Marked methylation changes in intestinal genes during the perinatal period of preterm neonates

Gao, Fei; Zhang, Jie; Jiang, Pingping; Gong, Desheng; Wang, Junwen; Xia, Yudong; Østergaard, Morten; Wang, Jun; Sangild, Per Torp

doi:10.1186/1471-2164-15-716

Cited by 54 publications

(56 citation statements)

References 54 publications

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“…This finding supports the notion that pigs are a useful and stable biomedical model 12, 27 . In both pigs and humans, the hypothalamus-pituitary-ovary (HPO) axis is one of the key endocrine systems involved in the regulation of reproduction.…”

Section: Introductionsupporting

confidence: 89%

Genome-wide DNA methylation analysis of the porcine hypothalamus-pituitary-ovary axis

Yuan

Zhang

et al. 2017

Sci Rep

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Previous studies have suggested that DNA methylation in both CpG and CpH (where H = C, T or A) contexts plays a critical role in biological functions of different tissues. However, the genome-wide DNA methylation patterns of porcine hypothalamus-pituitary-ovary (HPO) tissues remain virtually unexplored. In this study, methylomes of HPO tissues were profiled to investigate their differences and similarities. We found that HPO methylomes displayed tissue-specific methylation patterns in both CpG and CpH contexts. At gene locations, the methylation and density of CpGs was negatively linked at transcription start sites but positively linked at transcription end sites. The densities of CpGs and CpHs at CpG island (CGI) locations were negatively correlated with their methylation. Moreover, the methylation interactions between CGIs and genes showed similar pattern in the CpG context but tissue-specific pattern in the CpH context. CpGs located in CGIs, upstream regions and exons were protected from methylation dynamics, whereas CGI shores, CGI shelves and intergenic regions were more likely to be targets of methylation changes. The methylation dynamics enriching in a tissue-specific manner appeared to maintain and establish the biological functions of HPO tissues. Our analyses provided valuable insights into the tissue-specific methylomes of porcine HPO tissues.

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Section: Introductionsupporting

confidence: 89%

Genome-wide DNA methylation analysis of the porcine hypothalamus-pituitary-ovary axis

Yuan

Zhang

et al. 2017

Sci Rep

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“…Our results show that the developmental expression of these enzymes is relatively independent of environmental factors, such as diet (which was the same for preterm and term pigs), and that intrinsic mechanisms related to ontogenetic age and genetic control could be more important. We recently documented that both preterm birth and enteral food introduction induce epigenetic effects on some immune-related genes in the immature pig intestine (19,53). It will be important to know whether preterm birth also induces epigenetic modifications to the sucrase-isomaltase and maltaseglucoamylase genes because this may help to explain why their corresponding enzyme activities were affected more long term whereas other gene functions tended to adapt more rapidly after preterm birth.…”

Section: Discussionmentioning

confidence: 99%

Rapid gut growth but persistent delay in digestive function in the postnatal period of preterm pigs

