title: VDR/RXR and TCF4/β-catenin cistromes in colonic cells of colorectal tumor origin: impact on c-FOS and c-MYC gene expression.
abstract: Many of the transcriptional and growth regulating activities of 1α,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] in the intestine and colon are recapitulated in the human colorectal cancer cell LS180. We therefore used this line together with chromatin immunoprecipitation-seq and gene expression analyses to identify the vitamin D receptor (VDR)/retinoid X receptor (RXR) and transcription factor 7-like 2 (TCF7L2/TCF4)/β-catenin cistromes and the genes that they regulate. VDR and RXR colocalized to predominantly promoter distal, vitamin D response element-containing sites in a largely ligand-dependent manner. These regulatory sites control the expression of both known as well as novel 1,25-(OH)(2)D(3) target genes. TCF4 and β-catenin cistromes partially overlapped, contained TCF/lymphoid enhancer-binding factor consensus elements, and were only modestly influenced by 1,25-(OH)(2)D(3). However, the two heterodimer complexes colocalized at sites near a limited set of genes that included c-FOS and c-MYC; the expression of both genes was modulated by 1,25-(OH)(2)D(3). At the c-FOS gene, both VDR/RXR and TCF4/β-catenin bound to a single distal enhancer located 24 kb upstream of the transcriptional start site. At the c-MYC locus, however, binding was noted at a cluster of sites between -139 and -165 kb and at a site located -335 kb upstream. Examined as isolated enhancer fragments, these regions exhibited basal and 1,25-(OH)(2)D(3)-inducible activities that were interlinked to both VDR and β-catenin activation. These data reveal additional complexity in the regulation of target genes by 1,25-(OH)(2)D(3) and support a direct action of both VDR and the TCF4/β-catenin regulatory complex at c-FOS and c-MYC.
authors: Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
authors: Mark B
authors: MB
authors: Meyer
authors: Paul D
authors: PD
authors: Goetsch
authors: J Wesley
authors: JW
authors: Pike
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D002117:Calcitriol / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D015179:Colorectal Neoplasms; D005786:Gene Expression Regulation; D016762:Genes, fos; D016259:Genes, myc; D006801:Humans; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism; D047488:Retinoid X Receptors / Q000235:genetics* / Q000378:metabolism; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D030181:Vitamin D Response Element / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C489427:MYC protein, human; D016760:Proto-Oncogene Proteins c-fos; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D018167:Receptors, Calcitriol; D047488:Retinoid X Receptors; C532096:TCF4 protein, human; C544894:TCF7L2 protein, human; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin; D002117:Calcitriol