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Study on the consequences of prenatal famine exposure on DNA methylation.

ABSTRACT: The potential of the epigenome to undergo environmentally-induced changes during early development is central to its postulated role in human disease. Here, we report a genome-scale view of DNA methylation differences after early gestational malnutrition that was caused by the Dutch Hunger Winter, a severe famine at the end of World War II. We adopted an annotation guided analysis of reduced-representation bisulfite sequencing data generated in 24 middle-aged individuals who had been exposed to famine in utero and 24 unexposed sibling controls. We observed differential DNA methylation primarily at genomic regions with regulatory potential, including enhancers active during early development. In-depth annotation of 181 prenatally-induced differentially methylated regions (P-DMRs) showed that they were predominantly located in gene bodies and co-occurred with histone marks denoting an active state. In line with the early gestational timing of the exposure, the P-DMRs mapped to genes that were enriched for differential expression patterns during blastocyst development and early organogenesis. Validation and further explorative analyses of 6 P-DMRs mapping to SMAD7, CDH23, INSR, RFTN1, CPT1A and KLF13 highlighted the critical role of gestational timing, indicated that differential methylation extended along pathways involved in growth, development and metabolism, and suggested associations with birth weight and serum LDL cholesterol in adulthood and confirmed an enhancer function for the INSR and CPT1A P-DMRs. Our results point toward a link between prenatal malnutrition and epigenetic modulation of growth and lipid metabolism that may underlie the adverse metabolic phenotype of exposed individuals in later life.

PROVIDER: EGAS00001000668 | EGA |

REPOSITORIES: EGA

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Project description:[Background] DNA methylation plays a crucial role in regulating cell proliferation, differentiation, gene expression, and embryonic development. However, the comprehensive changes in genome-wide DNA methylation during early pregnancy in sows remain unknown. This study aimed to investigate the DNA methylation profiles and to construct an early gene pool of sows during early gestation.[Results] In this investigation, we utilized blood samples from 20 healthy sows and applied Reduced Representation Bisulfite Sequencing (RBSS) technology to systematically examine alterations in DNA methylation in sow blood during early pregnancy. Screening and validating the Methylation differential genes by using bisulfite sequencing PCR (BSP) and Quantitative Real-time PCR (RT-qPCR). Our findings indicated a significant increase in methylation levels on day 28 of pregnancy (pre28) compared to non-pregnancy (ctrl) across various gene elements, including CGI, promoter, and genebody. A total of 64,908 differentially methylated sites (DMCs) and 12,119 differentially methylated regions (DMRs) were identified, predominantly exhibiting methylation upregulation. Randomly selected five differentially methylated genes—VBP1, UPRT (upregulated methylation), RPL10, RAB33A, and CD93 (downregulated methylation)—were validated. Between the pregnant (pre28) and non-pregnant (ctrl) groups the BSP results showed highly significant methylation differences (P<0.01) in VBP1, UPRT, RPL10, and RAB33A. DMC gene ontology (GO) analysis revealed significant enrichment in nuclear receptor activity, negative regulation of cysteine-type endopeptidase activity during apoptosis, heme binding, and hormonal activity. DMRs GO analysis highlighted significant enrichment in 1-acylglycerol-3-phosphate O-acyltransferase activity, regulation of transforming growth factor β receptor signaling pathway, mitochondrial outer membrane and myotubular cell development, and cellular calcium homeostasis. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated significant enrichment in the MAPK signaling pathway and the PI3K-Akt signaling pathway.[Conclusion] During sow early gestation, DNA methylation is significant changes and is mainly upregulated. The observed upregulation of DNA methylation during early gestation in sows may regulate the MAPK and PI3K-Akt signaling pathways, potentially influencing embryonic development. Methylated differential genes VBP1 and RPL10 can be used as potential markers for early sow pregnancy diagnosis. These findings offer novel insights into the epigenetic changes occurring in sows during early gestation.

Project description:To further our understanding of the role of DNA methylation in development, Methylated DNA Immunoprecipitation (MeDIP) was used in conjunction with a NimbleGen promoter plus CpG island array to identify Tissue and Developmental Stage specific Differentially Methylated DNA Regions (T-DMRs and DS-DMRs) on a genome-wide basis. Four tissues (brain, heart, liver, and testis) from C57BL/6J mice were analyzed at three developmental stages (15 day embryo, E15; new born, NB; 12 week adult, AD). Almost 5,000 adult T-DMRs and 10,000 DS-DMRs were identified. Surprisingly, almost all DS-DMRs were tissue specific (i.e., methylated and ummenthylated in one or more non-overlapping tissues), indicating that the vast majority of unique sequence DNA methylation has tissue specificity. Also, many DS-DMRs were methylated at early development stages (E15 and NB) but unmethylated in adult, indicating “demethylation” has a prominent role in tissue differentiation. The pattern of DNA methylation in adult testis was dramatically different from somatic tissues in many aspects, mostly notably with a very strong bias of methylation in non-CpGi (CpG island) promoter regions (94%). Although the majority of T-DMRs and DS-DMRs tended to be in non-CpGi promoter regions, a relatively large number were also located in CpGi in promoter, intra-genic and inter-genic regions (>15% of all CpGi). Gene Ontology analysis of genes with methylation in non-CpGi promoters indicates enrichment of genes related to membrane proteins and G-protein coupled receptors. Our data also suggest regulatory roles of DNA methylation outside of promoter regions and in alternative promoter selection. Overall, our studies indicate that change in DNA methylation during development is a dynamic, widespread and tissue-specific process involving both DNA methylation and demethylation. Comparison of DNA methylation across 3 developmental stages (15 day embryo, newborn, and adult) for four tissues (brain, heart, liver and testis)

Project description:Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex heritability and higher prevalence in males. The neonatal epigenome has the potential to reflect past interactions between genetic and environmental factors during early development and influence future health outcomes. We performed whole-genome bisulfite sequencing of 152 umbilical cord blood samples from the MARBLES and EARLI high-familial risk prospective cohorts to identify an epigenomic signature of ASD at birth. Samples were split into discovery and replication sets and stratified by sex, and their DNA methylation profiles were tested for differentially methylated regions (DMRs) between ASD and typically developing control cord blood samples. DMRs were mapped to genes and assessed for enrichment in gene function, tissue expression, chromosome location, and overlap with prior ASD studies. DMR coordinates were tested for enrichment in chromatin states and transcription factor binding motifs. Results were compared between discovery and replication sets and between males and females. We identified DMRs stratified by sex that discriminated ASD from control cord blood samples in discovery and replication sets. At a region level, 7 DMRs in males and 31 DMRs in females replicated across two independent groups of subjects, while 537 DMR genes in males and 1762 DMR genes in females replicated by gene association. These DMR genes were significantly enriched for brain and embryonic expression, X chromosome location, and identification in prior epigenetic studies of ASD in post-mortem brain. In males and females, autosomal ASD DMRs were significantly enriched for promoter and bivalent chromatin states across most cell types, while sex differences were observed for X-linked ASD DMRs. Lastly, these DMRs identified in cord blood were significantly enriched for binding sites of methyl-sensitive transcription factors relevant to fetal brain development. At birth, prior to the diagnosis of ASD, a distinct DNA methylation signature was detected in cord blood over regulatory regions and genes relevant to early fetal neurodevelopment. Differential cord methylation in ASD supports the developmental and sex-biased etiology of ASD and provides novel insights for early diagnosis and therapy.

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Study on the consequences of prenatal famine exposure on DNA methylation.

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