title: A recombination silencer that specifies heterochromatin positioning and ikaros association in the immunoglobulin kappa locus.
abstract: Allelic exclusion ensures that individual B lymphocytes produce only one kind of antibody molecule. Previous studies have shown that allelic exclusion of the mouse Igkappa locus occurs by the combination of monoallelic silencing and a low level of monoallelic activation for rearrangement combined with a negative feedback loop blocking additional functional rearrangements. Using yeast artificial chromosome-based single-copy isotransgenic mice, we have identified a cis-acting element that negatively regulates rearrangement in this locus, specifically in B cells. The element, termed Sis, resides in the V-J intervening sequence. Sis specifies the targeting of Igkappa transgenes in pre-B and B cells to centromeric heterochromatin and associates with Ikaros, a repressor protein that also colocalizes with centromeric heterochromatin. Significantly, these are hallmarks of silenced endogenous germline Igkappa genes in B cells. These results lead us to propose that Sis participates in the monoallelic silencing aspect of allelic exclusion regulation.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, 75390, USA.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Liu
authors.forename: Piotr
authors.initials: P
authors.lastname: Widlak
authors.forename: Ying
authors.initials: Y
authors.lastname: Zou
authors.forename: Fei
authors.initials: F
authors.lastname: Xiao
authors.forename: Misook
authors.initials: M
authors.lastname: Oh
authors.forename: Shuyu
authors.initials: S
authors.lastname: Li
authors.forename: Mee Young
authors.initials: MY
authors.lastname: Chang
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
authors.forename: William T
authors.initials: WT
authors.lastname: Garrard
mesh_terms: D000818:Animals; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain / Q000235:genetics; D020868:Gene Silencing; D005803:Genes, Immunoglobulin; D006570:Heterochromatin / Q000235:genetics*; D051740:Ikaros Transcription Factor / Q000235:genetics*; D021621:Imaging, Three-Dimensional; D007145:Immunoglobulin kappa-Chains / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008822:Mice, Transgenic; D011995:Recombination, Genetic / Q000235:genetics*; D050436:Regulatory Elements, Transcriptional / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D006570:Heterochromatin; D007145:Immunoglobulin kappa-Chains; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor