title: CTCF-mediated topological boundaries during development foster appropriate gene regulation.
abstract: The genome is organized into repeating topologically associated domains (TADs), each of which is spatially isolated from its neighbor by poorly understood boundary elements thought to be conserved across cell types. Here, we show that deletion of CTCF (CCCTC-binding factor)-binding sites at TAD and sub-TAD topological boundaries that form within the HoxA and HoxC clusters during differentiation not only disturbs local chromatin domain organization and regulatory interactions but also results in homeotic transformations typical of Hox gene misregulation. Moreover, our data suggest that CTCF-dependent boundary function can be modulated by competing forces, such as the self-assembly of polycomb domains within the nucleus. Therefore, CTCF boundaries are not merely static structural components of the genome but instead are locally dynamic regulatory structures that control gene expression during development.
authors.affiliation: Howard Hughes Medical Institute, New York, New York 10016, USA.|Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Varun
authors.initials: V
authors.lastname: Narendra
authors.affiliation: Department of Biology, New York University, New York, New York 10003, USA.
authors.forename: Milica
authors.initials: M
authors.lastname: Bulajić
authors.affiliation: Howard Hughes Medical Institute, New York, New York 10016, USA.|Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Job
authors.initials: J
authors.lastname: Dekker
authors.affiliation: Department of Biology, New York University, New York, New York 10003, USA.
authors.forename: Esteban O
authors.initials: EO
authors.lastname: Mazzoni
authors.affiliation: Howard Hughes Medical Institute, New York, New York 10016, USA.|Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Danny
authors.initials: D
authors.lastname: Reinberg
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics; D000076246:CCCTC-Binding Factor; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D053595:Embryonic Stem Cells; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D040481:Genome Components / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D000072417:Protein Domains; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000076246:CCCTC-Binding Factor; C000619698:Ctcf protein, mouse; D018398:Homeodomain Proteins; D012097:Repressor Proteins
keywords: CTCF; Hox gene regulation; Polycomb/Trithorax; TADs; chromatin and epigenetics; chromosomal conformation