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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.

Original publication

DOI

10.1038/ncb3573

Type

Journal article

Journal

Nature cell biology

Publication Date

08/2017

Volume

19

Pages

952 - 961

Addresses

The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK.

Keywords

Hematopoietic Stem Cells, Cell Line, Chromatin, Erythroid Cells, Animals, Mice, Inbred C57BL, Cell Cycle Proteins, Chromosomal Proteins, Non-Histone, Repressor Proteins, Blood Group Antigens, Transfection, Chromatin Assembly and Disassembly, Gene Expression Regulation, Developmental, Binding Sites, Protein Binding, Genotype, Phenotype, Mutation, Multigene Family, Female, Male, Embryonic Stem Cells, Enhancer Elements, Genetic, Promoter Regions, Genetic, alpha-Globins