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First published online April 22, 2009
doi: 10.1242/10.1242/jcs.039990

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CTCF and its protein partners: divide and rule?

¹ Department of Molecular Biology, University of Wyoming, Laramie, WY 82071, USA
² Department of Cellular Biotechnology and Hematology, Second Faculty of Medicine and Surgery, University `La Sapienza', and Pasteur Institute-Fondazione Cenci Bolognetti, 00161 Rome, Italy

View larger version (45K): [in this window] [in a new window]   Fig. 1. Cellular functions, protein partners and structure of CTCF. (A) CTCF has important roles in numerous cellular processes. (B) Recognized protein partners of CTCF, broadly grouped according to function. The protein partners that are discussed in detail in this Commentary are highlighted in red. (C) Schematic of CTCF primary structure, showing its three domains, as well as those protein partners whose interactions with CTCF have been mapped to the individual domains. CHD8, chromodomain helicase DNA-binding protein 8; CIITA, MHC class II transactivator; CP190, centrosomal protein 190; H2A.Z, variant Z of histone H2A; LS, large subunit; HDAC, histone deacetylase; PARP1, poly(ADP-ribose) polymerase 1; SIN3A, SIN3 homolog A, transcription regulator (yeast); RFX, regulatory factor X; RNAP II, RNA polymerase II; Suz12, suppressor of zeste 12 homolog (Drosophila), Taf1/Set, SET translocation (myeloid leukemia-associated); Topo II, DNA topoisomerase II; YB1, Y-box binding protein 1; Yy1, yin and yang 1.

View larger version (14K): [in this window] [in a new window]   Fig. 2. Yy1 and CTCF collaborate in the regulation of X-chromosome inactivation. The portion of the X-inactivation center that encodes the three non-coding RNA transcripts, Xite, Tsix and Xist, that perform the binary switch function is shown; active Xist transcription initiates the actual inactivation of the randomly selected X chromosome (see text). The numerous groups of CTCF-binding sites (A, E, D, C and F) in this region are often paired with Yy1 sites (the orientation of these sites is represented by triangles). The direct interaction of CTCF with Yy1 at these sites is believed to enhance Xist transcription. Schematics modified from Ogawa et al. (Ogawa et al., 2008) and Donohoe et al. (Donohoe et al., 2007).

View larger version (53K): [in this window] [in a new window]   Fig. 3. A role for cohesin and CTCF in gene regulation. (A) The schematic on the left indicates the overall structure and composition of cohesin, showing the long coiled-coil domains in each monomer of Smc1 and Smc3, the hinge regions that connect the two monomers in the heterodimeric structure, and the two other proteins in the complex (Scc1 and Scc3) that close the cohesin ring. The schematic on the right shows the ring model of cohesin structure, in which cohesin embraces sister chromatids in cohesion [redrawn from Hirano (Hirano, 2006)]. (B) CTCF and cohesin colocalize at several CTCF-binding sites, including the Myc insulator element (MINE) (Gombert et al., 2003). CTCF is constitutively bound at MINE and at the Myc promoter, and binding is independent of the transcriptional status of the gene. The Myc gene and its insulator are embedded in a large (160 kb) domain that is flanked by matrix-attachment regions (MARs) and is devoid of other expressed genes; together, they constitute a euchromatic region embedded within a heterochromatic environment [this might be representative of a more general pattern that was recently recognized on mammalian chromosome arms (Regha et al., 2007) of active chromatin interspersed with repressive chromatin]. The CTCF-binding sites at MINE and the Myc promoter also bind to cohesin (Rubio et al., 2008; Stedman et al., 2008). Binding of the chromatin remodeler CHD8 to this region (see bracket) suggests that the chromatin structure in the region is actively altered (Ishihara et al., 2006). (C) The DM1 locus (which contains DMPK, the gene encoding myotonic dystrophy protein kinase), showing the position of the CTG repeat in the 3' UTR of DMPK that is expanded in individuals with myotonic dystrophy. The repeat is flanked by two CTCF-binding sites that are occupied by CTCF. In healthy individuals, the repeat is organized in a single positioned nucleosome (a nucleosome in which the histone octamer occupies a specific sequence). This strict positioning of the single nucleosome over the CTG repeat places the CTCF sites in the DNA-linker regions upstream and downstream of the nucleosome. The chromatin structure of the positioned nucleosome is highly heterochromatic [histone H3 is dimethylated at lysine 9 (H3K9me2)], but the rest of the region is characterized by the presence of `active' histone modifications [histone H3 is methylated at lysine 4 (H3K4me)]. CTCF restricts the length of the antisense transcript, which limits heterochromatin formation to only the positioned nucleosome. In individuals with myotonic dystrophy, expansion of the CTG repeats is associated with loss of CTCF binding and conversion of the entire region to heterochromatin. According to Rubio et al. (Rubio et al., 2008), the CTCF-binding sites on the human DM1 locus (integrated in mouse cells) are simultaneously bound by CTCF and cohesin, and binding of cohesin directly depends on the presence of CTCF. Schematic based on Filippova et al. (Filippova et al., 2001) and Cho et al. (Cho et al., 2005). HP1, heterochromatin protein 1.

View larger version (27K): [in this window] [in a new window]   Fig. 4. Nucleophosmin and CTCF associate with both 5' and 3' insulator elements in the chicken β-globin gene cluster in vivo. The schematic at the bottom depicts the developmentally regulated β-globin gene cluster and its locus control region (LCR), which encompasses DNase-I-hypersensitive sites 1-3 (HS1-HS3) and the βA/ enhancer (Gaszner and Felsenfeld, 2006). The domain is flanked by a region of highly compacted chromatin at the 5' end and a cluster of genes encoding olfactory receptors at the 3' end. Two further DNase-I-hypersensitive sites, HS4 and 3'HS, possess enhancer-blocking and insulator activities. 3'HS prevents the βA/ enhancer from activating the olfactory-receptor genes, and HS4 acts as both an insulator, to prevent spreading of heterochromatin into the gene cluster, and an enhancer-blocker, to prevent the enhancer located 5' of the condensed chromatin region from activating the globin genes (enhancer-blocking insulators are effective only when situated between a promoter and an enhancer). Nucleophosmin binds to both HS4 and 3'HS, as shown in the schematic and demonstrated by the ChIP data presented at the top of the figure [modified from Yusufzai et al. (Yusufzai et al., 2004)]. The RNA Pol II complex shown in brackets (Pol II) has been shown by ChIP analysis to localize to the HS4 site (Chernukhin et al., 2007) (see discussion on Pol II in text).

View larger version (8K): [in this window] [in a new window]   Fig. 5. Summary of the CTCF protein interaction network from the interactions discussed in this Commentary. The arrows connecting individual partners show recognized interactions. Thus, for example, both Yy1 and CTCF upregulate PARP1 activity; PARP1 and nucleophosmin interact directly, which might contribute to the inhibitory effect of CTCF on ribosomal gene transcription.

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