Study of FoxA Pioneer Factor at Silent Genes Reveals Rfx-Repressed Enhancer at Cdx2 and a Potential Indicator of Esophageal Adenocarcinoma Development

Fred Hutchinson Cancer Research Center, United States of America
PLoS Genetics (Impact Factor: 7.53). 09/2011; 7(9):e1002277. DOI: 10.1371/journal.pgen.1002277
Source: PubMed


Understanding how silent genes can be competent for activation provides insight into development as well as cellular reprogramming and pathogenesis. We performed genomic location analysis of the pioneer transcription factor FoxA in the adult mouse liver and found that about one-third of the FoxA bound sites are near silent genes, including genes without detectable RNA polymerase II. Virtually all of the FoxA-bound silent sites are within conserved sequences, suggesting possible function. Such sites are enriched in motifs for transcriptional repressors, including for Rfx1 and type II nuclear hormone receptors. We found one such target site at a cryptic "shadow" enhancer 7 kilobases (kb) downstream of the Cdx2 gene, where Rfx1 restricts transcriptional activation by FoxA. The Cdx2 shadow enhancer exhibits a subset of regulatory properties of the upstream Cdx2 promoter region. While Cdx2 is ectopically induced in the early metaplastic condition of Barrett's esophagus, its expression is not necessarily present in progressive Barrett's with dysplasia or adenocarcinoma. By contrast, we find that Rfx1 expression in the esophageal epithelium becomes gradually extinguished during progression to cancer, i.e, expression of Rfx1 decreased markedly in dysplasia and adenocarcinoma. We propose that this decreased expression of Rfx1 could be an indicator of progression from Barrett's esophagus to adenocarcinoma and that similar analyses of other transcription factors bound to silent genes can reveal unanticipated regulatory insights into oncogenic progression and cellular reprogramming.

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Available from: Andrés J Klein-Szanto
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    • "By definition, pioneer factors hold the property to bind nucleosomal DNA and compact chromatin, and remain bound during mitosis. FoxA is a typical pioneer factor, which is capable of transforming the actual enhancer to a state called ''poised'' for activation [63]. This state of the enhancers renders them for rapid activation once the specific signal or its downstream effector appears. "
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    • "t premature gene expression . It will be interesting to determine the generality of the model of pioneer factors recruiting corepressors in the silent but competent state . Indeed , a recent study of FoxA - binding events in the adult liver at genes that are transcriptionally silent revealed consistent patterns of repressor proteins bound nearby ( Watts et al . 2011 ) . This suggests a network of repressors interacting with FoxA at silent genes in cells where the factor otherwise functions as an activator of transcription ."
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