CTCF-mediated gene insulation via chromatin looping at several model loci. (A) Allele-specific, DNA methylation-sensitive binding of CTCF and chromatin looping account for parent-of-origin H19 and Igf2 gene expression patterns during mouse development. DMR indicates differentially methylated region; Ee, endodermal tissue enhancer; ICR, imprinting control region; and Em, mesodermal tissue enhancer. (B) In progenitor cells, mouse globin genes embedded within the olfactory receptor (OR) gene cluster are looped out from the CTCF-mediated chromatin hub, and ϵy and βh1 are expressed. On differentiation, dynamic interactions between the definitive erythroid genes β-major (βmaj) and β-minor (βmin) and the LCR are observed. HS indicates hypersensitive site. (C) IFN-γ treatment induces cotranscription of the human HLA-DRB1 and HLA-DQA1 genes in nonexpressing cell types by up-regulating the coactivator CIITA. Gene activation results from heterodimer formation between CIITA and the transcription factors RFX, CREB, and NF-Y bound to the inactive promoter of the MHC class II genes and the CTCF-bound XL9 enhancer. (D) On mouse Th1 cell differentiation, CTCF cooperates with T-bet to juxtapose distal regulatory elements, including the conserved noncoding sequence (CNS)–34 enhancer, to the Ifng gene. This results in a Th1-cell–specific chromatin structure at the Ifng locus for efficient IFN-γ transcription.