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Regulation of V(D)J recombinase expr...

Amin, Rupesh Harshad.

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Regulation of V(D)J recombinase expression and the role of germline transcription in recombinase targeting during mouse B-cell development.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Regulation of V(D)J recombinase expression and the role of germline transcription in recombinase targeting during mouse B-cell development./
Author:	Amin, Rupesh Harshad.
Description:	202 p.
Notes:	Adviser: Mark S. Schlissel.
Contained By:	Dissertation Abstracts International68-08B.
Subject:	Biology, Bioinformatics. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3275328
ISBN:	9780549164944

Regulation of V(D)J recombinase expression and the role of germline transcription in recombinase targeting during mouse B-cell development.
Amin, Rupesh Harshad.

Regulation of V(D)J recombinase expression and the role of germline transcription in recombinase targeting during mouse B-cell development. - 202 p.

Adviser: Mark S. Schlissel.

Thesis (Ph.D.)--University of California, Berkeley, 2007.

During B and T lymphocyte development, the antigen receptor variable region exons are assembled from fragments in a series of site specific DNA recombination reactions---a process known as V(D)J recombination. The reaction is highly regulated, both at the level of V(D)J recombinase expression, and substrate accessibility. Only B and T cells express the RAG1 and RAG2 proteins which form the recombinase, and within each cell type only the respective antigen receptor genes are rearranged completely. Within B-cells recombination is further ordered such that the heavy chain locus rearranges before the light chain loci. We conducted experiments aimed at answering two fundamental questions about this process: (1) what trans-acting factors regulate expression of the RAG1 and RAG2 proteins during B-cell development, and (2) when the recombinase is expressed, how is it specifically targeted to either the heavy chain or light chain loci.

ISBN: 9780549164944Subjects--Topical Terms:

1018415
Biology, Bioinformatics.

Regulation of V(D)J recombinase expression and the role of germline transcription in recombinase targeting during mouse B-cell development.
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020 $a 9780549164944
035 $a (UMI)AAI3275328
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100 1 $a Amin, Rupesh Harshad. $3 1271149
245 1 0 $a Regulation of V(D)J recombinase expression and the role of germline transcription in recombinase targeting during mouse B-cell development.
300 $a 202 p.
500 $a Adviser: Mark S. Schlissel.
500 $a Source: Dissertation Abstracts International, Volume: 68-08, Section: B, page: 5119.
502 $a Thesis (Ph.D.)--University of California, Berkeley, 2007.
520 $a During B and T lymphocyte development, the antigen receptor variable region exons are assembled from fragments in a series of site specific DNA recombination reactions---a process known as V(D)J recombination. The reaction is highly regulated, both at the level of V(D)J recombinase expression, and substrate accessibility. Only B and T cells express the RAG1 and RAG2 proteins which form the recombinase, and within each cell type only the respective antigen receptor genes are rearranged completely. Within B-cells recombination is further ordered such that the heavy chain locus rearranges before the light chain loci. We conducted experiments aimed at answering two fundamental questions about this process: (1) what trans-acting factors regulate expression of the RAG1 and RAG2 proteins during B-cell development, and (2) when the recombinase is expressed, how is it specifically targeted to either the heavy chain or light chain loci.
520 $a We created and screened a B-cell retroviral cDNA library, searching for cDNAs capable of increasing Rag1/2 transcription in a model B-cell line. The screen identified Gadd45a as a gene whose overexpression increases Rag transcript levels. Further, we found that the GADD45A overexpression phenotype was dependent on MEKK4 and p38 MAP kinases---which act downstream of GADD45A. Bioinformatic analysis of transcripts co-regulated by Gadd45a identified the transcription factor FOXO1 as being the ultimate target of the Gadd45a pathway. FOXO1 was found to directly increase Rag transcript levels both in the model cell line and in primary B-cells. This activity was unique among the Foxo family of transcription factors and could be blocked by a constitutively active mutant AKT. We propose that FOXO1 is the primary transcription factor driving Rag expression during B-cell development---and that the preBCR or BCR act through PI3K/AKT/PLCgamma2 to inhibit FOXO1 activity and thereby decrease Rag expression.
520 $a In order to identify how germline transcription of recombining loci may contribute to targeting or recruitment of the V(D)J recombinase we created two knock-in mouse lines which report activity of germline transcription in the Jkappa locus. In contrast to a previous report we found that at the pre-B cell stage of development all pre-B cells are actively transcribing the germline Jkappa locus on both alleles. We reconciled these results by describing a previously unidentified splice variant of the Jkappa distal transcript that overlaps completely with the proximal transcript. We believe that the distal germline Jkappa promoter becomes active on both alleles during the pre-B cell stage while the proximal promoter becomes active later at the immature B-cell stage. How the two promoters might collaborate to induce Igkappa locus accessibility is still under investigation. We also found that one of the new mouse lines has a bimodal distribution of the marker protein at the pre B-cell stage---and that whether a pre B-cell has a "high" or "intermediate" level of the marker correlates with which allele undergoes rearrangement first. Moreover, the distribution of the marker from one allele can be influenced by mutations on the other allele. This indicates that during development the two Igkappa loci may "communicate" in some way that dictates which allele rearranges first---perhaps giving rise to allelic exclusion.
590 $a School code: 0028.
650 4 $a Biology, Bioinformatics. $3 1018415
650 4 $a Health Sciences, Immunology. $3 1017716
690 $a 0715
690 $a 0982
710 2 $a University of California, Berkeley. $3 687832
773 0 $t Dissertation Abstracts International $g 68-08B.
790 $a 0028
790 1 0 $a Schlissel, Mark S., $e advisor
791 $a Ph.D.
792 $a 2007
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3275328