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Changing U1A levels regulate expression of immunoglobulin M and the transcriptional repressor Zhx1 during B cell differentiation
Descriptive
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Title
Changing U1A levels regulate expression of immunoglobulin M and the transcriptional repressor Zhx1 during B cell differentiation
Name
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Ma
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(type = given)
Jianglin
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Jianglin Ma
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(authority = RULIB)
author
Name
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Gunderson
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Samuel
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Advisory Committee
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Samuel Gunderson
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chair
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MEGERDIT
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Advisory Committee
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MEGERDIT KILEDJIAN
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internal member
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Phillips
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Catherine
Affiliation
Advisory Committee
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Catherine Phillips
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(authority = RULIB)
internal member
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kinzy
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Terri
Affiliation
Advisory Committee
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Terri Goss kinzy
Role
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(authority = RULIB)
outside member
Name
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NamePart
Rutgers University
Role
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(authority = RULIB)
degree grantor
Name
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NamePart
Graduate School - New Brunswick
Role
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(authority = RULIB)
school
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Text
Genre
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theses
OriginInfo
DateCreated
(qualifier = exact)
2008
DateOther
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(type = degree)
2008-01
Language
LanguageTerm
English
PhysicalDescription
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electronic
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application/pdf
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text/xml
Extent
xii, 147 pages
Abstract
During B cell differentiation U1A plays an important role in regulating the expression of the secretory poly(A) site by inhibiting both cleavage and polyadenylation. Previous work demonstrated that the inhibitory effect of U1A is alleviated in differentiated cells, which express the secretory poly(A) site, however, the mechanism underneath was unveiled. Using B cell lines representing different stages of B cell differentiation, here we show that U1A levels are reduced in differentiated cells. Undifferentiated B cells have more total U1A than differentiated cells and a greater proportion of U1A is not associated with the U1snRNP. We demonstrate that this non-snRNP associated U1A is available to inhibit poly(A) addition at the secretory poly(A) site. In addition, endogenous non-snRNP associated U1A--immunopurified from the different cell lines--inhibited poly(A) polymerase activity proportional to U1A recovered, suggesting that available U1A level alone is responsible for changes in its inhibitory effect at the secretory IgM poly(A) site.
It is known that U1A can regulate the expression of its own and IgM gene. Here we report that during mouse B cell differentiation U1A also regulates the expression of the transcriptional repressor, Zhx-1 (zinc fingers and homeoboxes 1), via alternative poly(A) site selection. Using affymetrix microarray analysis combined with RT-PCR techniques, we demonstrate that U1A binds to Zhx-1 mRNA in vivo. We show that the levels of Zhx-1 proteins and mRNA are negatively correlated with U1A levels in B cells and overexpression of U1A in HeLa cells significantly inhibits the expression of Zhx-1. Our in vitro and in vivo assays show that U1A regulates the expression of the upstream poly (A) site of Zhx-1 by binding to the five non-consensus motifs around the poly(A) site and inhibiting both poly(A) addition and cleavage. When the upstream poly(A) site of Zhx-1 is inhibited in mature B cells, the usage of the downstream poly(A) site of Zhx-1 results in the inclusion of ARE elements, which destabilize the mRNA transcript. As a result, less Zhx-1 RNA and protein are produced in mature B cells. We proposed one model about how U1A and ARE coordinately regulate the expression of Zhx-1 during B cell differentiation.
It is known that U1A can regulate the expression of its own and IgM gene. Here we report that during mouse B cell differentiation U1A also regulates the expression of the transcriptional repressor, Zhx-1 (zinc fingers and homeoboxes 1), via alternative poly(A) site selection. Using affymetrix microarray analysis combined with RT-PCR techniques, we demonstrate that U1A binds to Zhx-1 mRNA in vivo. We show that the levels of Zhx-1 proteins and mRNA are negatively correlated with U1A levels in B cells and overexpression of U1A in HeLa cells significantly inhibits the expression of Zhx-1. Our in vitro and in vivo assays show that U1A regulates the expression of the upstream poly (A) site of Zhx-1 by binding to the five non-consensus motifs around the poly(A) site and inhibiting both poly(A) addition and cleavage. When the upstream poly(A) site of Zhx-1 is inhibited in mature B cells, the usage of the downstream poly(A) site of Zhx-1 results in the inclusion of ARE elements, which destabilize the mRNA transcript. As a result, less Zhx-1 RNA and protein are produced in mature B cells. We proposed one model about how U1A and ARE coordinately regulate the expression of Zhx-1 during B cell differentiation.
Note
(type = degree)
Ph.D.
Note
(type = bibliography)
Includes bibliographical references (p. 124-146).
Subject
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(authority = RUETD)
Topic
Biochemistry
Subject
(ID = SUBJ2);
(authority = ETD-LCSH)
Topic
Immunoglobins
Subject
(ID = SUBJ3);
(authority = ETD-LCSH)
Topic
B cells--Differentiation
Subject
(ID = SUBJ4);
(authority = ETD-LCSH)
Topic
Repressors, Genetic
Subject
(ID = SUBJ5);
(authority = ETD-LCSH)
Topic
Genetic transcription
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TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier
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rucore19991600001
Identifier
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http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.17155
Identifier
ETD_625
Location
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NjNbRU
Identifier
(type = doi)
doi:10.7282/T3M045SK
Genre
(authority = ExL-Esploro)
ETD doctoral
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Rights
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The author owns the copyright to this work.
Copyright
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Copyright protected
Availability
Status
Open
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Name
Jianglin Ma
Role
Copyright holder
Affiliation
Rutgers University. Graduate School - New Brunswick
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Non-exclusive ETD license
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License
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Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
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