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Study of foxA pioneer factor at silent genes reveals Rfx-repressed enhancer at Cdx2 and a potential indicator of esophageal adenocarcinoma development

Publication ,  Journal Article
Watts, JA; Zhang, C; Klein-Szanto, AJ; Kormish, JD; Fu, J; Zhang, MQ; Zaret, KS
Published in: PLoS Genetics
2011

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. © 2011 Watts et al.

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Published In

PLoS Genetics

DOI

ISSN

1553-7390

Publication Date

2011

Volume

7

Issue

9

Related Subject Headings

  • Developmental Biology
  • 0604 Genetics
 

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Watts, J. A., Zhang, C., Klein-Szanto, A. J., Kormish, J. D., Fu, J., Zhang, M. Q., & Zaret, K. S. (2011). Study of foxA pioneer factor at silent genes reveals Rfx-repressed enhancer at Cdx2 and a potential indicator of esophageal adenocarcinoma development. PLoS Genetics, 7(9). https://doi.org/10.1371/journal.pgen.1002277
Watts, J. A., C. Zhang, A. J. Klein-Szanto, J. D. Kormish, J. Fu, M. Q. Zhang, and K. S. Zaret. “Study of foxA pioneer factor at silent genes reveals Rfx-repressed enhancer at Cdx2 and a potential indicator of esophageal adenocarcinoma development.” PLoS Genetics 7, no. 9 (2011). https://doi.org/10.1371/journal.pgen.1002277.
Watts, J. A., et al. “Study of foxA pioneer factor at silent genes reveals Rfx-repressed enhancer at Cdx2 and a potential indicator of esophageal adenocarcinoma development.” PLoS Genetics, vol. 7, no. 9, 2011. Scival, doi:10.1371/journal.pgen.1002277.
Watts JA, Zhang C, Klein-Szanto AJ, Kormish JD, Fu J, Zhang MQ, Zaret KS. Study of foxA pioneer factor at silent genes reveals Rfx-repressed enhancer at Cdx2 and a potential indicator of esophageal adenocarcinoma development. PLoS Genetics. 2011;7(9).

Published In

PLoS Genetics

DOI

ISSN

1553-7390

Publication Date

2011

Volume

7

Issue

9

Related Subject Headings

  • Developmental Biology
  • 0604 Genetics