A multifunctional element in the mouse Ig? 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 V?-J? intervening sequence of germline Ig? transgenes, which we termed Sis. We now have generated Sis knockout mice in the endogenous locus. Intriguingly, Sis(-/-) mice exhibit a skewed Ig? repertoire with markedly decreased distal and enhanced proximal V? gene usage for primary rearrangement, which is associated with reduced occupancy of Ikaros and CCCTC-binding factor in the V?-J? intervening sequence in pre-B cells, proteins believed to be responsible for dampening the recombination of nearby V? genes and altering higher-order chromatin looping. Furthermore, monoallelic heterochromatin localization is significantly reduced in Sis(-/-) mice for Ig? in cis and IgH loci in trans in pre-B cells. Because Sis(-/-) mice still allelically excluded Ig? 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.

SUBMITTER: Xiang Y 

PROVIDER: S-EPMC3080443 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature