title: The distal V(H) gene cluster of the Igh locus contains distinct regulatory elements with Pax5 transcription factor-dependent activity in pro-B cells.
abstract: V(H)-DJ(H) recombination of the immunoglobulin heavy chain (Igh) locus is temporally and spatially controlled during early B cell development, and yet no regulatory elements other than the V(H) gene promoters have been identified throughout the entire V(H) gene cluster. Here, we discovered regulatory sequences that are interspersed in the distal V(H) gene region. These conserved repeat elements were characterized by the presence of Pax5 transcription factor-dependent active chromatin by binding of the regulators Pax5, E2A, CTCF, and Rad21, as well as by Pax5-dependent antisense transcription in pro-B cells. The Pax5-activated intergenic repeat (PAIR) elements were no longer bound by Pax5 in pre-B and B cells consistent with the loss of antisense transcription, whereas E2A and CTCF interacted with PAIR elements throughout early B cell development. The pro-B cell-specific and Pax5-dependent activity of the PAIR elements suggests that they are involved in the regulation of distal V(H)-DJ(H) recombination at the Igh locus.
authors.affiliation: Research Institute of Molecular Pathology, Vienna Biocenter, Dr. Bohr-Gasse 7, Vienna, Austria.
authors.forename: Anja
authors.initials: A
authors.lastname: Ebert
authors.forename: Shane
authors.initials: S
authors.lastname: McManus
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tagoh
authors.forename: Jasna
authors.initials: J
authors.lastname: Medvedovic
authors.forename: Giorgia
authors.initials: G
authors.lastname: Salvagiotto
authors.forename: Maria
authors.initials: M
authors.lastname: Novatchkova
authors.forename: Ido
authors.initials: I
authors.lastname: Tamir
authors.forename: Andreas
authors.initials: A
authors.lastname: Sommer
authors.forename: Markus
authors.initials: M
authors.lastname: Jaritz
authors.forename: Meinrad
authors.initials: M
authors.lastname: Busslinger
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology; D001665:Binding Sites; D000076246:CCCTC-Binding Factor; D002843:Chromatin / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D017124:Conserved Sequence; D021901:DNA, Intergenic / Q000235:genetics*; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D005803:Genes, Immunoglobulin / Q000235:genetics*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D051757:PAX5 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism; D016372:RNA, Antisense / Q000096:biosynthesis / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D012097:Repressor Proteins / Q000502:physiology; D014158:Transcription, Genetic
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000076246:CCCTC-Binding Factor; D002843:Chromatin; D021901:DNA, Intergenic; D007143:Immunoglobulin Heavy Chains; D051757:PAX5 Transcription Factor; D016372:RNA, Antisense; D012097:Repressor Proteins; C000619698:Ctcf protein, mouse; C497282:Pax5 protein, mouse; C075668:Tcf3 protein, mouse