Hansen

Thymann

Andersen

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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Preterm infants often tolerate full enteral nutrition a few weeks after birth but it is not known how this is related to gut maturation. Using pigs as models, we hypothesized that intestinal structure and digestive function are similar in preterm and term individuals at 3-4 wk after birth and that early enteral nutrition promotes maturation. Preterm or term cesareandelivered pigs were fed total parenteral nutrition, or partial enteral nutrition [Enteral (Ent), 16 -64 ml·kg Ϫ1 ·day Ϫ1 of bovine colostrum] for 5 days, followed by full enteral milk feeding until day 26. The intestine was collected for histological and biochemical analyses at days 0, 5, and 26 (n ϭ 8 -12 in each of 10 treatment groups). Intestinal weight (relative to body weight) was reduced in preterm pigs at 0 -5 days but ENT feeding stimulated the mucosal volume and peptidase activities. Relative to term pigs, mucosal volume remained reduced in preterm pigs until 26 days although plasma glucagon-like peptide 2 (GLP-2) and glucose-dependent insulin-trophic peptide (GIP) levels were increased. Preterm pigs also showed reduced hexose absorptive capacity and brush-border enzyme (sucrase, maltase) activities at 26 days, relative to term pigs. Intestinal structure shows a remarkable growth adaptation in the first week after preterm birth, especially with enteral nutrition, whereas some digestive functions remain immature until at least 3-4 wk. It is important to identify feeding regimens that stimulate intestinal maturation in the postnatal period of preterm infants because some intestinal functions may show long-term developmental delay. prematurity; gut development; enzymes; digestion; glucagon-like peptide 2 ABOUT 10% OF ALL INFANTS are born preterm (Ͻ37 weeks of gestation) and the proportion is increasing in most countries (6). Preterm infants show an increased susceptibility to infections, respiratory distress syndrome, intracranial hemorrhage, bronchopulmonary dysplasia, retinopathy of prematurity, extrauterine growth restriction, neurodevelopmental disturbances, and necrotizing enterocolitis (NEC) (21, 31). The challenges are inversely related to gestational age at birth and the most severe adaptation problems occur during the first few weeks after birth. If preterm infants survive the difficult neonatal period, their body functions often adapt well, although some organ systems may show long-term developmental delay or deficits (18). It remains unknown how different organ systems adapt in preterm infants and when parameters of structure and function become similar to those in term infants. For gastrointestinal (GI) functions, eating disorders and dysregulated appetite have been reported in preterm infants (44) but very little is known about the long-term adaptation of the GI tract in preterm neonates.Investigations of postnatal GI adaptation in preterm neonates are difficult without an animal model that combines preterm birth, high NEC risk, and clinically relevant feeding interventions, such as parenteral and enteral nutrition. Piglets delivere...

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“…10,11 Relevant to preterm infants, at a molecular level, epigenetic processes constitute a major mechanism by which environmental factors may establish a new phenotypic trait during the plastic neonatal interval, 12,13 Recent studies have suggested that pre-and post-natal alterations to intestinal DNA methylation patterns contribute to high NEC susceptibility in preterm neonates. 14 An optimal early gut colonization may alter epigenetic signatures to establish inflammatory and barrier properties that protect against later insults that trigger NEC. It has also been shown that the epigenome of the host can be altered prior to exposure to early microbiota by gestational environmental exposures (e.g., nutrition, infection, drugs) or due to transgenerational inheritance.…”

Section: Introductionmentioning

confidence: 99%

Epigenome-Microbiome crosstalk: A potential new paradigm influencing neonatal susceptibility to disease

et al. 2016

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Preterm birth is the leading cause of infant morbidity and mortality. Necrotizing enterocolitis (NEC) is an inflammatory bowel disease affecting primarily premature infants, which can be lethal. Microbial intestinal colonization may alter epigenetic signatures of the immature gut establishing inflammatory and barrier properties predisposing to the development of NEC. We hypothesize that a crosstalk exists between the epigenome of the host and the initial intestinal colonizing microbiota at critical neonatal stages. By exposing immature enterocytes to probiotic and pathogenic bacteria, we showed over 200 regions of differential DNA modification, which were specific for each exposure. Reciprocally, using a mouse model of prenatal exposure to dexamethasone we demonstrated that antenatal treatment with glucocorticoids alters the epigenome of the host. We investigated the effects on the expression profiles of genes associated with inflammatory responses and intestinal barrier by qPCR-based gene expression array and verified the DNA modification changes in 5 candidate genes by quantitative methylation specific PCR (qMSP). Importantly, by 16S RNA sequencing-based phylogenetic analysis of intestinal bacteria in mice at 2 weeks of life, we showed that epigenome changes conditioned early microbiota colonization leading to differential bacterial colonization at different taxonomic levels. Our findings support a novel conceptual framework in which epigenetic changes induced by intrauterine influences affect early microbial colonization and intestinal development, which may alter disease susceptibility.

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Marked methylation changes in intestinal genes during the perinatal period of preterm neonates

Cited by 54 publications

References 54 publications

Genome-wide DNA methylation analysis of the porcine hypothalamus-pituitary-ovary axis

Genome-wide DNA methylation analysis of the porcine hypothalamus-pituitary-ovary axis

Rapid gut growth but persistent delay in digestive function in the postnatal period of preterm pigs

Epigenome-Microbiome crosstalk: A potential new paradigm influencing neonatal susceptibility to disease

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