Chromatin remodeling mediated by the FOXA1/A2 transcription factors activates CFTR expression in intestinal epithelial cells.
The forkhead box A transcription factors, FOXA1 and FOXA2, function as pioneer factors to open condensed chromatin and facilitate binding of other proteins. We showed previously that these factors are key components of a transcriptional network that drives enhancer function at the cystic fibrosis transmembrane conductance regulator (CFTR) locus in intestinal epithelial cells. The CFTR promoter apparently lacks tissue-specific regulatory elements and expression of the gene is controlled by multiple cis-acting elements, which coordinate gene expression in different cell types. Here we show that concurrent depletion of FOXA1 and FOXA2 represses CFTR expression and alters the three-dimensional architecture of the active locus by diminishing interactions between the promoter and intronic cis-acting elements. Reduction of FOXA1/A2 also modifies the enrichment profile of the active enhancer marks H3K27ac and H3K4me2 across the CFTR locus and alters chromatin accessibility at individual cis-elements. Moreover, loss of FOXA1/A2 suppresses the recruitment of other members of the transcriptional network including HNF1 and CDX2, to multiple cis-elements. These data reveal a complex molecular mechanism underlying the role of FOXA1/A2 in achieving high levels of CFTR expression in intestinal epithelial cells.
Human Molecular Genetics Program; Lurie Children's Research Center; Chicago, IL USA; Department of Pediatrics; Northwestern University Feinberg School of Medicine; Chicago, IL USA.
Jenny L
JL
Kerschner
Human Molecular Genetics Program; Lurie Children's Research Center; Chicago, IL USA; Department of Pediatrics; Northwestern University Feinberg School of Medicine; Chicago, IL USA.
Nehal
N
Gosalia
Human Molecular Genetics Program; Lurie Children's Research Center; Chicago, IL USA; Department of Pediatrics; Northwestern University Feinberg School of Medicine; Chicago, IL USA.
Shih-Hsing
SH
Leir
Human Molecular Genetics Program; Lurie Children's Research Center; Chicago, IL USA; Department of Pediatrics; Northwestern University Feinberg School of Medicine; Chicago, IL USA.
Ann
A
Harris
D002460:Cell Line; D042002:Chromatin Assembly and Disassembly; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism*; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism*; D007438:Introns; D011499:Protein Processing, Post-Translational
C505032:CFTR protein, human; C496499:FOXA1 protein, human; C496502:FOXA2 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D006657:Histones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D051542:Hepatocyte Nuclear Factor 3-beta
CFTR; FOXA; chromatin remodeling; pioneer factor; transcriptional network