Postnatal DNA demethylation and its role in tissue maturation

• Published in: Nature communications Vol. 9; no. 1; pp. 2040 - 11
• Main Authors: Reizel, Yitzhak, Sabag, Ofra, Skversky, Yael, Spiro, Adam, Steinberg, Benjamin, Bernstein, Diana, Wang, Amber, Kieckhaefer, Julia, Li, Catherine, Pikarsky, Eli, Levin-Klein, Rena, Goren, Alon, Rajewsky, Klaus, Kaestner, Klaus H., Cedar, Howard
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.05.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/31; 38/15; 38/22; 38/23; 38/39; 38/91; 45; 5-Methylcytosine - metabolism; 631/337/176; 631/337/572/2102; Animals; Animals, Newborn; Cells, Cultured; Chromatin; Cytosine; Demethylation; Deoxyribonucleic acid; Dioxygenases; DNA; DNA Demethylation; DNA-Binding Proteins - genetics; Epigenesis, Genetic - physiology; Epigenetics; Female; Gene expression; Gene Expression Regulation, Developmental - physiology; Gene sequencing; Hepatocytes - metabolism; High-Throughput Nucleotide Sequencing; Humanities and Social Sciences; Liver; Liver - cytology; Liver - growth & development; Male; Maturation; Methylation; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular chains; multidisciplinary; Phenotypes; Primary Cell Culture; Proto-Oncogene Proteins - genetics; Science; Science (multidisciplinary); Sequence Analysis, RNA; Signal Transduction - physiology; Transcription activation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-04456-6

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. Here the authors show that a large fraction of the tissue-specific methylation pattern is generated postnatally. These changes, which occur in response to hormone signaling, appear to play a major role in the regulation of gene expression and tissue maturation in the liver.