Long-range enhancers on 8q24 regulate c-Myc.
Recent genomewide association studies have found multiple genetic variants on chromosome 8q24 that are significantly associated with an increased susceptibility to prostate, colorectal, and breast cancer. These risk loci are located in a "gene desert," a few hundred kilobases telomeric to the Myc gene. To date, the biological mechanism(s) underlying these associations remain unclear. It has been speculated that these 8q24 genetic variant(s) might affect Myc expression by altering its regulation or amplification status. Here, we show that multiple enhancer elements are present within this region and that they can regulate transcription of Myc. We also demonstrate that one such enhancer element physically interacts with the Myc promoter via transcription factor Tcf-4 binding and acts in an allele specific manner to regulate Myc expression.
Laboratory of Molecular Technology, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
Jose
J
Sotelo
Dominic
D
Esposito
Maria Ana
MA
Duhagon
Kelley
K
Banfield
Jennifer
J
Mehalko
Hongling
H
Liao
Robert M
RM
Stephens
Timothy J R
TJ
Harris
David J
DJ
Munroe
Xiaolin
X
Wu
D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D019295:Computational Biology; D017931:DNA Primers / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008156:Luciferases; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D017931:DNA Primers; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin; D008156:Luciferases