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

Delahaye, Fabien; Wijetunga, N. Ari; Heo, Hye; Tozour, Jessica N.; Zhao, Yong; Greally, John M.; Einstein, Francine

doi:10.1101/008482

Cited by 4 publications

(21 citation statements)

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“…Interestingly, a sexual dimorphic effect was observed in which the number of hypermethylated loci was markedly higher in IUGR male infants and LGA female infants [10]. Furthermore, methylation differences were found in genes belonging to pathways for MODY and hedgehog (HH) signalling, both of which are associated with premature glucose intolerance, type 2 diabetes and stem cell proliferation/ renewal [10]. These studies highlight the potential role of dysregulated DNA methylation in key metabolic pathways in metabolic disease susceptibility.…”

Section: Introductionmentioning

confidence: 87%

“…Other studies have shown distinct methylation patterns in haematopoietic CD34 + stem cells purified from cord blood of infants exposed to IUGR (referred to as 'IUGR infants') as well as those who were large for gestational age (LGA), when compared with infants who were appropriate for gestational age (AGA). Interestingly, a sexual dimorphic effect was observed in which the number of hypermethylated loci was markedly higher in IUGR male infants and LGA female infants [10]. Furthermore, methylation differences were found in genes belonging to pathways for MODY and hedgehog (HH) signalling, both of which are associated with premature glucose intolerance, type 2 diabetes and stem cell proliferation/ renewal [10].…”

Section: Introductionmentioning

confidence: 96%

“…Functional enrichment analysis The Bioconductor package GoSeq [28] was adapted to control for bias associated with the variation in the number of HpaII sites associated with different genes as previously described [10]. The candidate DML were assigned to genes only if they overlapped with candidate promoters within ±2 kb (features 1 and 3) or candidate enhancers within ±5 kb (features 0 and 6), features with a greater likelihood of having functional consequences.…”

Section: Methodsmentioning

confidence: 99%

“…Annotation involved processing the raw data for chromatin accessibility (DNAse hypersensitivity) along with ChIP-seq data for six histone modifications (H3K4me1, H3K27me3, H3K27ac, H3K4me3, H3K36me3 and H3K9me3), followed by use of the Segway algorithm [27] to predict seven features as previously described [10]. Annotation was generated by analysing enrichment of each feature for the different chromatin tracks with a one-way proportion test performed with continuity correction of the observed vs expected proportion.…”

Section: Methodsmentioning

confidence: 99%

“…CD3 + T cells are metabolically relevant cells due to their role in inflammatory responses and represent a relatively homogenous population composed of terminally differentiated CD4 + and CD8 + cells [19]. We elected to study male IUGR infants based on our previous studies demonstrating greater methylation changes in CD34 + haematopoietic stem cells from IUGR male infants compared with female infants [10]. By identifying DML in CD3 + T cells associated with IUGR using a genome-wide approach, we identify potential functional targets that may be related to inflammatory changes seen in metabolic disease pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

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DNA hypermethylation of CD3+ T cells from cord blood of infants exposed to intrauterine growth restriction

et al. 2016

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Aims/hypothesis Intrauterine growth restriction (IUGR) is associated with increased susceptibility to obesity, metabolic syndrome and type 2 diabetes. Although the mechanisms underlying the developmental origins of metabolic disease are poorly understood, evidence suggests that epigenomic alterations play a critical role. We sought to identify changes in DNA methylation patterns that are associated with IUGR in CD3 + T cells purified from umbilical cord blood obtained from male newborns who were appropriate for gestational age (AGA) or who had been exposed to IUGR. Methods CD3 + T cells were isolated from cord blood obtained from IUGR and AGA infants. The genome-wide methylation profile in eight AGA and seven IUGR samples was determined using the HELP tagging assay. Validation analysis using targeted bisulfite sequencing and bisulfite massARRAY was performed on the original cohort as well as biological replicates consisting of two AGA and four IUGR infants. The Segway algorithm was used to identify methylation changes within regulatory regions of the genome. Results A global shift towards hypermethylation in IUGR was seen compared with AGA (89.8% of 4,425 differentially methylated loci), targeted to regulatory regions of the genome, specifically promoters and enhancers. Pathway analysis identified dysregulation of pathways involved in metabolic disease (type 2 diabetes mellitus, insulin signalling, mitogen-activated protein kinase signalling) and T cell development, regulation and activation (T cell receptor signalling), as well as transcription factors (TCF3, LEF1 and NFATC) that regulate T cells. Furthermore, bump-hunting analysis revealed differentially methylated regions in PRDM16 and HLA-DPB1, genes important for adipose tissue differentiation, stem cell maintenance and function and T cell activation. Conclusions/interpretation Our findings suggest that the alterations in methylation patterns observed in IUGR CD3 + T cells may have functional consequences in targeted genes, regulatory regions and transcription factors. These may serve as biomarkers to identify those at 'high risk' for diminished attainment of full health potential who can benefit from early interventions.

