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.
Highlights
Development is based on a series of cell-fate decisions and commitments
Animal bodies are constructed from many different specialized cell types that are generated during embryogenesis from a single fertilized egg, and acquire their specific characteristics through a series of differentiation steps
Genomic DNA methylation patterns in early embryonic cells are established in a cell-type-dependent manner, and these specific patterns are propagated through cell divisions in a clonal manner
Summary
Transcription factors and epigenetic mechanisms coordinately regulate these processes [1,2]. Transcription factors play dominant roles in instructing lineage determination and cell reprogramming [3,4]. Transcription factor and co-factor networks regulate cell-specific gene programs, allowing a given transcription factor to be used repeatedly in different cellular and developmental contexts [5]. Epigenetic mechanisms, which establish and maintain cell-specific chromatin states (or epigenomes) during differentiation and development [6], modulate the functions of transcription factors in cell-type-dependent manners [7,8]. Alterations of chromatin states can increase the efficiency of transcription factor-induced cell reprogramming [9,10] and lineage conversion in vivo [11,12]. How epigenetic mechanisms and transcription factor networks coordinately regulate cell differentiation remains elusive
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
