title: A multifunctional element in the mouse Igκ locus that specifies repertoire and Ig loci subnuclear location.
abstract: Nonbiased V gene usage for V(D)J joining is essential for providing an optimal immune system, but no cis-acting sequence with this function has been uncovered. We previously identified a recombination silencer and heterochromatin targeting element in the Vκ-Jκ intervening sequence of germline Igκ transgenes, which we termed Sis. We now have generated Sis knockout mice in the endogenous locus. Intriguingly, Sis(-/-) mice exhibit a skewed Igκ repertoire with markedly decreased distal and enhanced proximal Vκ gene usage for primary rearrangement, which is associated with reduced occupancy of Ikaros and CCCTC-binding factor in the Vκ-Jκ intervening sequence in pre-B cells, proteins believed to be responsible for dampening the recombination of nearby Vκ genes and altering higher-order chromatin looping. Furthermore, monoallelic heterochromatin localization is significantly reduced in Sis(-/-) mice for Igκ in cis and IgH loci in trans in pre-B cells. Because Sis(-/-) mice still allelically excluded Igκ and IgH loci and still exhibited IgL isotype exclusion, we concluded that stable localization at pericentromeric heterochromatin is neither necessary nor sufficient for the establishment or maintenance of allelic exclusion. Hence, Sis is a novel multifunctional element that specifies repertoire and heterochromatin localization to Ig genes.
authors: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Yougui
authors: Y
authors: Xiang
authors: Xiaorong
authors: X
authors: Zhou
authors: Susannah L
authors: SL
authors: Hewitt
authors: Jane A
authors: JA
authors: Skok
authors: William T
authors: WT
authors: Garrard
mesh_terms: D000818:Animals; D002469:Cell Separation; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain / Q000235:genetics*; D005803:Genes, Immunoglobulin / Q000235:genetics*; D006570:Heterochromatin / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007136:Immunoglobulins / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D018345:Mice, Knockout; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D006570:Heterochromatin; C014609:IgK; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D007136:Immunoglobulins