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Sexual dimorphism in epigenomic responses of stem cells to extreme fetal growth.

Delahaye F, Wijetunga NA, Heo HJ, Tozour JN, Zhao YM, Greally JM, Einstein FH - Nat Commun (2014)

Bottom Line: Extreme fetal growth is associated with increased susceptibility to a range of adult diseases through an unknown mechanism of cellular memory.We tested whether heritable epigenetic processes in long-lived CD34(+) haematopoietic stem/progenitor cells showed evidence for re-programming associated with the extremes of fetal growth.Here we show that both fetal growth restriction and over-growth are associated with global shifts towards DNA hypermethylation, targeting cis-regulatory elements in proximity to genes involved in glucose homeostasis and stem cell function.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics &Gynecology and Women's Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Block Building, Room 631, Bronx, New York 10461, USA.

ABSTRACT
Extreme fetal growth is associated with increased susceptibility to a range of adult diseases through an unknown mechanism of cellular memory. We tested whether heritable epigenetic processes in long-lived CD34(+) haematopoietic stem/progenitor cells showed evidence for re-programming associated with the extremes of fetal growth. Here we show that both fetal growth restriction and over-growth are associated with global shifts towards DNA hypermethylation, targeting cis-regulatory elements in proximity to genes involved in glucose homeostasis and stem cell function. We find a sexually dimorphic response; intrauterine growth restriction is associated with substantially greater epigenetic dysregulation in males, whereas large for gestational age growth predominantly affects females. The findings are consistent with extreme fetal growth interacting with variable fetal susceptibility to influence cellular ageing and metabolic characteristics through epigenetic mechanisms, potentially generating biomarkers that could identify infants at higher risk for chronic disease later in life.

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Sexual dimorphism in IUGR males and LGA females for differentially methylated lociThe lower panels show volcano plots of DNA methylation score differences, the upper panels quantify the densities of differentially methylated loci (p value<0.05 using ANOVA with pairwise two-tailed Tukey-tests, methylation difference >/20/). (a) IUGR compared with controls, (b) LGA compared with controls.
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Figure 2: Sexual dimorphism in IUGR males and LGA females for differentially methylated lociThe lower panels show volcano plots of DNA methylation score differences, the upper panels quantify the densities of differentially methylated loci (p value<0.05 using ANOVA with pairwise two-tailed Tukey-tests, methylation difference >/20/). (a) IUGR compared with controls, (b) LGA compared with controls.

Mentions: Sex-specific comparisons for DNA methylation patterns are shown between control and IUGR and LGA subjects (Fig. 2). Both IUGR males and females show a shift in DNA methylation profiles compared to controls, but the number of hypermethylated loci is markedly higher in males compared to females (Fig. 2a). Sex-specific differences are also seen in the comparison of LGA to controls, with LGA females showing an increase in the overall number of candidate differentially-methylated loci compared to males (Fig. 2b). These findings indicate a sexual dimorphism in the epigenetic responses of HSPCs to the extremes of growth conditions in utero.


Sexual dimorphism in epigenomic responses of stem cells to extreme fetal growth.

Delahaye F, Wijetunga NA, Heo HJ, Tozour JN, Zhao YM, Greally JM, Einstein FH - Nat Commun (2014)

Sexual dimorphism in IUGR males and LGA females for differentially methylated lociThe lower panels show volcano plots of DNA methylation score differences, the upper panels quantify the densities of differentially methylated loci (p value<0.05 using ANOVA with pairwise two-tailed Tukey-tests, methylation difference >/20/). (a) IUGR compared with controls, (b) LGA compared with controls.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4197137&req=5

Figure 2: Sexual dimorphism in IUGR males and LGA females for differentially methylated lociThe lower panels show volcano plots of DNA methylation score differences, the upper panels quantify the densities of differentially methylated loci (p value<0.05 using ANOVA with pairwise two-tailed Tukey-tests, methylation difference >/20/). (a) IUGR compared with controls, (b) LGA compared with controls.
Mentions: Sex-specific comparisons for DNA methylation patterns are shown between control and IUGR and LGA subjects (Fig. 2). Both IUGR males and females show a shift in DNA methylation profiles compared to controls, but the number of hypermethylated loci is markedly higher in males compared to females (Fig. 2a). Sex-specific differences are also seen in the comparison of LGA to controls, with LGA females showing an increase in the overall number of candidate differentially-methylated loci compared to males (Fig. 2b). These findings indicate a sexual dimorphism in the epigenetic responses of HSPCs to the extremes of growth conditions in utero.

Bottom Line: Extreme fetal growth is associated with increased susceptibility to a range of adult diseases through an unknown mechanism of cellular memory.We tested whether heritable epigenetic processes in long-lived CD34(+) haematopoietic stem/progenitor cells showed evidence for re-programming associated with the extremes of fetal growth.Here we show that both fetal growth restriction and over-growth are associated with global shifts towards DNA hypermethylation, targeting cis-regulatory elements in proximity to genes involved in glucose homeostasis and stem cell function.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics &Gynecology and Women's Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Block Building, Room 631, Bronx, New York 10461, USA.

ABSTRACT
Extreme fetal growth is associated with increased susceptibility to a range of adult diseases through an unknown mechanism of cellular memory. We tested whether heritable epigenetic processes in long-lived CD34(+) haematopoietic stem/progenitor cells showed evidence for re-programming associated with the extremes of fetal growth. Here we show that both fetal growth restriction and over-growth are associated with global shifts towards DNA hypermethylation, targeting cis-regulatory elements in proximity to genes involved in glucose homeostasis and stem cell function. We find a sexually dimorphic response; intrauterine growth restriction is associated with substantially greater epigenetic dysregulation in males, whereas large for gestational age growth predominantly affects females. The findings are consistent with extreme fetal growth interacting with variable fetal susceptibility to influence cellular ageing and metabolic characteristics through epigenetic mechanisms, potentially generating biomarkers that could identify infants at higher risk for chronic disease later in life.

Show MeSH
Related in: MedlinePlus