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

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 activation-dependent intrachromosomal interactions. Th...

Full description

Saved in:

Bibliographic Details
Published in:	Proceedings of the National Academy of Sciences - PNAS 2007-10, Vol.104 (43), p.16850-16855
Main Authors:	Tsytsykova, Alla V, Rajsbaum, Ricardo, Falvo, James V, Ligeiro, Filipa, Neely, Simon R, Goldfeld, Anne E
Format:	Article
Language:	eng
Subjects:	Acetylation Animals Biochemistry Biological Sciences CD4-Positive T-Lymphocytes - metabolism Cell lines Cells, Cultured Chromatin Chromosomes Chromosomes, Mammalian - metabolism Deoxyribonuclease I - metabolism DNA Enhancer Elements, Genetic - genetics Gene loci Genes Genetic loci Genomics Histones - metabolism Lymphotoxin-alpha - genetics Mice Models, Genetic NFATC Transcription Factors - metabolism Polymerase chain reaction Promoter regions Promoter Regions, Genetic - genetics Protein Binding Proteins T cell receptors T lymphocytes Transcription Factor RelA - metabolism Transcription, Genetic Tumor Necrosis Factor-alpha - genetics
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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 activation-dependent 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.
ISSN:	0027-8424 1091-6490