CTCF: the protein, the binding partners, the binding sites and their chromatin loops

Abstract

CTCF has it all. The transcription factor binds to tens of thousands of genomic sites, some tissue-specific, others ultra-conserved. It can act as a transcriptional activator, repressor and insulator, and it can pause transcription. CTCF binds at chromatin domain boundaries, at enhancers and gene promoters, and inside gene bodies. It can attract many other transcription factors to chromatin, including tissue-specific transcriptional activators, repressors, cohesin and RNA polymerase II, and it forms chromatin loops. Yet, or perhaps therefore, CTCF's exact function at a given genomic site is unpredictable. It appears to be determined by the associated transcription factors, by the location of the binding site relative to the transcriptional start site of a gene, and by the site's engagement in chromatin loops with other CTCF-binding sites, enhancers or gene promoters. Here, we will discuss genome-wide features of CTCF binding events, as well as locus-specific functions of this remarkable transcription factor.

Keywords: CTCF; chromatin loops; cohesin; nuclear organization; transcription.

Figure 1.

CTCF, chromatin loops and transcription regulation at selected gene loci. (a) Genes at the β-globin locus are under control of the locus control region (LCR). CTCF-binding sites interact to create a chromatin hub with a loop encompassing the LCR and the β-globin genes. Upon erythroid differentiation, erythroid-specific transcription factors and cohesin enable the formation of an active chromatin hub in which the LCR contacts the genes and enhances their expression. (b) Imprinted expression of the H19 and Igf2 genes is mediated by methylation-dependent binding of CTCF at the imprinted control region (ICR). (i) On the paternal allele, methylation of the ICR prevents CTCF binding and allows expression of the Igf2 gene mediated by contacts between the distal enhancer (E) and the Igf2 promoter. (ii) CTCF binding at the ICR blocks communication between the Igf2 gene and the distal enhancer resulting in expression of the H19 gene from the maternal allele.

Figure 2.

A versatile role for CTCF in chromatin biology. (a) Functional categories of CTCF binding sites across the genome, adopted from Chen et al. [36]. (b) (i) CTCF binding sites are found at boundaries that separate active and inactive domains. CTCF binding to (ii) enhancer-like sequences and (iv) gene promoters can facilitate looping between these sequences. (iii) CTCF binding in between enhancers and gene promoters can block the interaction between an enhancer and its target promoter.

Figure 3.

CTCF acts as an insulator by hampering DNA contacts across its binding sites. (a) CTCF hampers sequences within 10 kb of its binding sites to reach across [77]. Decreased thickness of lines indicates a decrease in interaction probability. (b) CTCF binding sites are often found at the borders of topological domains. (i) Hi-C data in ESCs and in cortex, with colour-coded contact frequencies between sequences on mouse chromosome 12. Triangles reveal and highlight topological domains [15], being chromosomal regions within which sequences preferentially interact with each other. (ii) Lamina-associated domain (LAD) data [14,35], showing that LAD boundaries coincide with the borders of topological domains. (iii) CTCF ChIP-seq profiles, showing clusters of CTCF binding sites at the borders [10]. Note that such CTCF clusters also exist elsewhere, particularly in non-LADs. Region shown: chr12: 112.3–119.3 Mb (mm9).