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Epigenetic switch involved in activation of pioneer factor FOXA1-dependent enhancers.
- Source :
-
Genome research [Genome Res] 2011 Apr; Vol. 21 (4), pp. 555-65. Date of Electronic Publication: 2011 Jan 13. - Publication Year :
- 2011
-
Abstract
- Transcription factors (TFs) bind specifically to discrete regions of mammalian genomes called cis-regulatory elements. Among those are enhancers, which play key roles in regulation of gene expression during development and differentiation. Despite the recognized central regulatory role exerted by chromatin in control of TF functions, much remains to be learned regarding the chromatin structure of enhancers and how it is established. Here, we have analyzed on a genomic-scale enhancers that recruit FOXA1, a pioneer transcription factor that triggers transcriptional competency of these cis-regulatory sites. Importantly, we found that FOXA1 binds to genomic regions showing local DNA hypomethylation and that its cell-type-specific recruitment to chromatin is linked to differential DNA methylation levels of its binding sites. Using neural differentiation as a model, we showed that induction of FOXA1 expression and its subsequent recruitment to enhancers is associated with DNA demethylation. Concomitantly, histone H3 lysine 4 methylation is induced at these enhancers. These epigenetic changes may both stabilize FOXA1 binding and allow for subsequent recruitment of transcriptional regulatory effectors. Interestingly, when cloned into reporter constructs, FOXA1-dependent enhancers were able to recapitulate their cell type specificity. However, their activities were inhibited by DNA methylation. Hence, these enhancers are intrinsic cell-type-specific regulatory regions of which activities have to be potentiated by FOXA1 through induction of an epigenetic switch that includes notably DNA demethylation.
- Subjects :
- Animals
Binding Sites genetics
Cell Differentiation genetics
Cell Line, Tumor
Chromatin metabolism
DNA Methylation genetics
DNA-Binding Proteins genetics
DNA-Binding Proteins metabolism
Histones metabolism
Humans
Mice
Models, Genetic
Neurons cytology
Neurons metabolism
Enhancer Elements, Genetic
Epigenomics
Hepatocyte Nuclear Factor 3-alpha genetics
Hepatocyte Nuclear Factor 3-alpha metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1549-5469
- Volume :
- 21
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Genome research
- Publication Type :
- Academic Journal
- Accession number :
- 21233399
- Full Text :
- https://doi.org/10.1101/gr.111534.110