Activation-dependent intrachromosomal interactions formed by the TNF gene promoter and two distal enhancers

Alla V. Tsytsykova, Ricardo Rajsbaum, James V. Falvo, Filipa Ligeiro, Simon R. Neely, Anne E. Goldfeld

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

Here we provide a mechanism for specific, efficient transcription of the TNF gene and, potentially, other genes residing within multigene loci. We identify and characterize highly conserved noncoding elements flanking the TNF gene, which undergo activationdependent intrachromosomal interactions. These elements, hypersensitive site (HSS)-9 and HSS+3 (9 kb upstream and 3 kb downstream of the TNF gene, respectively), contain DNase I hypersensitive sites in naive, T helper 1, and T helper 2 primary T cells. Both HSS-9 and HSS+3 inducibly associate with acetylated histones, indicative of chromatin remodeling, bind the transcription factor nuclear factor of activated T cells (NFAT)p in vitro and in vivo, and function as enhancers of NFAT-dependent transactivation mediated by the TNF promoter. Using the chromosome conformation capture assay, we demonstrate that upon T cell activation intrachromosomal looping occurs in the TNF locus. HSS-9 and HSS+3 each associate with the TNF promoter and with each other, circularizing the TNF gene and bringing NFAT-containing nucleoprotein complexes into close proximity. TNF gene regulation thus reveals a mode of intrachromosomal interaction that combines a looped gene topology with interactions between enhancers and a gene promoter.

Original languageEnglish (US)
Pages (from-to)16850-16855
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number43
DOIs
StatePublished - Oct 23 2007

Keywords

  • Chromatin
  • Chromosome conformation capture assay
  • Nuclear factor of activated T cells
  • Transcriptional regulation

ASJC Scopus subject areas

  • General

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