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Chromatin loops play important roles in the dynamic spatial organization of genes in the nucleus. Growing evidence has revealed that the multivalent functional zinc finger protein CCCTC-binding factor (CTCF) is a master regulator of genome spatial organization, and mediates the ubiquitous chromatin loops within the genome. Using circular chromosome conformation capture (4C) methodology, we discovered that CTCF may be a master organizer in mediating the spatial organization of the kcnq5 gene locus. We characterized the cell-type specific spatial organization of the kcnq5 gene locus mediated by CTCF in detail using chromosome conformation capture (3C) and 3C-derived techniques. Cohesion also participated in mediating the organization of this locus. RNAi-mediated knockdown of CTCF sharply diminished the interaction frequencies between the chromatin loops of the kcnq5 gene locus and down-regulated local gene expression. Functional analysis showed that the interacting chromatin loops of the kcnq5 gene locus can repress the gene expression in a luciferase reporter assay. These interacting chromatin fragments were a series of repressing elements whose contacts were mediated by CTCF. Therefore, these findings suggested that the dynamical spatial organization of the kcnq5 locus regulates local gene expression. 相似文献
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More than 109 base pairs of the genome in higher eucaryotes are positioned in the interphase nucleus such that gene activation, gene repression,
remote gene regulation by enhancer elements, and reading as well as adjusting epigenetic marks are possible. One important
structural and functional component of chromatin organization is the zinc finger factor CTCF. Two decades of research has
advanced the understanding of the fundamental role that CTCF plays in regulating such a vast expanse of DNA. 相似文献
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CCCTC-binding factor controls its own nuclear transport via regulating the expression of importin 13
CCCTC-binding factor (CTCF), a multivalent zinc-finger protein, is involved in different aspects of regulation including promoter activation or repression, gene silencing, chromatin insulation, gene imprinting, X-chromosome inactivation, cell growth or differentiation and tumor genesis. However, the molecular mechanisms of CTCF nuclear import remains unclear. In this study, we showed that the expression of CTCF influenced the intracellular distribution of itself, which might go through transport receptor - import 13 (IPO13). We further confirmed that there is a CTCF target site in ipo13 -774∼-573 bp promoter region and CTCF regulates the expression of IPO13. Besides, GST pull-down and Co-IP experiments demonstrated that CTCF interacts with IPO13. Immunofluorescence staining showed that IPO13 influenced intracellular distribution of CTCF. In all, we conclude that CTCF regulates the expression of IPO13, which, in turn, mediates the nuclear import of CTCF. 相似文献
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CTCF is a uniquely versatile transcription regulator linked to epigenetics and disease 总被引:20,自引:0,他引:20
CTCF is an evolutionarily conserved zinc finger (ZF) phosphoprotein that binds through combinatorial use of its 11 ZFs to approximately 50 bp target sites that have remarkable sequence variation. Formation of different CTCF-DNA complexes, some of which are methylation-sensitive, results in distinct functions, including gene activation, repression, silencing and chromatin insulation. Disrupting the spectrum of target specificities by ZF mutations or by abnormal selective methylation of targets is associated with cancer. CTCF emerges, therefore, as a central player in networks linking expression domains with epigenetics and cell growth regulation. 相似文献
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Histone acetylation plays an important role in chromatin remodeling and gene expression. The molecular mechanisms involved in cell-specific expression of CTP:phosphocholine cytidylyltransferase alpha (CTalpha) are not fully understood. In this study, we investigated whether or not histone deacetylation is involved in repression of CTalpha expression in quiescent C3H10T1/2 mouse embryo fibroblasts. We have examined the contributions of the Sp1 and E2F binding sites in the repression of CTalpha gene expression. Immunoprecipitation experiments showed that histone deacetylase 1 (HDAC1) and HDAC activity are associated with Sp1 in serum-starved cells or during serum stimulation. However, HDAC1 association with E2F was only detected in serum-starved cells. By chromatin immunoprecipitation assays, we detected both direct and indirect association of HDAC1 with the CTalpha promoter. Treatment with the HDAC inhibitor trichostatin A induced CTalpha expression. Our data suggest that HDAC1 plays a critical role in CTalpha repression and that Sp1 and E2F may serve as key targets for HDAC1-mediated CTalpha repression in fibroblasts. 相似文献
