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.

Download full-text


Available from: Andrés J Klein-Szanto, Oct 04, 2015
11 Reads
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The information encoded in genomes supports the differentiation and function of the more than 200 unique cell types, which exist in various mammalian species. The major mechanism drivingcellular differentiation and specification is differential gene expression regulation. Cis-acting enhancers and silencers appear to have key roles in regulating the expression of mammalian genes. However, these cis-acting elements are often located very far away from the regulated gene. Therefore, it is hard to find all of them and link them to the regulated gene. An intriguing and unresolved issue of the field is to identify all of the enhancers of a particular gene and link these short regulatory sequences to the genes they regulate and thus, reliably identify gene regulatory enhancer networks. Recent advances in molecular biological methods coupled with Next-Generation Sequencing (NGS) technologies have opened up new possibilities in this area of genomics. In this review we summarize the technological advances, bioinformatics challenges and the potential molecular mechanisms allowing the construction of enhancer networks operating in specific cell types and/or activated by various signals.
    FEBS Letters 08/2014; · 3.17 Impact Factor
  • Source
    • "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 ."
    [Show abstract] [Hide abstract]
    ABSTRACT: Transcription factors are adaptor molecules that detect regulatory sequences in the DNA and target the assembly of protein complexes that control gene expression. Yet much of the DNA in the eukaryotic cell is in nucleosomes and thereby occluded by histones, and can be further occluded by higher-order chromatin structures and repressor complexes. Indeed, genome-wide location analyses have revealed that, for all transcription factors tested, the vast majority of potential DNA-binding sites are unoccupied, demonstrating the inaccessibility of most of the nuclear DNA. This raises the question of how target sites at silent genes become bound de novo by transcription factors, thereby initiating regulatory events in chromatin. Binding cooperativity can be sufficient for many kinds of factors to simultaneously engage a target site in chromatin and activate gene expression. However, in cases in which the binding of a series of factors is sequential in time and thus not initially cooperative, special "pioneer transcription factors" can be the first to engage target sites in chromatin. Such initial binding can passively enhance transcription by reducing the number of additional factors that are needed to bind the DNA, culminating in activation. In addition, pioneer factor binding can actively open up the local chromatin and directly make it competent for other factors to bind. Passive and active roles for the pioneer factor FoxA occur in embryonic development, steroid hormone induction, and human cancers. Herein we review the field and describe how pioneer factors may enable cellular reprogramming.
    Genes & development 11/2011; 25(21):2227-41. DOI:10.1101/gad.176826.111 · 10.80 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This paper, in the form of a frequently asked questions page (FAQ), addresses outstanding questions about "shadow enhancers", quasi-redundant cis-regulatory elements, and their proposed roles in transcriptional control. Questions include: What exactly are shadow enhancers? How many genes have shadow/redundant/distributed enhancers? How redundant are these elements? What is the function of distributed enhancers? How modular are enhancers? Is it useful to study a single enhancer in isolation? In addition, a revised definition of "shadow enhancers" is proposed, and possible mechanisms of shadow enhancer function and evolution are discussed.
    BioEssays 02/2012; 34(2):135-41. DOI:10.1002/bies.201100121 · 4.73 Impact Factor
Show more