Higher-order chromatin regulation and differential gene expression in the human tumor necrosis factor/lymphotoxin locus in hepatocellular carcinoma cells

Takehisa Watanabe, Ko Ishihara, Akiyuki Hirosue, Sugiko Watanabe, Shinjiro Hino, Hidenori Ojima, Yae Kanai, Yutaka Sasaki, Mitsuyoshi Nakao

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22 Citations (Scopus)


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 LTκ 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.

Original languageEnglish
Pages (from-to)1529-1541
Number of pages13
JournalMolecular and Cellular Biology
Issue number8
Publication statusPublished - 2012 Apr 1
Externally publishedYes


ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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