Functional study of the intronic enhancer, Emu, after immunoglobulin heavy chain variable region gene assembly.
Item
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Title
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Functional study of the intronic enhancer, Emu, after immunoglobulin heavy chain variable region gene assembly.
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Identifier
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AAI3330130
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identifier
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3330130
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Creator
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Li, Fubin.
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Contributor
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Adviser: Laurel Eckhardt
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Date
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2008
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology, Molecular | Biology, Genetics
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Abstract
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A series of somatic rearrangement and mutation processes underlie the function of B lymphocytes: V(D)J rearrangement assembles immunoglobulin heavy and light chain (IgH and IgL) variable region (VH and VL) genes, and therefore generates a large repertoire of antibody specificity; class switch recombination and somatic hypermutation enable B cells to produce antibodies with different effector functions and high affinity in response to antigens. The intronic enhancer (Emicro) of the Igh locus has been shown required for efficient VH gene assembly previously. In order to study its subsequent function, mice bearing a modified endogenous Igh allele with Emicro knockout and VH knockin were generated and analyzed. In mice homozygous for this Emicro-deficient allele, B cell development was normal and indistinguishable from that of mice with the same VH knock-in and Emicro intact. In mice heterozygous for the Emicro-deficient allele, however, allelic exclusion was severely compromised. Surprisingly, this was not due to reduced suppression of V-DJ assembly on the second allele. Rather, the striking breakdown in allelic exclusion took place at the pre-B to immature B cell transition. These findings reveal both an important role for Emicro in influencing the fate of newly-arising B cells and a second "checkpoint" for allelic exclusion. In addition, we detected a substantial decrease in somatic hypermutation frequency on the Emicro-deficient allele, but this was not due to a decrease in transcription, suggesting that Emicro contributes to somatic hypermutation through a transcription-independent mechanism.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
