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Postnatal Development is Associated with Genome-scale Changes in DNA Methylation in Mouse Liver

ABSTRACT: DNA methylation marks are thought to be set up during early development and to remain static thereafter in healthy tissues. Here, we characterize the liver DNA methylation patterns of mice before birth, during early postnatal development (from birth until weaning) and in adulthood. Our analyses show extensive epigenetic reprogramming in the liver occurring during postnatal development. 118,877 of 261,317 CpGs analyzed throughout the genome significantly changed their methylation level by more than 5% from birth to nine weeks of age, with some changing by up to 86%. Interestingly, changes in DNA methylation occur primarily in intergenic enhancer regions while gene promoters seem little affected. Analysis of 166 CpGs at multiple time points by locus-specific bisulfite sequencing reveals that this reprogramming primarily occurs between postnatal day 1 and day 20. This time period coincides with two major cellular changes in the liver: the differentiation of hepatocytes and extensive cell division. While cell multiplication leaves a distinct footprint on the DNA methylation patterns, we show that the extensive epigenetic reprogramming likely results from differentiation of hepatoblasts into hepatocytes. Overall, our data suggest that epigenetic remodeling is an important aspect of normal liver maturation and involves a large number of gene enhancers.

ORGANISM(S): Mus musculus

PROVIDER: GSE79775 | GEO | 2017/02/08

SECONDARY ACCESSION(S): PRJNA316985

REPOSITORIES: GEO

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Project description:Background: Low birth weight is associated with an increased adult metabolic disease risk. It is widely discussed that poor intrauterine conditions could induce long-lasting epigenetic modifications, leading to systemic changes in regulation of metabolic genes. In a unique cohort of 17 monozygotic (MZ) monochorionic female twins very discordant for birth weight (relative differences ranging from 21.3-35.7%), we examined if adverse prenatal growth conditions experienced by the smaller co-twins lead to systemic long-lasting DNA methylation changes. Genome-wide DNA methylation profiles were acquired from saliva DNA using the Infinium HumanMethylation450 BeadChip, targeting ~2% of all CpGs in the genome. Results: Overall, co-twins showed very similar genome-wide DNA methylation profiles. Since observed differences were almost exclusively caused by variable cellular composition, an original marker-based adjustment strategy was developed to eliminate such variation at affected CpGs. Among adjusted and unchanged CpGs 3153 were differentially methylated between the heavy and light co-twins at nominal significance (p<0.01), of which 45 showed absolute mean β-value differences >0.05 (max=0.08). Deep bisulfite sequencing of eight such loci revealed that differences remained in the range of technical variation, arguing against a reproducible biological effect. Analysis of methylation in repetitive elements using methylation-dependent primer extension assays also indicated no significant intra-pair differences. Conclusions: Severe intrauterine growth differences observed within these MZ twins are not associated with long-lasting DNA methylation differences in cells composing saliva, detectable with up-to-date technologies. Additionally, our results indicate that uneven cell type composition can lead to spurious results and should be addressed in epigenomic studies. DNA methylation profiles of saliva from 17 Adult Female MZ MC Twins discordant for birth weight.

Project description:Age-related changes in DNA methylation occurring in blood leukocytes during early childhood may reflect epigenetic maturation. We hypothesized that some of these changes involve gene networks of critical relevance in leukocyte biology and conducted a prospective study to elucidate the dynamics of DNA methylation. Serial blood samples were collected at 3, 6, 12, 24, 36, 48 and 60 months after birth in 10 healthy girls born in Finland and participating in the Type 1 Diabetes Prediction and Prevention Study. DNA methylation was measured using the HumanMethylation450 BeadChip. After filtering for the presence of polymorphisms and cell-lineage-specific signatures, 794 CpGs showed significant DNA methylation differences as a function of age in all children (41.5% age-methylated and 58.4% age-demethylated, bonferroni corrected p-value <0.001). Age-methylated CpGs were more frequently located in gene bodies and within +5 to +50 kilobases (kb) of transcription start sites (TSS), and enriched in developmental, neuronal and plasma membrane genes. Age-demethylated CpGs were associated to promoters and DNAse-I hypersensitivity sites, located within -5 to +5 kb of the nearest TSS, and enriched in genes related to immunity, antigen presentation, the polycomb-group protein complex and cytoplasm. This study reveals that susceptibility loci for complex inflammatory diseases (e.g. IRF5, NOD2, PTGER4) and genes encoding histone modifiers and chromatin remodeling factors (e.g. HDAC4, KDM2A, KDM2B, JARID2, ARID3A, SMARCD3) undergo DNA methylation changes in leukocytes during early childhood. These results open new perspectives to understand leukocyte maturation and provide a catalog of CpGs that may need to be corrected for age effects when performing DNA methylation studies in children. We analysed the longitudinal changes in DNA methylation in a total of 60 samples at 3, 6, 12, 24, 36, 48, and 60 months after birth, using serial DNA samples extracted from peripheral blood leukocytes of 10 healthy girls of the Diabetes Prediction and Prevention Study (DIPP).

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Postnatal Development is Associated with Genome-scale Changes in DNA Methylation in Mouse Liver

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