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Developmental genes targeted for epigenetic variation between twin-twin transfusion syndrome children.

Marsit CJ, Koestler DC, Watson-Smith D, Boney CM, Padbury JF, Luks F - Clin Epigenetics (2013)

Bottom Line: The unequal flow results in reciprocal hypo- and hypervolemia in the affected twins, striking growth differences and physiologic adaptations in response to this significant stressor.This condition can now be effectively treated through the use of fetal laparoscopic procedures, but the potential for lifelong morbidity related to this condition during development is apparent.These preliminary results suggest that coordinated epigenetic alterations result from the intrauterine environment experienced by infants with TTTS and may, at least in part, be responsible for downstream health conditions experienced by individuals surviving this condition.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology and Toxicology, Geisel Medical School at Dartmouth, Hanover, NH 03755, USA. Carmen.j.marsit@dartmouth.edu.

ABSTRACT

Background: Epigenetic mechanisms are thought to be critical in mediating the role of the intrauterine environment on lifelong health and disease. Twin-twin transfusion syndrome (TTTS) is a rare condition wherein fetuses share the placenta and develop vascular anastomoses, which allow blood to flow between the fetuses. The unequal flow results in reciprocal hypo- and hypervolemia in the affected twins, striking growth differences and physiologic adaptations in response to this significant stressor. The donor twin in the TTTS syndrome can be profoundly growth restricted and there is likely a nutritional imbalance between the twins. The consequences of TTTS on fetal programming are unknown. This condition can now be effectively treated through the use of fetal laparoscopic procedures, but the potential for lifelong morbidity related to this condition during development is apparent. As this condition and the resulting uteroplacental discordance can play a role in the epigenetic process, we sought to investigate the DNA methylation profiles of childhood survivors of TTTS (n = 14). We focused on differences in both global measures and genome-wide CpG specific DNA methylation between donor and recipient children in this pilot study in order to generate hypotheses for further research.

Results: We identified significant hypomethylation of the LINE1 repetitive element in the peripheral blood of donor children and subtle variation in the genome-wide profiles of CpG specific methylation most prominent at CpG sites which are targets for polycomb group repressive complexes.

Conclusions: These preliminary results suggest that coordinated epigenetic alterations result from the intrauterine environment experienced by infants with TTTS and may, at least in part, be responsible for downstream health conditions experienced by individuals surviving this condition.

No MeSH data available.


Related in: MedlinePlus

Scatterplots of autosomal CpG loci DNA methylation relationships between individual donor and recipient twin pairs. Panels A-C each depict a twin pair in saliva with donor twins on the X-axes and recipient twins on the Y-axes, while Panels D-E depict twin pair comparisons of methylation in peripheral blood samples. The ages of the children at the time of sample collection are provided on each panel.
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Figure 3: Scatterplots of autosomal CpG loci DNA methylation relationships between individual donor and recipient twin pairs. Panels A-C each depict a twin pair in saliva with donor twins on the X-axes and recipient twins on the Y-axes, while Panels D-E depict twin pair comparisons of methylation in peripheral blood samples. The ages of the children at the time of sample collection are provided on each panel.

Mentions: Variation in the methylation at these loci could potentially be arising from other sources, and so we next examined the relationship between genome-wide methylation among the available twin pairs in the study, stratified by sample type. In this case, only ten samples, or five pairs, satisfied our stringent quality control criteria. Figure 3 depicts these individual comparisons, and again, saliva samples showed greater variation between donor and recipient individuals. Particularly, in saliva samples there appeared to be deviations from the diagonal with recipients showing greater methylation of loci whose methylation beta in donors is between 0.2 to 0.3 and lesser methylation of loci whose methylation beta in donors is between 0.7 to 0.9. In general, the blood samples showed less variability between donors and recipients, although in the comparison of the five month old twins’ blood samples, there appeared to be a number of variable loci at the lowest levels of methylation. In addition to the age of the child when the samples were obtained, the gestational age at which the fetal laser surgery was performed could also affect the variability in methylation between donors and recipients, considering that infants with earlier surgery may have a longer period to equalize their methylation patterns. We attempted to address this as well as the issue of age at sampling by examining the number of loci whose methylation beta differed between donor and recipient pair by greater than 0.2 or less than −0.2, which corresponds to greater than three standard deviations of the mean difference in saliva. The number of loci with these extreme changes is tabulated in Table 2. We then compared the subjects’ age when sampled, as well as their gestational age at fetal surgery. There was a trend for a greater number of highly differential loci among subjects with a later age at surgery and with increasing age at the time of sampling, with both correlations >0.85, although the sample sizes here limited formal examinations of inference, particularly for blood samples.


