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Regulating V(D)J recombination: Rol...

Liang, Hong-Erh.

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Regulating V(D)J recombination: Roles of the "dispensable" portion of RAG2 and the immunoglobulin kappa 3' enhancer element in developmentally regulated antigen receptor gene rearrangement.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Regulating V(D)J recombination: Roles of the "dispensable" portion of RAG2 and the immunoglobulin kappa 3' enhancer element in developmentally regulated antigen receptor gene rearrangement./
Author:	Liang, Hong-Erh.
Description:	168 p.
Notes:	Adviser: Mark Schlissel.
Contained By:	Dissertation Abstracts International63-03B.
Subject:	Biology, Molecular. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3046494
ISBN:	049360684X

Regulating V(D)J recombination: Roles of the "dispensable" portion of RAG2 and the immunoglobulin kappa 3' enhancer element in developmentally regulated antigen receptor gene rearrangement.
Liang, Hong-Erh.

Regulating V(D)J recombination: Roles of the "dispensable" portion of RAG2 and the immunoglobulin kappa 3' enhancer element in developmentally regulated antigen receptor gene rearrangement. - 168 p.

Adviser: Mark Schlissel.

Thesis (Ph.D.)--The Johns Hopkins University, 2002.

Immunoglobulin (Ig) and T cell receptor (TCR) genes are assembled during B and T lymphocyte development through a series of site-specific recombination events referred to as V(D)J recombination. All gene segments utilized in V(D)J recombination are flanked by conserved recombination signal sequences (RSS) that are recognized by a common recombinase machinery composed of two lymphoid-specific gene products, RAG1 and RAG2. In order to characterize the role of the C-terminal “dispensable” portion of RAG2 in endogenous V(D)J recombination, we generated core-RAG2 knock-in mice. Despite the accumulation of the truncated protein, the recombinase complex containing core-RAG2 is selectively defective in catalyzing V-to-DJ rearrangement at IgH and TCRβ locus, which results in corresponding developmental blocks in B and T lymphopoiesis. Further analysis of the recombination intermediates showed defects at the cleavage phase of the reaction. We also observed a reduction of recombinase activity in core-RAG2 expressing thymocytes leading us to suggest that the interaction of a defective recombinase and the intrinsic character of the VH/Vβ RSS substrates may underlie the specific V-to-DJ rearrangement defect in core-RAG2 mice. Carried out by common recombinase machinery, the rearrangement of particular Ig and TCR gene segments, however, is tightly regulated with respect to cell lineage and developmental stage. It has been shown that chromatin structure plays a critical role in regulating the activity of the V(D)J recombinase and the structural change of a particular locus or group of gene segments within chromatin is determined by the lineage and developmental stage of the cell. Remodeling of chromatin during development to establish accessibility to the V(D)J recombinase may be directed in part by <italic> cis</italic>-regulatory elements, including transcriptional enhancers. Through analysis of mice carrying germline deletion of the Ig kappa chain 3<super> ′</super>enhancer (3<super>′</super>Eκ), we found that deletion of the <italic>cis</italic>-acting 3<super>′</super>Eκ has no effect on the lineage and stage-specificity of Igκ rearrangement <italic> per se</italic> but rather causes the deregulated recombinase accessibility at Ig heavy chain (IgH) locus which is located on another chromosome. This <italic> trans</italic>-effect also suggests that transcription factors bound to the 3<super>′</super>Eκ enhancer may participate in uncharacterized processes involving in cross-communication between different Ig gene loci as well as the enforcement of the IgH gene allelic exclusion.

ISBN: 049360684XSubjects--Topical Terms:

1017719
Biology, Molecular.

Regulating V(D)J recombination: Roles of the "dispensable" portion of RAG2 and the immunoglobulin kappa 3' enhancer element in developmentally regulated antigen receptor gene rearrangement.
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245 1 0 $a Regulating V(D)J recombination: Roles of the "dispensable" portion of RAG2 and the immunoglobulin kappa 3' enhancer element in developmentally regulated antigen receptor gene rearrangement.
300 $a 168 p.
500 $a Adviser: Mark Schlissel.
500 $a Source: Dissertation Abstracts International, Volume: 63-03, Section: B, page: 1250.
502 $a Thesis (Ph.D.)--The Johns Hopkins University, 2002.
520 $a Immunoglobulin (Ig) and T cell receptor (TCR) genes are assembled during B and T lymphocyte development through a series of site-specific recombination events referred to as V(D)J recombination. All gene segments utilized in V(D)J recombination are flanked by conserved recombination signal sequences (RSS) that are recognized by a common recombinase machinery composed of two lymphoid-specific gene products, RAG1 and RAG2. In order to characterize the role of the C-terminal “dispensable” portion of RAG2 in endogenous V(D)J recombination, we generated core-RAG2 knock-in mice. Despite the accumulation of the truncated protein, the recombinase complex containing core-RAG2 is selectively defective in catalyzing V-to-DJ rearrangement at IgH and TCRβ locus, which results in corresponding developmental blocks in B and T lymphopoiesis. Further analysis of the recombination intermediates showed defects at the cleavage phase of the reaction. We also observed a reduction of recombinase activity in core-RAG2 expressing thymocytes leading us to suggest that the interaction of a defective recombinase and the intrinsic character of the VH/Vβ RSS substrates may underlie the specific V-to-DJ rearrangement defect in core-RAG2 mice. Carried out by common recombinase machinery, the rearrangement of particular Ig and TCR gene segments, however, is tightly regulated with respect to cell lineage and developmental stage. It has been shown that chromatin structure plays a critical role in regulating the activity of the V(D)J recombinase and the structural change of a particular locus or group of gene segments within chromatin is determined by the lineage and developmental stage of the cell. Remodeling of chromatin during development to establish accessibility to the V(D)J recombinase may be directed in part by <italic> cis</italic>-regulatory elements, including transcriptional enhancers. Through analysis of mice carrying germline deletion of the Ig kappa chain 3<super> ′</super>enhancer (3<super>′</super>Eκ), we found that deletion of the <italic>cis</italic>-acting 3<super>′</super>Eκ has no effect on the lineage and stage-specificity of Igκ rearrangement <italic> per se</italic> but rather causes the deregulated recombinase accessibility at Ig heavy chain (IgH) locus which is located on another chromosome. This <italic> trans</italic>-effect also suggests that transcription factors bound to the 3<super>′</super>Eκ enhancer may participate in uncharacterized processes involving in cross-communication between different Ig gene loci as well as the enforcement of the IgH gene allelic exclusion.
590 $a School code: 0098.
650 4 $a Biology, Molecular. $3 1017719
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