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Section: Introductionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 96%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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DNA hypermethylation of CD3+ T cells from cord blood of infants exposed to intrauterine growth restriction

et al. 2016

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Offspring from maternal nutrient restriction in mice show variations in adult glucose metabolism similar to human fetal growth restriction

Radford

Han

2018

J Dev Orig Health Dis

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Fetal growth restriction (FGR) is a pregnancy condition in which fetal growth is suboptimal for gestation, and this population is at increased risk for type 2 diabetes as adults. In humans, maternal malnutrition and placental insufficiency are the most common causes of FGR, and both result in fetal undernutrition. We hypothesized that maternal nutrient restriction (MNR) in mice will cause FGR and alter glucose metabolism in adult offspring. Pregnant CD-1 mice were subjected to MNR (70% of average ad libitum) or control (ad libitum) from E6.5 to birth. Following birth, mice were fostered by mothers on ad libitum feeds. Weight, blood glucose, glucose tolerance and tissue-specific insulin sensitivity were assessed in male offspring. MNR resulted in reduced fetal sizes but caught up to controls by 3 days postnatal age. As adults, glucose intolerance was detected in 19% of male MNR offspring. At 6 months, liver size was reduced (P = 0.01), but pAkt-to-Akt ratios in response to insulin were increased 2.5-fold relative to controls (P = 0.004). These data suggest that MNR causes FGR and long-term glucose intolerance in a population of male offspring similar to human populations. This mouse model can be used to investigate the impacts of FGR on tissues of importance in glucose metabolism.

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Intrauterine Hyperglycemia Is Associated with an Impaired Postnatal Response to Oxidative Damage

Tozour

Delahaye

Suzuki

et al. 2018

Stem Cells and Development

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Hyperglycemia and other adverse exposures early in life that reprogram stem cells may lead to long-lasting phenotypic influences over the lifetime of an individual. Hyperglycemia and oxidative stress cause DNA damage when they exceed the protective capabilities of the cell, in turn affecting cellular function. DNA damage in response to hyperglycemia and oxidative stress was studied in human umbilical cord mesenchymal stem cells (hUC-MSCs) from large-for-gestational-age (LGA) infants of mothers with gestational diabetes mellitus (LGA-GDM) and control subjects. We tested the response of these cells to hyperglycemia and oxidative stress, measuring reactive oxygen species (ROS) levels and antioxidant enzyme activities. We find that hUC-MSCs from LGA-GDM infants have increased DNA damage when exposed to oxidative stress. With the addition of hyperglycemic conditions, these cells have an increase in ROS and a decrease in antioxidant glutathione peroxidase (GPx) activity, indicating a mechanism for the increased ROS and DNA damage. This study demonstrates that a memory of in utero hyperglycemia, mediated through downregulation of GPx activity, leads to an increased susceptibility to oxidative stress. The alteration of GPx function in self-renewing stem cells, can mediate the effect of intrauterine hyperglycemia to be propagated into adulthood and contribute to disease susceptibility.

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

Cited by 4 publications

References 68 publications

DNA hypermethylation of CD3+ T cells from cord blood of infants exposed to intrauterine growth restriction

DNA hypermethylation of CD3+ T cells from cord blood of infants exposed to intrauterine growth restriction

Offspring from maternal nutrient restriction in mice show variations in adult glucose metabolism similar to human fetal growth restriction

Intrauterine Hyperglycemia Is Associated with an Impaired Postnatal Response to Oxidative Damage

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