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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.

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

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