YY1 controls immunoglobulin class switch recombination and nuclear aid levels / Kristina Zaprazna.

Zaprazna, Kristina.
xii, 156 p. : ill. ; 29 cm.
Local subjects:
Penn dissertations -- Biology.
Biology -- Penn dissertations.
YY1 is a multifunctional zinc finger transcription factor that regulates activation, repression and transcriptional initiation of many genes. YY1 functions in diverse biological processes, including embryonic development, cell cycle, Polycomb Group function, lineage differentiation, X-chromosome inactivation, imprinting and cancer. Recently, a new role for YY1 was described in early B cell development. Ablation of transcription factor YY1 in the B cell lineage results in arrest at the pro-B cell stage, reduced immunoglobulin locus contraction, and reduced rearrangement of distal variable genes. However, the role of YY1 in late B cell functions is unknown. Activation induced deaminase (AID) normally expressed in activated germinal center B cells is required for late stage B cell functions including somatic hypermutation (SHM) and class switch recombination (CSR). AID deaminates cytosines on DNA to inititate SHM and CSR. AID must be transported to the nucleus to mediate its activities, but the mechanism of AID nuclear localization is unclear. To investigate role of YY1 in late B cell development we employed a conditional knockout system using mature splenic B cells purified from yy1flox/flox mice treated with recombinant TAT-CRE protein ex vivo. In this thesis we show that YY1 ablation interferes with CSR. Loss of YY1 does not affect B cell proliferation, levels of switch region germline transcripts, or expression of the Aicda or IgM genes. However, YY1 physically interacts with AID and controls nuclear accumulation of AID. AID also interacts with PU.1 and PAX5 but these transcription factors do not affect AID nuclear localization. We propose that YY1 regulates CSR by controlling amounts of AID in the nucleus. We show for the first time that YY1 plays a novel role in regulating CSR.
Adviser: Greg Guild.
Thesis (Ph.D. in Biology) -- University of Pennsylvania, 2010.
Includes bibliographical references.
Guild, Greg, advisor.
University of Pennsylvania.
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