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Department of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea
Efficient transcription depends upon efficient physical and functional interactions between transcriptosome complexes and DNA. We have previously shown that IL-1β-induced lymphoid enhancer binding factor 1 (Lef1) regulates the transcription of its target genes COX2 and MMP13 in mouse chondrocytes by binding to the Lef1 binding sites located in the 3' region. In this study, we investigated how the 3' region-bound Lef1 regulates expression of target genes. IL-1β stimulation induced gene looping in COX2 and MMP13 genomic loci, which is mediated by the physical interaction of Lef1 with its binding partners, including β-catenin, AP-1, and NF-
B. As shown by chromosome conformation capture (3C) assay, the 5' and 3' genomic regions of these genes were juxtaposed in an IL-1β-stimulation dependent manner. Lef1 played a pivotal role in this gene looping; Lef1 knockdown decreased the incidence of gene looping, while Lef1 overexpression induced it. Physical interactions between the 3' region-bound Lef1 and promoter-bound transcription factors AP-1 or NF-B in COX2 and MMP13, respectively, were increased upon stimulation, leading to synergistic up-regulation of gene expression. Knockdown of RelA or c-Jun decreased the formation of gene loop and down-regulated cyclooxygenase 2 (COX2) or matrix metalloproteinase 13 (MMP13) transcription levels. However, overexpression of RelA or c-Jun along with Lef1 increased the looping and their expression levels. Our results indicate a novel function of Lef1, as a mediator of gene looping between 5' and 3' regions. Gene looping may serve to delineate the transcription unit in the inducible gene transcription of mammalian cells.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This research was supported by grants from the 21C Frontier Functional Human Genome Project, Grant RTI05-01-01 from the Regional Technology Innovation Program of the Ministry of Commerce, Industry and Energy, by the Korea Research Foundation funded by the Korean government (KRF-2007-313-C00507), by the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare and Family Affairs (A080588-5), by the Center for Distributed Sensor Network at the Gwangju Institute of Science and Technology, and by a Systems Biology Infrastructure Establishment Grant provided by the Gwangju Institute of Science and Technology.
2 K.Y. and J.-S.S. equally contributed to this work.
3 Current address: Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, 49 Convent Drive, Bethesda, MD 20892.
4 Address correspondence and reprint requests to Dr. Sin-Hyeog Im, Department of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-dong, Puk-ku, Gwangju 500-712, Korea. E-mail address: imsh{at}gist.ac.kr
5 Abbreviations used in this paper: CTCF, CCCTC-binding factor; 3C, chromatin conformation capture; ChIP, chromatin immunoprecipitation; COX2, cyclooxygenase 2; Lef1, lymphoid enhancer binding factor 1; MMP13, matrix metalloproteinase 13; siRNA, small interfering RNA; HA, hemagglutinin; BMP2, bone morphogenetic protein 2.
6 The online version of this article contains supplemental material.
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