A genome-wide screen for β-catenin binding sites identifies a downstream enhancer element that controls c-Myc gene expression

Gregory Yochum, Ryan Cleland, Richard H. Goodman

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

Mutations in components of the Wnt signaling pathway initiate colorectal carcinogenesis by deregulating the β-catenin transcriptional coactivator. β-Catenin activation of one target in particular, the c-Myc protooncogene, is required for colon cancer pathogenesis. β-Catenin is known to regulate c-Myc expression via sequences upstream of the transcription start site. Here, we report that a more robust β-catenin binding region localizes 1.4 kb downstream from the c-Myc transcriptional stop site. This site was discovered using a genome-wide method for identifying transcription factor binding sites termed serial analysis of chromatin occupancy. Chromatin immunoprecipitation- scanning assays demonstrate that the 5′ enhancer and the 3′ binding element are the only β-catenin and TCF4 binding regions across the c-Myc locus. When placed downstream of a simian virus 40-driven promoter-luciferase construct, the 3′ element activated luciferase transcription when introduced into HCT116 cells. c-Myc transcription is negligible in quiescent HCT116 cells but is induced when cells reenter the cell cycle after the addition of mitogens. Using these cells, we found that β-catenin and TCF4 occupancy at the 3′ enhancer precede occupancy at the 5′ enhancer. Association of c-Jun, β-catenin, and TCF4 specifically with the downstream enhancer underlies mitogen stimulation of c-Myc transcription. Our findings indicate that a downstream enhancer element provides the principal regulation of c-Myc expression.

Original languageEnglish (US)
Pages (from-to)7368-7379
Number of pages12
JournalMolecular and cellular biology
Volume28
Issue number24
DOIs
StatePublished - Dec 1 2008

Fingerprint

Catenins
myc Genes
Binding Sites
Genome
Gene Expression
HCT116 Cells
Luciferases
Mitogens
Wnt Signaling Pathway
Simian virus 40
Chromatin Immunoprecipitation
Transcription Initiation Site
Colonic Neoplasms
Chromatin
Cell Cycle
Carcinogenesis
Transcription Factors
Mutation

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

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abstract = "Mutations in components of the Wnt signaling pathway initiate colorectal carcinogenesis by deregulating the β-catenin transcriptional coactivator. β-Catenin activation of one target in particular, the c-Myc protooncogene, is required for colon cancer pathogenesis. β-Catenin is known to regulate c-Myc expression via sequences upstream of the transcription start site. Here, we report that a more robust β-catenin binding region localizes 1.4 kb downstream from the c-Myc transcriptional stop site. This site was discovered using a genome-wide method for identifying transcription factor binding sites termed serial analysis of chromatin occupancy. Chromatin immunoprecipitation- scanning assays demonstrate that the 5′ enhancer and the 3′ binding element are the only β-catenin and TCF4 binding regions across the c-Myc locus. When placed downstream of a simian virus 40-driven promoter-luciferase construct, the 3′ element activated luciferase transcription when introduced into HCT116 cells. c-Myc transcription is negligible in quiescent HCT116 cells but is induced when cells reenter the cell cycle after the addition of mitogens. Using these cells, we found that β-catenin and TCF4 occupancy at the 3′ enhancer precede occupancy at the 5′ enhancer. Association of c-Jun, β-catenin, and TCF4 specifically with the downstream enhancer underlies mitogen stimulation of c-Myc transcription. Our findings indicate that a downstream enhancer element provides the principal regulation of c-Myc expression.",
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A genome-wide screen for β-catenin binding sites identifies a downstream enhancer element that controls c-Myc gene expression. / Yochum, Gregory; Cleland, Ryan; Goodman, Richard H.

In: Molecular and cellular biology, Vol. 28, No. 24, 01.12.2008, p. 7368-7379.

Research output: Contribution to journalArticle

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