bet that a study of twins that have twin-to-twin-transfusion syndrome would show even greater epigenetic differences than normal identical twins.

Avatar of: JohnDoe45698765

JohnDoe45698765

Posts: 7

July 21, 2012

Unfortunately, the researchers make a major error by assuming that monozygotic twins that share the same umbilicus are in fact treated the same in utero. It is well known that monoamniotic-monoamniotic twins have a higher incidence of twin to twin transfusion syndrome when compared to monochorionic-diamniotic. Dichorionic-diamniotic twins generally do not suffer from twin-to-twin-transfusion syndrome.
This clearly illustrates that sharing a placenta is not "arguably coming as close as possible to sharing similar environments" as one fetus usually gets "the lions share" of nutrients, oxygen and even toxins than the other. I would be willing to bet that a study of twins that have twin-to-twin-transfusion syndrome would show even greater epigenetic differences than normal identical twins.

Avatar of: Gordon Robinson

Gordon Robinson

Posts: 1

July 24, 2012

This study provides a fascinating glimpse into the potential significance of epigenetics for shaping differences among individuals and may lead to a better understanding of the basis of "common" versus monogenic diseases.  If methylation patterns are strong predictors of transcriptional activity then this mechanism could help explain many of the "genetic" phenomena poorly explained by Mendelian genetics.  Unfortunately, epigenetic drugs currently available are unsuitable for engineering changes in an individual's methylation pattern because they are intrinsically untargeted and would likely lead to the introduction of as many "undesirable" changes as "desired" ones.  Thus, their use will probably be limited to patients suffering from life-threatening diseases.

Avatar of: James Kohl

James Kohl

Posts: 53

July 24, 2012

For contrast, the use of nutrient chemicals and pheromones that epigenetically effect differences in brain development in other mammals might be due more consideration. For example, by simple comparison with the epigenetic effects of endocrine disruptors on the development of the brain and behavior in other vertebrates, I can link to the biological core of mammalian reproduction (i.e., the diet-responsive hypothalamic gonadotropin releasing hormone (GnRH) neurogenic niche). The link to GnRH also includes one from a monogenic form of the disease: Kallmann's syndrome, which is also linked directly to the social environment, and to behavioral deficits associated with the mother-infant bond and many other developmental perturbations associated with anosmia. I have a detailed model for this -- based on the more speculative representation in our 1996 work. See for example: Human pheromones and food odors: epigenetic influences on the socioaffective nature of evolved behaviors http://dx.doi.org/10.3402/snp....

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