title: β-Catenin and peroxisome proliferator-activated receptor-δ coordinate dynamic chromatin loops for the transcription of vascular endothelial growth factor A gene in colon cancer cells.
abstract: Vascular endothelial growth factor A (VEGFA) mRNA is regulated by β-catenin and peroxisome proliferator activated receptor δ (PPAR-δ) activation in colon cancer cells, but the detailed mechanism remains to be elucidated. As chromatin loops are generally hubs for transcription factors, we tested here whether β-catenin could modulate chromatin looping near the VEGFA gene and play any important role for PPAR-δ activated VEGFA transcription. First, we identified the far upstream site as an important site for VEGFA transcription by luciferase assay and chromatin immunoprecipitation in colorectal carcinoma HCT116 cells. Chromatin conformation capture analysis also revealed the chromatin loops formed by the β-catenin bindings on these sites near the VEGFA gene. Dynamic association and dissociation of β-catenin/TCF-4/PPAR-δ on the far upstream site and β-catenin/NF-κB p65 on the downstream site were also detected depending on PPAR-δ activation. Interestingly, β-catenin-mediated chromatin loops were relieved by PPAR-δ activation, suggesting a regulatory role of β-catenin for VEGFA transcription. Based on these data, we propose a model for PPAR-δ-activated VEGFA transcription that relies on β-catenin-mediated chromatin looping as a prerequisite for the activation. Our findings could extend to other β-catenin regulated target genes and could provide a general mechanism and novel paradigm for β-catenin-mediated oncogenesis.
authors.affiliation: National Research Lab for RNA Cell Biology, BK21 Graduate Program for RNA Biology, Institute of Nanosensor and Biotechnology, and Department of Molecular Biology, Dankook University, Gyeonggi-do 448-701, Republic of Korea.
authors.forename: Injoo
authors.initials: I
authors.lastname: Hwang
authors.forename: Jeeho
authors.initials: J
authors.lastname: Kim
authors.forename: Sunjoo
authors.initials: S
authors.lastname: Jeong
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008954:Models, Biological; D016296:Mutagenesis; D047494:PPAR delta / Q000378:metabolism*; D011485:Protein Binding; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002843:Chromatin; D047494:PPAR delta; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin