title: Higher-order chromatin regulation and differential gene expression in the human tumor necrosis factor/lymphotoxin locus in hepatocellular carcinoma cells.
abstract: The three-dimensional context of endogenous chromosomal regions may contribute to the regulation of gene clusters by influencing interactions between transcriptional regulatory elements. In this study, we investigated the effects of tumor necrosis factor (TNF) signaling on spatiotemporal enhancer-promoter interactions in the human tumor necrosis factor (TNF)/lymphotoxin (LT) gene locus, mediated by CCCTC-binding factor (CTCF)-dependent chromatin insulators. The cytokine genes LTα, TNF, and LTβ are differentially regulated by NF-κB signaling in inflammatory and oncogenic responses. We identified at least four CTCF-enriched sites with enhancer-blocking activities and a TNF-responsive TE2 enhancer in the TNF/LT locus. One of the CTCF-enriched sites is located between the early-inducible LTα/TNF promoters and the late-inducible LTβ promoter. Depletion of CTCF reduced TNF expression and accelerated LTβ induction. After TNF stimulation, via intrachromosomal dynamics, these insulators mediated interactions between the enhancer and the LTα/TNF promoters, followed by interaction with the LTβ promoter. These results suggest that insulators mediate the spatiotemporal control of enhancer-promoter associations in the TNF/LT gene cluster.
authors.affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, and the Global Center of Excellence Cell Fate Regulation Research and EducationUnit,Kumamoto University, Kumamoto, Japan.
authors.forename: Takehisa
authors.initials: T
authors.lastname: Watanabe
authors.forename: Ko
authors.initials: K
authors.lastname: Ishihara
authors.forename: Akiyuki
authors.initials: A
authors.lastname: Hirosue
authors.forename: Sugiko
authors.initials: S
authors.lastname: Watanabe
authors.forename: Shinjiro
authors.initials: S
authors.lastname: Hino
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ojima
authors.forename: Yae
authors.initials: Y
authors.lastname: Kanai
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Nakao
mesh_terms: D000368:Aged; D000076246:CCCTC-Binding Factor; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics*; D016207:Cytokines / Q000235:genetics; D004742:Enhancer Elements, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D008233:Lymphotoxin-alpha / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D005810:Multigene Family; D016328:NF-kappa B / Q000235:genetics; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D002843:Chromatin; D016207:Cytokines; D008233:Lymphotoxin-alpha; D016328:NF-kappa B; D012097:Repressor Proteins; D014409:Tumor Necrosis Factor-alpha