title: The three-dimensional architecture of Hox cluster silencing.
abstract: Spatial chromatin organization is emerging as an important mechanism to regulate the expression of genes. However, very little is known about genome architecture at high-resolution in vivo. Here, we mapped the three-dimensional organization of the human Hox clusters with chromosome conformation capture (3C) technology. We show that computational modeling of 3C data sets can identify candidate regulatory proteins of chromatin architecture and gene expression. Hox genes encode evolutionarily conserved master regulators of development which strict control has fascinated biologists for over 25 years. Proper transcriptional silencing is key to Hox function since premature expression can lead to developmental defects or human disease. We now show that the HoxA cluster is organized into multiple chromatin loops that are dependent on transcription activity. Long-range contacts were found in all four silent clusters but looping patterns were specific to each cluster. In contrast to the Drosophila homeotic bithorax complex (BX-C), we found that Polycomb proteins are only modestly required for human cluster looping and silencing. However, computational three-dimensional Hox cluster modeling identified the insulator-binding protein CTCF as a likely candidate mediating DNA loops in all clusters. Our data suggest that Hox cluster looping may represent an evolutionarily conserved structural mechanism of transcription regulation.
authors.affiliation: Department of Biochemistry, and Goodman Cancer Research Center, McGill University, 3655 Promenade Sir-William-Osler, Montréal, Québec, Canada.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Ferraiuolo
authors.forename: Mathieu
authors.initials: M
authors.lastname: Rousseau
authors.forename: Carol
authors.initials: C
authors.lastname: Miyamoto
authors.forename: Solomon
authors.initials: S
authors.lastname: Shenker
authors.forename: Xue Qing David
authors.initials: XQ
authors.lastname: Wang
authors.forename: Michelle
authors.initials: M
authors.lastname: Nadler
authors.forename: Mathieu
authors.initials: M
authors.lastname: Blanchette
authors.forename: Josée
authors.initials: J
authors.lastname: Dostie
mesh_terms: D000076246:CCCTC-Binding Factor; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry*; D020868:Gene Silencing; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D005810:Multigene Family; D012097:Repressor Proteins / Q000737:chemistry / Q000502:physiology; D014158:Transcription, Genetic; D055815:Young Adult
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D002843:Chromatin; D018398:Homeodomain Proteins; D012097:Repressor Proteins; C088144:HoxA protein