CTCF

For the prison, see Colorado Territorial Correctional Facility.

CCCTC-binding factor (zinc finger protein)
PDB rendering based on 1x6h.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1X6H, 2CT1
Identifiers
Symbols	CTCF ; MRD21
External IDs	OMIM: 604167 MGI: 109447 HomoloGene: 4786 GeneCards: CTCF Gene
Gene ontology Molecular function • RNA polymerase II core promoter proximal region sequence-specific DNA binding • transcriptional repressor activity, RNA polymerase II core promoter proximal region sequence-specific binding • transcriptional activator activity, RNA polymerase II transcription regulatory region sequence-specific binding • transcription factor activity, sequence-specific DNA binding • transcription corepressor activity • protein binding • zinc ion binding • chromatin insulator sequence binding • sequence-specific DNA binding • transcription regulatory region DNA binding Cellular component • chromosome, centromeric region • condensed chromosome • nucleus • nucleoplasm • nucleolus Biological process • negative regulation of transcription from RNA polymerase II promoter • DNA methylation • regulation of gene expression by genetic imprinting • transcription from RNA polymerase II promoter • chromosome segregation • maintenance of DNA methylation • positive regulation of gene expression • chromatin modification • nucleosome positioning • regulation of histone methylation • regulation of histone acetylation • regulation of gene expression, epigenetic • regulation of molecular function, epigenetic • negative regulation of transcription, DNA-templated • positive regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase II promoter • regulation of centromeric sister chromatid cohesion Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	10664	13018
Ensembl	ENSG00000102974	ENSMUSG00000005698
UniProt	P49711	Q61164
RefSeq (mRNA)	NM_001191022	NM_181322
RefSeq (protein)	NP_001177951	NP_851839
Location (UCSC)	Chr 16: 67.56 – 67.64 Mb	Chr 8: 105.64 – 105.68 Mb
PubMed search	[1]	[2]

Transcriptional repressor CTCF also known as 11-zinc finger protein or CCCTC-binding factor is a transcription factor that in humans is encoded by the CTCF gene. CTCF is involved in many cellular processes, including transcriptional regulation, insulator activity, V(D)J recombination and regulation of chromatin architecture.

Discovery

CCCTC-Binding factor or CTCF was initially discovered as a negative regulator of the chicken c-myc gene. This protein was found to be binding to three regularly spaced repeats of the core sequence CCCTC and thus was named CCCTC binding factor.

Function

The primary role of CTCF is thought to be in regulating the 3D structure of chromatin. CTCF binds together strands of DNA, thus forming chromatin loops, and anchors DNA to cellular structures like the nuclear lamina. It also defines the boundaries between active and heterochromatic DNA.

Since the 3D structure of DNA influences the regulation of genes, CTCF's activity influences the expression of genes. CTCF is thought to be a primary part of the activity of insulators, sequences that block the interaction between enhancers and promoters. CTCF binding has also been both shown to promote and repress gene expression. It is unknown whether CTCF affects gene expression solely through its looping activity, or if it has some other, unknown, activity.

Observed activity

The binding of CTCF has been shown to have many effects, which are enumerated below. In each case, it is unknown if CTCF directly evokes the outcome or if it does so indirectly (in particular through its looping role).

Transcriptional regulation

The protein CTCF plays a heavy role in repressing the insulin-like growth factor 2 gene, by binding to the H-19 imprinting control region (ICR) along with differentially-methylated region-1 (DMR1) and MAR3.

Insulation

Binding of targeting sequence elements by CTCF can block the interaction between enhancers and promoters, therefore limiting the activity of enhancers to certain functional domains. Besides acting as enhancer blocking, CTCF can also act as a chromatin barrier by preventing the spread of heterochromatin structures.

Regulation of chromatin architecture

CTCF physically binds to itself to form homodimers, which causes the bound DNA to form loops. CTCF also occurs frequently at the boundaries of sections of DNA bound to the nuclear lamina. Using chromatin immuno-precipitation (ChIP) followed by ChIP-seq, it was found that CTCF localizes with cohesin genome-wide and affects gene regulatory mechanisms and the higher-order chromatin structure.

Regulation of RNA splicing

CTCF binding has been shown to influence mRNA splicing.

DNA binding

CTCF binds to the consensus sequence CCGCGNGGNGGCAG (in IUPAC notation). This sequence is defined by 11 zinc finger motifs in its structure. CTCF's binding is disrupted by CpG methylation of the DNA it binds to.

CTCF binds to an average of about 55,000 DNA sites in 19 diverse cell types (12 normal and 7 immortal) and in total 77,811 distinct binding sites across all 19 cell types. CTCF’s ability to bind to multiple sequences through the usage of various combinations of its zinc fingers earned it the status of a “multivalent protein”. More than 30,000 CTCF binding sites have been characterized. The human genome contains anywhere between 15,000-40,000 CTCF binding sites depending on cell type, suggesting a widespread role for CTCF in gene regulation. In addition CTCF binding sites act as nucleosome positioning anchors so that, when used to align various genomic signals, multiple flanking nucleosomes can be readily identified. On the other hand, high-resolution nucleosome mapping studies have demonstrated that the differences of CTCF binding between cell types may be attributed to the differences in nucleosome locations.

Protein-protein interactions

CTCF binds to itself to form homodimers. This activity is one possibility of the mechanism of its looping activity.

CTCF has also been shown to interact with Y box binding protein 1. CTCF also co-localizes with cohesin, which stabilizes the repressive loops organized by the CTCF.

External links

• CCCTC-binding factor at the US National Library of Medicine Medical Subject Headings (MeSH)
• FactorBook CTCF