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Chernukhin IV Shamsuddin S Robinson AF Carne AF Paul A El-Kady AI Lobanenkov VV Klenova EM 《The Journal of biological chemistry》2000,275(38):29915-29921
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Kobby Essien Sebastien Vigneau Sofia Apreleva Larry N Singh Marisa S Bartolomei Sridhar Hannenhalli 《Genome biology》2009,10(11):R131-15
Background
CTCF (CCCTC-binding factor) is an evolutionarily conserved zinc finger protein involved in diverse functions ranging from negative regulation of MYC, to chromatin insulation of the beta-globin gene cluster, to imprinting of the Igf2 locus. The 11 zinc fingers of CTCF are known to differentially contribute to the CTCF-DNA interaction at different binding sites. It is possible that the differences in CTCF-DNA conformation at different binding sites underlie CTCF's functional diversity. If so, the CTCF binding sites may belong to distinct classes, each compatible with a specific functional role. 相似文献13.
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Kim YS Kim JM Jung DL Kang JE Lee S Kim JS Seol W Shin HC Kwon HS Van Lint C Hernandez N Hur MW 《The Journal of biological chemistry》2005,280(22):21545-21552
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Thyroid hormone-regulated enhancer blocking: cooperation of CTCF and thyroid hormone receptor
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Lutz M Burke LJ LeFevre P Myers FA Thorne AW Crane-Robinson C Bonifer C Filippova GN Lobanenkov V Renkawitz R 《The EMBO journal》2003,22(7):1579-1587
The highly conserved, ubiquitously expressed, zinc finger protein CTCF is involved in enhancer blocking, a mechanism crucial for shielding genes from illegitimate enhancer effects. Interestingly, CTCF-binding sites are often flanked by thyroid hormone response elements (TREs), as at the chicken lysozyme upstream silencer. Here we identify a similar composite site positioned upstream of the human c-myc gene. For both elements, we demonstrate that thyroid hormone abrogates enhancer blocking. Relief of enhancer blocking occurs even though CTCF remains bound to the lysozyme chromatin. Furthermore, chromatin immunoprecipitation analysis of the lysozyme upstream region revealed that histone H4 is acetylated at the CTCF-binding site. Loss of enhancer blocking by the addition of T3 led to increased histone acetylation, not only at the CTCF site, but also at the enhancer and the promoter. Thus, when TREs are adjacent to CTCF-binding sites, thyroid hormone can regulate enhancer blocking, thereby providing a new property for what was previously thought to be constitutive enhancer shielding by CTCF. 相似文献
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Oliver Weth Christine Paprotka Katharina Günther Astrid Schulte Manuel Baierl Joerg Leers Niels Galjart Rainer Renkawitz 《Nucleic acids research》2014,42(19):11941-11951
Insulators functionally separate active chromatin domains from inactive ones. The insulator factor, CTCF, has been found to bind to boundaries and to mediate insulator function. CTCF binding sites are depleted for the histone modification H3K27me3 and are enriched for the histone variant H3.3. In order to determine whether demethylation of H3K27me3 and H3.3 incorporation are a requirement for CTCF binding at domain boundaries or whether CTCF causes these changes, we made use of the LacI DNA binding domain to control CTCF binding by the Lac inducer IPTG. Here we show that, in contrast to the related factor CTCFL, the N-terminus plus zinc finger domain of CTCF is sufficient to open compact chromatin rapidly. This is preceded by incorporation of the histone variant H3.3, which thereby removes the H3K27me3 mark. This demonstrates the causal role for CTCF in generating the chromatin features found at insulators. Thereby, spreading of a histone modification from one domain through the insulator into the neighbouring domain is inhibited. 相似文献
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