A beta-catenin/TCF-coordinated chromatin loop at MYC integrates 5' and 3' Wnt responsive enhancers.
Aberrant MYC gene expression by the Wnt/beta-catenin pathway is implicated in colorectal carcinogenesis. Wnt/beta-catenin signaling stimulates association of the beta-catenin coactivator complex with two Wnt responsive enhancers (WREs) located in close proximity to MYC gene boundaries. Each enhancer directly binds members of the TCF/Lef family of transcription factors that, in turn, recruit beta-catenin. In a previous report, we showed that the downstream MYC enhancer (MYC 3' WRE) cooperated with the upstream enhancer (MYC 5' WRE) to activate expression of a heterologous reporter gene in response to Wnt/beta-catenin and mitogen signaling. Here we use chromatin conformation capture (3C) to show that the MYC 5' and 3' WREs are juxtaposed at the genomic MYC locus during active transcription. This MYC 5'3' chromatin loop is present in HCT116 human colorectal cancer cells that contain high levels of nuclear beta-catenin and is absent in HEK293 cells that contain trace amounts of nuclear beta-catenin. Depletion of functional beta-catenin/TCF complexes blocks formation of the MYC 5'3 chromatin loop. Furthermore, we find that the chromatin loop is absent in quiescent cells, but is rapidly and transiently induced by serum mitogens in a beta-catenin-dependent manner. Thus, we propose that a distinct chromatin architecture coordinated by beta-catenin/TCF-bound WREs accompanies transcriptional activation of MYC gene expression.
Yochum
Gregory S
GS
Vollum Institute and Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR 97239, USA. gsy3@psu.edu
Sherrick
Colette M
CM
Macpartlin
Mary
M
Goodman
Richard H
RH
D002460:Cell Line; D002843:Chromatin / Q000737:chemistry* / Q000235:genetics; D004742:Enhancer Elements, Genetic; D015870:Gene Expression; D045325:HCT116 Cells; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism; D009690:Nucleic Acid Conformation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D002843:Chromatin; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D016271:Proto-Oncogene Proteins c-myc; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin