CCCTC-Binding Factor (CTCF)

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  • CCCTC-binding factor (CTCF) is a highly conserved and multifunctional DNA-binding protein that plays a central role in the organization of the three-dimensional (3D) structure of the genome. 
  • It is best known as a chromatin architectural protein that contributes to the formation of topologically associating domains (TADs), insulates regulatory elements, and orchestrates long-range chromatin interactions. By binding to specific DNA sequences via its 11-zinc finger domains, CTCF acts as a master regulator of genome topology and transcriptional regulation in diverse biological contexts.
  • One of CTCF’s primary functions is its role as an insulator—a DNA element that can block the interaction between enhancers and promoters when positioned between them. This insulator activity helps ensure that gene expression is tightly controlled and that enhancers activate only their intended target genes. CTCF’s ability to mediate this function depends on its sequence-specific binding and its cooperation with other proteins, most notably the cohesin complex. Together, CTCF and cohesin form chromatin loops that delineate TADs, spatially confining enhancer-promoter interactions and creating domains of gene regulation that are largely conserved across cell types and species.
  • Beyond its architectural role, CTCF also participates directly in transcriptional regulation. It can act as both a transcriptional activator and repressor, depending on its binding context. For instance, CTCF can recruit co-repressors or block the progression of RNA polymerase II, effectively silencing genes, or it can help maintain an open chromatin conformation at certain loci to facilitate transcription. In imprinting control regions (ICRs), CTCF binding is often allele-specific and methylation-sensitive, playing a crucial role in parent-of-origin-specific gene expression. A prominent example is the H19/Igf2 locus, where CTCF binding on the maternal allele maintains insulation and prevents Igf2 activation.
  • CTCF’s role in epigenetic regulation is also significant. Its binding can be influenced by DNA methylation status, as methylation of CpG dinucleotides within CTCF motifs often prevents binding. This sensitivity links CTCF to developmental regulation and epigenetic memory, as differential methylation patterns can dynamically modulate its occupancy and, consequently, gene expression patterns. Moreover, CTCF has been implicated in X-chromosome inactivation and the maintenance of pluripotency in embryonic stem cells.
  • Disruption of CTCF function has been linked to various diseases, especially cancer. Mutations in the CTCF gene or changes in its binding sites can lead to altered chromatin structure, aberrant gene expression, and genomic instability. CTCF loss or mislocalization can result in the fusion of TADs, allowing inappropriate enhancer-promoter contacts that activate oncogenes or repress tumor suppressors. In addition, CTCF is emerging as a key player in neurological disorders and developmental syndromes, further underscoring its critical role in genome function.
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