Cell-type selective chromatin remodeling defines the active subset of FOXA1-bound enhancers.
Selective activity of a specific set of enhancers defines tissue-specific gene transcription. The pioneer factor FOXA1 has been shown to induce functional enhancer competency through chromatin openings. We have previously found that FOXA1 is recruited to thousands of regions across the genome of a given cell type. Here, we monitored the chromatin structure at FOXA1 binding sites on a chromosome-wide scale using formaldehyde assisted isolation of regulatory elements (FAIRE). Surprisingly, we find that a significant fraction of FOXA1-bound sites have a relatively closed chromatin conformation linked to a shift of the epigenetic signature toward repressive histone marks. Importantly, these sites are not correlated with gene expression in a given cell type suggesting that FOXA1 is required, but not sufficient, for the functional activity of bound enhancers. Interestingly, we find that a significant proportion of the inactive FOXA1-bound regulatory sites in one cell type are actually functional in another cellular context. We found that at least half of the FOXA1 binding sites from a given cell type are shared with another cell lineage. Mechanisms that restrict the activity of shared FOXA1-bound enhancers likely play a significant role in defining the cell-type-specific functions of FOXA1.
Eeckhoute
Jérôme
J
Université de Rennes I, CNRS, UMR 6026, Equipe SPARTE, Campus de Beaulieu, 35042 Rennes cedex, France.
Lupien
Mathieu
M
Meyer
Clifford A
CA
Verzi
Michael P
MP
Shivdasani
Ramesh A
RA
Liu
X Shirley
XS
Brown
Myles
M
D001665:Binding Sites / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D042002:Chromatin Assembly and Disassembly / Q000502:physiology*; D002874:Chromosome Mapping; D017124:Conserved Sequence; D004742:Enhancer Elements, Genetic / Q000502:physiology; D020869:Gene Expression Profiling; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D009928:Organ Specificity / Q000235:genetics; D011485:Protein Binding; D015533:Transcriptional Activation / Q000235:genetics* / Q000502:physiology; D014407:Tumor Cells, Cultured
C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha