A recombination silencer that specifies heterochromatin positioning and ikaros association in the immunoglobulin kappa locus.
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.
Liu
Zhe
Z
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, 75390, USA.
Widlak
Piotr
P
Zou
Ying
Y
Xiao
Fei
F
Oh
Misook
M
Li
Shuyu
S
Chang
Mee Young
MY
Shay
Jerry W
JW
Garrard
William T
WT
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
D006570:Heterochromatin; D007145:Immunoglobulin kappa-Chains; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor