Abstract
Development in mammals is accompanied by specific de novo and demethylation events that are thought to stabilize differentiated cell phenotypes. We demonstrate that a large percentage of the tissue-specific methylation pattern is generated postnatally. Demethylation in the liver is observed in thousands of enhancer-like sequences associated with genes that undergo activation during the first few weeks of life. Using a conditional gene ablation strategy we show that the removal of these methyl groups is stable and necessary for assuring proper hepatocyte gene expression and function through its effect on chromatin accessibility. These postnatal changes in methylation come about through exposure to hormone signaling. These results define the molecular rules of 5-methyl-cytosine regulation as an epigenetic mechanism underlying cellular responses to a changing environment.
Highlights
Development in mammals is accompanied by specific de novo and demethylation events that are thought to stabilize differentiated cell phenotypes
DNA methylation patterns are established during mammalian embryogenesis through a programmed process that involves both de novo and demethylation events
It is generally believed that the DNA methylation patterns established during development do not undergo further alterations, but recent studies indicate that methylation changes may occur postnatally in terminally differentiated tissues
Summary
Development in mammals is accompanied by specific de novo and demethylation events that are thought to stabilize differentiated cell phenotypes. All subsequent changes in DNA methylation appear to be gene specific, with pluripotency genes, for example, becoming de novo methylated at the time of gastrulation[2,3], while tissue-specific regulatory regions undergo demethylation during embryonic development[4,5] or during adult stem cell differentiation[6]. It is generally believed that the DNA methylation patterns established during development do not undergo further alterations, but recent studies indicate that methylation changes may occur postnatally in terminally differentiated tissues This has been observed, for example, in cardiomyocytes where many gene regions become hypomethylated or hypermethylated during heart muscle maturation[7] and stable programmed demethylation of defined regulatory sites occurs postnatally in the mammary tissue following pregnancy[8] as well as in the liver[9,10], where some of these events are mediated by the secretion of testosterone[11]. By employing genetic intervention, we show that these methylation changes play a role in the process
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