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  • Review Article
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CTCF: an architectural protein bridging genome topology and function

Nature Reviews Genetics volume 15, pages 234–246 (2014)Cite this article

Subjects

Key Points

  • CCCTC-binding factor (CTCF) is an architectural protein that can mediate both interchromosomal and intrachromosomal interactions.

  • The functional outcomes of these interactions depend on the nature of the sequences adjacent to CTCF-binding sites and perhaps on the presence of other chromatin proteins.

  • CTCF-mediated chromatin loops regulate diverse nuclear processes, including V(D)J recombination, enhancer–promoter interactions, transcriptional pausing and alternative mRNA splicing.

  • The consensus sequence of CTCF-binding sites is highly conserved. Its variable DNA occupancy pattern is regulated by DNA methylation, non-coding RNAs and post-translational modification.

  • CTCF and other architectural proteins, such as cohesin and TFIIIC, maintain genome organization by clustering at the boundaries of megabase-scale topologically associating domains.

  • Cell-type-specific chromatin organization occurs at the sub-megabase scale; CTCF, either alone or in combination with other proteins, regulates specific transcriptional processes.

Abstract

The eukaryotic genome is organized in the three-dimensional nuclear space in a specific manner that is both a cause and a consequence of its function. This organization is partly established by a special class of architectural proteins, of which CCCTC-binding factor (CTCF) is the best characterized. Although CTCF has been assigned various roles that are often contradictory, new results now help to draw a unifying model to explain the many functions of this protein. CTCF creates boundaries between topologically associating domains in chromosomes and, within these domains, facilitates interactions between transcription regulatory sequences. Thus, CTCF links the architecture of the genome to its function.

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Figure 1: Features of CTCF-binding sites in the genome.
Figure 2: Regulation of CTCF binding to DNA.
Figure 3: CTCF regulates enhancer–promoter interactions in a multigene cluster.
Figure 4: CTCF facilitates endodermal enhancer–promoter interactions in ESCs.
Figure 5: CTCF regulates V(D)J recombination.
Figure 6: CTCF promotes alternative mRNA splicing.
Figure 7: CTCF regulates three-dimensional genome architecture.

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Acknowledgements

Work in the authors' laboratory is supported by US Public Health Service Award R01 GM035463 from the US National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health.

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  1. Department of Biology, Emory University, 1510 Clifton Rd NE, Atlanta, 30322, Georgia, USA

    Chin-Tong Ong & Victor G. Corces

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  1. Chin-Tong Ong
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Correspondence to Victor G. Corces.

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Glossary

Chromosome conformation capture

(3C). A ligation-based technique that is used to map interactions between two specific genomic regions.

ChIP-exo

An extension of chromatin immunoprecipitation followed by sequencing (ChIP–seq) that includes exonuclease trimming after ChIP to increase the resolution of the mapped transcription factor bound sites.

Circular chromosome conformation capture

(4C). The combination of inverse PCR and high-throughput sequencing with the chromosome conformation capture (3C) technique that allows the profiling of chromatin interactions between a known specific locus and multiple unknown sites.

DNase I hypersensitive sites

Chromosomal regions that are readily degraded by deoxyribonuclease I (DNase I) owing to decreased nucleosome occupancy. These sites are associated with open chromatin conformation and the binding of transcription factors.

Nuclear lamina

A scaffold of proteins comprised mainly of lamin A/C and B that is predominantly found in the nuclear periphery; it is associated with the inner surface of the nuclear membrane.

Chromatin interaction analysis with paired-end tag sequencing

(ChIA–PET). A technique used to determine the chromosomal interactions that are mediated by a specific chromatin-binding protein by combining chromatin immunoprecipitation with a chromosome conformation capture (3C)-type analysis.

Chromosome conformation capture carbon copy

(5C). A technique used to profile all chromatin interactions in specific regions of the genome by the hybridization of a mixture of DNA primers to chromosome conformation capture (3C) templates followed by high-throughput sequencing.

Mediator complex

The ~30-subunit co-activator complex that is required for successful transcription of RNA polymerase II (Pol II) promoters of metazoans genes. Its interaction with Pol II and site-specific factors facilitates enhancer–promoter communication.

Adaptive response

The acquired immune response to the specific antigen presented on a pathogen that typically triggers immunological memory.

Pro-B cells

B cells at their earliest developmental stage in the bone marrow that are defined as the CD19+ cytoplasmic IgM− or B220+CD43+ population and that have incomplete rearrangement of the immunoglobulin heavy chain.

Double-positive thymocytes

Immature T cells characterized by the expression of CD4 and CD8 cell surface markers that will differentiate into single-positive thymocytes after their T cell receptors interact with self-peptide major histocompatibility complex ligands in the thymus.

Pre-pro-B cells

The lymphoid progenitors found in the bone marrow that contain the CLP-2s surface marker and lack heavy-chain diversity (D)–joining (J) rearrangements.

Hi-C

An extension of the chromosome conformation capture (3C) technique that incorporates a biotin-labelled nucleotide at the ligation junction to allow selective purification of chimeric DNA ligated products for high-throughput sequencing. This method generates matrices of interaction frequencies across the genome.

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Ong, CT., Corces, V. CTCF: an architectural protein bridging genome topology and function. Nat Rev Genet 15, 234–246 (2014). https://doi.org/10.1038/nrg3663

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