YY1 functions in B lymphocyte development / Xuan Pan.
xii, 197 p. : ill ; 29 cm. + CD-ROM (4 3/4 in.)
- Medical subjects:
- Cell and Molecular Biology.
- Local subjects:
- Penn dissertations -- Cell and molecular biology.
Cell and molecular biology -- Penn dissertations.
- Ying Yang 1 (YY1) is a multifunctional transcription factor that plays important roles in gene regulation, early embryonic development, and lineage differentiation. YY1 binds to multiple enhancer binding sites in immunoglobulin loci and plays vital roles in early B cell development. Conditional knockout of yy1 in the B cell lineage results in pro-B cell arrest, and reduced immunoglobulin locus contraction needed for distal variable gene rearrangement. YY1 is the only mammalian Polycomb Group (PcG) protein with DNA binding specificity and numerous PcG proteins show important functions in hematopoietic development. To investigate the function of YY1 in hematopoiesis, we utilized an in vivo bone marrow reconstitution system. We found that the B cell lineage was particularly sensitive to YY1 over-expression, and that there was a significant selective disadvantage as cells progressed from hematopoietic stem/progenitor cells to the pro-B, pre-B, immature B and re-circulating B cell stages. In contrast to the B lineage phenotype, lineage Sca-1 + cKithi (LSK) hematopoietic progenitors over-expressing YY1 demonstrated enrichment for long-term hematopoietic stem cells (LT-HSC). To explore YY1 PcG functions in B cell development, we deleted the 25 amino acid REPO domain that is necessary for YY1 PcG function, and used this mutant (YY1DeltaREPO), and wild-type YY1 constructs, to transduce bone marrow from YY1 conditional knock-out mice. While wild type YY1 rescued B cell development, YY1DeltaREPO failed to rescue the B cell lineage with dramatic reduction of cells past the kappa gene rearrangement. The YY1REPO domain interacted with proteins from the condensin and cohesin complexes, and that YY1, EZH2 and condensin proteins co-localized at numerous sites across the Ig kappa locus. Knock-down of condensin subunit proteins reduced Ig kappa rearrangement. These findings, in conjunction with the diverse phenotypes resulted from elevated YY1 expression in B, myeloid and LT-HSC cells, suggest the complexity of YY1 in hematopoiesis.
- Adviser: Michael L. Atchison.
Thesis (Ph.D. in Cell and Molecular Biology) -- University of Pennsylvania, 2010.
Includes bibliographical references.
- Atchison, Michael L., advisor.
University of Pennsylvania.
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