A Multifunctional Element in the Mouse Ig kappa Locus That Specifies Repertoire and Ig Loci Subnuclear Location

作者：Xiang, Yougui; Zhou, Xiaorong; Hewitt, Susannah L.; Skok, Jane A.; Garrard, William T.^*

来源：The Journal of Immunology, 2011, 186(9): 5356-5366.

DOI：10.4049/jimmunol.1003794

• B-CELL DEVELOPMENT
• HEAVY-CHAIN GENE
• IMMUNOGLOBULIN LOCI
• ALLELIC EXCLUSION
• V(D)J RECOMBINATION
• X-INACTIVATION
• LYMPHOCYTE DEVELOPMENT
• CONTROL REGION
• CHROMATIN
• CTCF

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 kappa-J kappa intervening sequence of germline Ig kappa transgenes, which we termed Sis. We now have generated Sis knockout mice in the endogenous locus. Intriguingly, Sis(-/-) mice exhibit a skewed Ig kappa repertoire with markedly decreased distal and enhanced proximal V kappa gene usage for primary rearrangement, which is associated with reduced occupancy of Ikaros and CCCTC-binding factor in the V kappa-J kappa intervening sequence in pre-B cells, proteins believed to be responsible for dampening the recombination of nearby V kappa genes and altering higher-order chromatin looping. Furthermore, monoallelic heterochromatin localization is significantly reduced in Sis(-/-) mice for Igk in cis and IgH loci in trans in pre-B cells. Because Sis(-/-) mice still allelically excluded Ig kappa 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. The Journal of Immunology, 2011, 186: 5356-5366.

• 出版日期2011-5-1
• 单位南通大学