CTCF (CCCTC BINDING FACTOR)

CTCF (CCCTC Binding Factor)



CTCF (CCCTC Binding Factor)

Electron micrographs of transcribing rDNA loci by O. L. Miller, Jr. and colleagues have provided a cytological foundation to subsequent studies showing histone modification-, DNA methylation-, and regulatory RNA-mediated epigenetic regulation of the rDNA loci across kingdoms. Many studies have led to the prevailing view that only about one-half of the rDNA cistrons are active, while the remainder are kept silent through epigenetic modification of chromatin structure. Although much is now known about rDNA chromatin structure, relatively little is known about the decisions of how many and which cistrons are inactive, whether all cell types make this decision, and once made how active and inactive chromatin domains are kept separate. Balance between activating and repressive factors may control the ratio, although such a model does not account for the preferential inactivation of the subset of cistrons that might be interrupted by transposable element. To account for this, a simple model suggests a sequence-specific repressor might inactivate some rDNA cistrons, and a boundary element may maintain separation of active and inactive regions. Although RNA Polymerase III, RNA Polymerase I regulators, or DNA-replication proteins may serve to separate domains in yeasts . little is known of how similar regulation may be accomplished in animals and plants.

In arthropods, the R1 and R2 non-long-terminal-repeat (non-LTR) retrotransposable elements interrupt a high proportion of 35S rDNA cistrons (17%-67% rDNA copies are interrupted by R1, 2%-28% by R2, and up to 16% by both), and molecular and cytological evidence show that these are almost always inactivated. These elements are inserted in a conserved site within the 28S subunit and are colinearly transcribed with the 35S rDNA, showing that transcriptional silencing due to their presence affects the rDNA promoter approximately four kilobases away.

CTCF is a protein with complex roles in gene regulation, having been shown to act as both transcriptional activator and repressor, and be responsible for two features of genomic “boundary elements,” namely the abilities to separate chromatin with activating and inactivating histone modifications and to block enhancer-promoter interactions (recently reviewed in ). CTCF plays regulatory roles in the large Homeotic gene complexes of flies and mammals , , is thought to be necessary to maintain monoallelic expression of genomic imprinted loci in mouse and humans , and binds the inactive (dosage compensated) female mammalian X chromosome . Hence, it possess the properties expected for a protein that might regulate and separate interspersed active and inactive rDNA cistrons. Unraveling the overlapping and separate properties of CTCF has been difficult, since consensus DNA binding sites, interaction partners, and genetic properties have proven difficult to exhaustively enumerate , .

Torrano and colleagues noted that CTCF moves to the nucleoli of terminally-differentiated mammalian (human and rat) cells . It has been suggested that the localization might be a necessary step for CTCF to regulate the euchromatin , implying that it has no active role in the nucleolus. This view is perhaps appealing because of the example of p53 and ARF, whose regulation ...