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.

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.

Although CTCF was initially discovered as a transcription factor , and most of its binding is at cis-regulatory regions in combination with other transcription factors , later research has shifted to its role in regulating the 3D structure of chromatin. CTCF bookmarks distant regions on the DNA which can be connected by chromatin loops, and such loops can account for creating chromatin compartments, domains, nanodomains, territories, and specific structures like topologically associating domain (TAD) or lamina-associated domain (LAD). 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. In a recent study, it has been shown that, in addition to demarcating TADs, CTCF mediates promoter–enhancer loops, often located in promoter-proximal regions, to facilitate the promoter–enhancer interactions within one TAD. This is in line with the concept that a subpopulation of CTCF associates with the RNA polymerase II (Pol II) protein complex to activate transcription. It is likely that CTCF helps to bridge the transcription factor-bound enhancers to transcription start site-proximal regulatory elements and to initiate transcription by interacting with Pol II, thus supporting a role of CTCF in facilitating contacts between transcription regulatory sequences. This model has been demonstrated by the previous work on the beta-globin locus.

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).

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.

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.

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. It is currently believed that the DNA loops are formed by the loop extrusion mechanism, whereby the cohesin ring is actively being translocated along the DNA until it meets CTCF. CTCF has to be in a proper orientation to stop cohesin.