Transcriptional repression and DNA looping associated with a novel regulatory element in the final exon of the lymphotoxin-β gene
Open Access
- 20 January 2011
- journal article
- Published by Springer Science and Business Media LLC in Genes & Immunity
- Vol. 12 (2), 126-135
- https://doi.org/10.1038/gene.2010.62
Abstract
Transcriptional regulation has a critical role in the coordinate and context-specific expression of a cluster of genes encoding members of the tumour necrosis factor (TNF) superfamily found at chromosome 6p21, comprising TNF, LTA (encoding lymphotoxin-α) and LTB (encoding lymphotoxin-β). This is important, as dysregulated expression of these genes is implicated in susceptibility to many autoimmune, inflammatory and infectious diseases. We describe here a novel regulatory element in the fourth exon of LTB, which is highly conserved, localises to the only CpG island in the locus, and is associated with a DNase I hypersensitive site and specific histone modifications. We find evidence of binding by Yin Yang 1 (YY1), cyclic AMP response element (CRE)-binding protein (CREB) and CCCTC-binding factor (CTCF) to this region in Jurkat T cells, which is associated with transcriptional repression on reporter gene analysis. Chromatin conformation capture experiments show evidence of DNA looping, involving interaction of this element with the LTB promoter, LTA promoter and TNF 3′ untranslated region (UTR). Small interfering RNA (siRNA) experiments demonstrate a functional role for YY1 and CREB in LTB expression. Our findings provide evidence of additional complexity in the transcriptional regulation of LTB with implications for coordinate expression of genes in this important genomic locus.This publication has 57 references indexed in Scilit:
- CTCF: Master Weaver of the GenomeCell, 2009
- Chromatin profiling across the human tumour necrosis factor gene locus reveals a complex, cell type-specific landscape with novel regulatory elementsNucleic Acids Research, 2008
- CTCFBSDB: a CTCF-binding site database for characterization of vertebrate genomic insulatorsNucleic Acids Research, 2007
- Activation-dependent intrachromosomal interactions formed by the TNF gene promoter and two distal enhancersProceedings of the National Academy of Sciences of the United States of America, 2007
- Clustal W and Clustal X version 2.0Bioinformatics, 2007
- Genome-wide maps of chromatin state in pluripotent and lineage-committed cellsNature, 2007
- High-Resolution Profiling of Histone Methylations in the Human GenomeCell, 2007
- Analysis of the Vertebrate Insulator Protein CTCF-Binding Sites in the Human GenomeCell, 2007
- Polycomb recruitment to DNA in vivo by the YY1 REPO domainProceedings of the National Academy of Sciences of the United States of America, 2006
- enoLOGOS: a versatile web tool for energy normalized sequence logosNucleic Acids Research, 2005