title: DNA methylation restricts lineage-specific functions of transcription factor Gata4 during embryonic stem cell differentiation.
abstract: DNA methylation changes dynamically during development and is essential for embryogenesis in mammals. However, how DNA methylation affects developmental gene expression and cell differentiation remains elusive. During embryogenesis, many key transcription factors are used repeatedly, triggering different outcomes depending on the cell type and developmental stage. Here, we report that DNA methylation modulates transcription-factor output in the context of cell differentiation. Using a drug-inducible Gata4 system and a mouse embryonic stem (ES) cell model of mesoderm differentiation, we examined the cellular response to Gata4 in ES and mesoderm cells. The activation of Gata4 in ES cells is known to drive their differentiation to endoderm. We show that the differentiation of wild-type ES cells into mesoderm blocks their Gata4-induced endoderm differentiation, while mesoderm cells derived from ES cells that are deficient in the DNA methyltransferases Dnmt3a and Dnmt3b can retain their response to Gata4, allowing lineage conversion from mesoderm cells to endoderm. Transcriptome analysis of the cells' response to Gata4 over time revealed groups of endoderm and mesoderm developmental genes whose expression was induced by Gata4 only when DNA methylation was lost, suggesting that DNA methylation restricts the ability of these genes to respond to Gata4, rather than controlling their transcription per se. Gata4-binding-site profiles and DNA methylation analyses suggested that DNA methylation modulates the Gata4 response through diverse mechanisms. Our data indicate that epigenetic regulation by DNA methylation functions as a heritable safeguard to prevent transcription factors from activating inappropriate downstream genes, thereby contributing to the restriction of the differentiation potential of somatic cells.
authors.affiliation: Laboratory for Mammalian Epigenetic Studies, Center for Developmental Biology, RIKEN, Kobe, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Oda
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kumaki
authors.forename: Masaki
authors.initials: M
authors.lastname: Shigeta
authors.forename: Lars Martin
authors.initials: LM
authors.lastname: Jakt
authors.forename: Chisa
authors.initials: C
authors.lastname: Matsuoka
authors.forename: Akiko
authors.initials: A
authors.lastname: Yamagiwa
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Niwa
authors.forename: Masaki
authors.initials: M
authors.lastname: Okano
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D004707:Endoderm / Q000166:cytology / Q000254:growth & development; D044127:Epigenesis, Genetic; D050991:GATA4 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D017348:Microscopy, Electron, Scanning Transmission
chemical_list: D004268:DNA-Binding Proteins; C000715535:Dnmt3a protein, mouse; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A