title: Increased expression of PcG protein YY1 negatively regulates B cell development while allowing accumulation of myeloid cells and LT-HSC cells.
abstract: Ying Yang 1 (YY1) is a multifunctional Polycomb Group (PcG) transcription factor that binds to multiple enhancer binding sites in the immunoglobulin (Ig) loci and plays vital roles in early B cell development. PcG proteins have important functions in hematopoietic stem cell renewal and YY1 is the only mammalian PcG protein with DNA binding specificity. Conditional knock-out of YY1 in the mouse B cell lineage results in arrest at the pro-B cell stage, and dosage effects have been observed at various YY1 expression levels. To investigate the impact of elevated YY1 expression on hematopoetic development, we utilized a mouse in vivo bone marrow reconstitution system. We found that mouse bone marrow cells expressing elevated levels of YY1 exhibited a selective disadvantage as they progressed from hematopoietic stem/progenitor cells to pro-B, pre-B, immature B and re-circulating B cell stages, but no disadvantage of YY1 over-expression was observed in myeloid lineage cells. Furthermore, mouse bone marrow cells expressing elevated levels of YY1 displayed enrichment for cells with surface markers characteristic of long-term hematopoietic stem cells (HSC). YY1 expression induced apoptosis in mouse B cell lines in vitro, and resulted in down-regulated expression of anti-apoptotic genes Bcl-xl and NFκB2, while no impact was observed in a mouse myeloid line. B cell apoptosis and LT-HSC enrichment induced by YY1 suggest that novel strategies to induce YY1 expression could have beneficial effects in the treatment of B lineage malignancies while preserving normal HSCs.
authors.affiliation: Department of Animal Biology, School of Veterinary, University of Pennsylvania, Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Xuan
authors.initials: X
authors.lastname: Pan
authors.forename: Morgan
authors.initials: M
authors.lastname: Jones
authors.forename: Jie
authors.initials: J
authors.lastname: Jiang
authors.forename: Kristina
authors.initials: K
authors.lastname: Zaprazna
authors.forename: Duonan
authors.initials: D
authors.lastname: Yu
authors.forename: Warren
authors.initials: W
authors.lastname: Pear
authors.forename: Ivan
authors.initials: I
authors.lastname: Maillard
authors.forename: Michael L
authors.initials: ML
authors.lastname: Atchison
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism / Q000502:physiology*; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D013997:Time Factors; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology; D050986:YY1 Transcription Factor / Q000235:genetics* / Q000378:metabolism / Q000502:physiology
chemical_list: D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D050986:YY1 Transcription Factor; C494699:Yy1 protein, mouse