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Genome-wide DNA methylation analysis in jejunum of Sus scrofa with intrauterine growth restriction.

ABSTRACT: Intrauterine growth restriction (IUGR) may elicit a series of postnatal body developmental and metabolic diseases due to their impaired growth and development in the mammalian embryo/fetus during pregnancy. In the present study, we hypothesized that IUGR may lead to abnormally regulated DNA methylation in the intestine, causing intestinal dysfunctions. We applied reduced representation bisulfite sequencing (RRBS) technology to study the jejunum tissues from four newborn IUGR piglets and their normal body weight (NBW) littermates. The results revealed extensively regional DNA methylation changes between IUGR/NBW pairs from different gilts, affecting dozens of genes. Hiseq-based bisulfite sequencing PCR (Hiseq-BSP) was used for validations of 19 genes with epigenetic abnormality, confirming three genes (AIFM1, MTMR1, and TWIST2) in extra samples. Furthermore, integrated analysis of these 19 genes with proteome data indicated that there were three main genes (BCAP31, IRAK1, and AIFM1) interacting with important immunity- or metabolism-related proteins, which could explain the potential intestinal dysfunctions of IUGR piglets. We conclude that IUGR can lead to disparate DNA methylation in the intestine and these changes may affect several important biological processes such as cell apoptosis, cell differentiation, and immunity, which provides more clues linking IUGR and its long-term complications.

SUBMITTER: Hu Y

PROVIDER: S-EPMC6061055 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Project description:Intrauterine growth restriction (IUGR), which refers to reduced fetal growth in the context of placental insufficiency, is etiologically heterogeneous. IUGR is associated not only with perinatal morbidity and mortality but also with adult-onset disorders, such as cardiovascular disease and diabetes, posing a major health burden. Placental epigenetic dysregulation has been proposed as one mechanism that causes IUGR; however, the spectrum of epigenetic pathophysiological mechanisms leading to IUGR remains to be elucidated. Monozygotic monochorionic twins are particularly affected by IUGR, in the setting of severe discordant growth. Because monozygotic twins have the same genotype at conception and a shared maternal environment, they provide an ideal model system for studying epigenetic dysregulation of the placenta.We compared genome-wide placental DNA methylation patterns of severely growth-discordant twins to identify novel candidate genes for IUGR. Snap-frozen placental samples for eight severely growth-discordant monozygotic monochorionic twin pairs were obtained at delivery from each twin. A high-resolution DNA methylation array platform was used to identify methylation differences between IUGR and normal twins. Our analysis revealed differentially methylated regions in the promoters of eight genes: DECR1, ZNF300, DNAJA4, CCL28, LEPR, HSPA1A/L, GSTO1, and GNE. The largest methylation differences between the two groups were in the promoters of DECR1 and ZNF300. The significance of these group differences was independently validated by bisulfite pyrosequencing, implicating aberrations in fatty acid beta oxidation and transcriptional regulation, respectively. Further analysis of the array data identified methylation changes most prominently affecting the Wnt and cadherin pathways in the IUGR cohort.Our results suggest that IUGR in monozygotic twins is associated with impairments in lipid metabolism and transcriptional regulation as well as cadherin and Wnt signaling. We show that monozygotic monochorionic twins discordant for growth provide a useful model to study one type of the epigenetic placental dysregulation that drives IUGR.

Project description:Paratuberculosis in cattle causes substantial economic losses to the dairy industry. Exploring functional genes and corresponding regulatory pathways related to resistance or susceptibility to paratuberculosis is essential to the breeding of disease resistance in cattle. Co-analysis of genome-wide DNA methylation and transcriptome profiles is a critically important approach to understand potential regulatory mechanism underlying the development of diseases. In this study, we characterized the profiles of DNA methylation of jejunum from nine Holstein cows in clinical, subclinical, and healthy groups using whole-genome bisulfite sequencing (WGBS). The average methylation level in functional regions was 29.95% in the promoter, 29.65% in the 5' untranslated region (UTR), 68.24% in exons, 71.55% in introns, and 72.81% in the 3' UTR. A total of 3,911, 4,336, and 4,094 differentially methylated genes (DMGs) were detected in clinical vs. subclinical, clinical vs. healthy, and subclinical vs. healthy comparative group, respectively. Gene ontology (GO) and analysis based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that these DMGs were significantly enriched in specific biological processes related to immune response, such as Th1 and Th2 cell differentiation, wnt, TNF, MAPK, ECM-receptor interaction, cellular senescence, calcium, and chemokine signaling pathways (q value <0.05). The integration of information about DMGs, differentially expressed genes (DEGs), and biological functions suggested nine genes CALCRL, TNC, GATA4, CD44, TGM3, CXCL9, CXCL10, PPARG, and NFATC1 as promising candidates related to resistance/susceptibility to Mycobacterium avium subspecies paratuberculosis (MAP). This study reports on the high-resolution DNA methylation landscapes of the jejunum methylome across three conditions (clinical, subclinical, and healthy) in dairy cows. Our investigations integrated different sources of information about DMGs, DEGs, and pathways, enabling us to find nine functional genes that might have potential application in resisting paratuberculosis in dairy cattle.

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Genome-wide DNA methylation analysis in jejunum of Sus scrofa with intrauterine growth restriction.

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