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.