The genome is organized via CTCF-cohesin-binding sites, which partition chromosomes into 1-5 megabase (Mb) topologically associated domains (TADs), and further into smaller sub-domains (sub-TADs). Here we examined in vivo an ∼80 kb sub-TAD, containing the mouse α-globin gene cluster, lying within a ∼1 Mb TAD. We find that the sub-TAD is flanked by predominantly convergent CTCF-cohesin sites that are ubiquitously bound by CTCF but only interact during erythropoiesis, defining a self-interacting erythroid compartment. Whereas the α-globin regulatory elements normally act solely on promoters downstream of the enhancers, removal of a conserved upstream CTCF-cohesin boundary extends the sub-TAD to adjacent upstream CTCF-cohesin-binding sites. The α-globin enhancers now interact with the flanking chromatin, upregulating expression of genes within this extended sub-TAD. Rather than acting solely as a barrier to chromatin modification, CTCF-cohesin boundaries in this sub-TAD delimit the region of chromatin to which enhancers have access and within which they interact with receptive promoters.
Nat Cell Biol
952 - 961
Animals, Binding Sites, Blood Group Antigens, CCCTC-Binding Factor, Cell Cycle Proteins, Cell Line, Chromatin, Chromatin Assembly and Disassembly, Chromosomal Proteins, Non-Histone, Embryonic Stem Cells, Enhancer Elements, Genetic, Erythroid Cells, Female, Gene Expression Regulation, Developmental, Genotype, Hematopoietic Stem Cells, Male, Mice, Inbred C57BL, Multigene Family, Mutation, Phenotype, Promoter Regions, Genetic, Protein Binding, Repressor Proteins, Transfection, alpha-Globins