Epigenetic priming of a pre-B cell-specific enhancer through binding of Sox2 and Foxd3 at the ESC stage.
Modifications to the core histones are thought to contribute to ESC pluripotency by priming tissue-specific promoters and enhancers for later activation. However, it is unclear how these marks are targeted in ESCs and maintained during differentiation. Here, we show that the ESC factor Sox2 targets H3K4 methylation to monovalent and bivalent domains. In ESCs, Sox2 contributes to the formation of a monovalent mark at an enhancer in the pro/pre-B cell-specific lambda5-VpreB1 locus. Binding of Foxd3 suppresses intergenic transcription of the enhancer and surrounding sequences. In pro-B cells, enhancer activity is dependent on the Sox and Fox binding sites, and the enhancer is bound by Sox4, which is required for efficient expression of lambda5. Our results lead us to propose a factor relay model whereby ESC factors establish active epigenetic marks at tissue specific elements before being replaced by cell type-specific factors as cells differentiate.
Liber
Daniel
D
MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
Domaschenz
Renae
R
Holmqvist
Per-Henrik
PH
Mazzarella
Luca
L
Georgiou
Andrew
A
Leleu
Marion
M
Fisher
Amanda G
AG
Labosky
Patricia A
PA
Dillon
Niall
N
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D018983:DNA Footprinting; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics / Q000502:physiology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D055018:Hemangioblasts / Q000166:cytology; D054444:Immunoglobulin Light Chains, Surrogate / Q000235:genetics*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism*; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D055751:SOXC Transcription Factors / Q000235:genetics / Q000378:metabolism
D051858:Forkhead Transcription Factors; C101757:Foxd3 protein, mouse; D054444:Immunoglobulin Light Chains, Surrogate; D012097:Repressor Proteins; D055748:SOXB1 Transcription Factors; D055751:SOXC Transcription Factors; C527783:Sox2 protein, mouse; C489990:Sox4 protein, mouse