Foxa1 functions as a pioneer transcription factor at transposable elements to activate Afp during differentiation of embryonic stem cells. J Biol Chem 2010 May 21;285(21):16135-44
Date
03/30/2010Pubmed ID
20348100Pubmed Central ID
PMC2871482DOI
10.1074/jbc.M109.088096Scopus ID
2-s2.0-77952354898 (requires institutional sign-in at Scopus site) 70 CitationsAbstract
Epigenetic control of genes that are silent in embryonic stem cells, but destined for expression during differentiation, includes distinctive hallmarks, such as simultaneous activating/repressing (bivalent) modifications of chromatin and DNA hypomethylation at enhancers of gene expression. Although alpha-fetoprotein (Afp) falls into this class of genes, as it is silent in pluripotent stem cells and activated during differentiation of endoderm, we find that Afp chromatin lacks bivalent histone modifications. However, critical regulatory sites for Afp activation, overlapping Foxa1/p53/Smad-binding elements, are located within a 300-bp region lacking DNA methylation, due to transposed elements underrepresented in CpG sequences: a short interspersed transposable element and a medium reiterated sequence 1 element. Forkhead family member Foxa1 is activated by retinoic acid treatment of embryonic stem cells, binds its DNA consensus site within the short interspersed transposable/medium reiterated sequence 1 elements, and displaces linker histone H1 from silent Afp chromatin. Small interfering RNA depletion of Foxa1 showed that Foxa1 is essential in providing chromatin access to transforming growth factor beta-activated Smad2 and Smad4 and their subsequent DNA binding. Together these transcription factors establish highly acetylated chromatin and promote expression of Afp. Foxa1 acts as a pioneer transcription factor in de novo activation of Afp, by exploiting a lack of methylation at juxtaposed transposed elements, to bind and poise chromatin for intersection with transforming growth factor beta signaling during differentiation of embryonic stem cells.
Author List
Taube JH, Allton K, Duncan SA, Shen L, Barton MCMESH terms used to index this publication - Major topics in bold
AnimalsAntineoplastic Agents
Cell Differentiation
Cell Line
Chromatin Assembly and Disassembly
DNA Methylation
DNA Transposable Elements
Embryonic Stem Cells
Gene Expression Regulation, Developmental
Hepatocyte Nuclear Factor 3-alpha
Histones
Mice
Pluripotent Stem Cells
Protein Processing, Post-Translational
Response Elements
Signal Transduction
Smad2 Protein
Smad4 Protein
Transforming Growth Factor beta
Tretinoin
alpha-Fetoproteins