Developmental genes targeted for epigenetic variation between twin-twin transfusion syndrome children.

Marsit CJ, Koestler DC, Watson-Smith D, Boney CM, Padbury JF, Luks F - Clin Epigenetics (2013)

Scatterplots of autosomal CpG loci DNA methylation relationships between individual donor and recipient twin pairs. Panels A-C each depict a twin pair in saliva with donor twins on the X-axes and recipient twins on the Y-axes, while Panels D-E depict twin pair comparisons of methylation in peripheral blood samples. The ages of the children at the time of sample collection are provided on each panel.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016001&req=5

Figure 3: Scatterplots of autosomal CpG loci DNA methylation relationships between individual donor and recipient twin pairs. Panels A-C each depict a twin pair in saliva with donor twins on the X-axes and recipient twins on the Y-axes, while Panels D-E depict twin pair comparisons of methylation in peripheral blood samples. The ages of the children at the time of sample collection are provided on each panel.
Mentions: Variation in the methylation at these loci could potentially be arising from other sources, and so we next examined the relationship between genome-wide methylation among the available twin pairs in the study, stratified by sample type. In this case, only ten samples, or five pairs, satisfied our stringent quality control criteria. Figure 3 depicts these individual comparisons, and again, saliva samples showed greater variation between donor and recipient individuals. Particularly, in saliva samples there appeared to be deviations from the diagonal with recipients showing greater methylation of loci whose methylation beta in donors is between 0.2 to 0.3 and lesser methylation of loci whose methylation beta in donors is between 0.7 to 0.9. In general, the blood samples showed less variability between donors and recipients, although in the comparison of the five month old twins’ blood samples, there appeared to be a number of variable loci at the lowest levels of methylation. In addition to the age of the child when the samples were obtained, the gestational age at which the fetal laser surgery was performed could also affect the variability in methylation between donors and recipients, considering that infants with earlier surgery may have a longer period to equalize their methylation patterns. We attempted to address this as well as the issue of age at sampling by examining the number of loci whose methylation beta differed between donor and recipient pair by greater than 0.2 or less than −0.2, which corresponds to greater than three standard deviations of the mean difference in saliva. The number of loci with these extreme changes is tabulated in Table 2. We then compared the subjects’ age when sampled, as well as their gestational age at fetal surgery. There was a trend for a greater number of highly differential loci among subjects with a later age at surgery and with increasing age at the time of sampling, with both correlations >0.85, although the sample sizes here limited formal examinations of inference, particularly for blood samples.

Bottom Line: The unequal flow results in reciprocal hypo- and hypervolemia in the affected twins, striking growth differences and physiologic adaptations in response to this significant stressor.This condition can now be effectively treated through the use of fetal laparoscopic procedures, but the potential for lifelong morbidity related to this condition during development is apparent.These preliminary results suggest that coordinated epigenetic alterations result from the intrauterine environment experienced by infants with TTTS and may, at least in part, be responsible for downstream health conditions experienced by individuals surviving this condition.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology and Toxicology, Geisel Medical School at Dartmouth, Hanover, NH 03755, USA. Carmen.j.marsit@dartmouth.edu.

ABSTRACT

Background: Epigenetic mechanisms are thought to be critical in mediating the role of the intrauterine environment on lifelong health and disease. Twin-twin transfusion syndrome (TTTS) is a rare condition wherein fetuses share the placenta and develop vascular anastomoses, which allow blood to flow between the fetuses. The unequal flow results in reciprocal hypo- and hypervolemia in the affected twins, striking growth differences and physiologic adaptations in response to this significant stressor. The donor twin in the TTTS syndrome can be profoundly growth restricted and there is likely a nutritional imbalance between the twins. The consequences of TTTS on fetal programming are unknown. This condition can now be effectively treated through the use of fetal laparoscopic procedures, but the potential for lifelong morbidity related to this condition during development is apparent. As this condition and the resulting uteroplacental discordance can play a role in the epigenetic process, we sought to investigate the DNA methylation profiles of childhood survivors of TTTS (n = 14). We focused on differences in both global measures and genome-wide CpG specific DNA methylation between donor and recipient children in this pilot study in order to generate hypotheses for further research.

Results: We identified significant hypomethylation of the LINE1 repetitive element in the peripheral blood of donor children and subtle variation in the genome-wide profiles of CpG specific methylation most prominent at CpG sites which are targets for polycomb group repressive complexes.

Conclusions: These preliminary results suggest that coordinated epigenetic alterations result from the intrauterine environment experienced by infants with TTTS and may, at least in part, be responsible for downstream health conditions experienced by individuals surviving this condition.

No MeSH data available.


Related in: MedlinePlus