The Justy mutation disrupts the regulation of gene expression and cell cycle progression during B lymphopoiesis

• Main Author: Barr, Jennifer Yamaoka
• Other Authors: Colgan, John D.
• Format: Others
• Language: English
• Published: University of Iowa 2015
• Subjects: publicabstract; B cell development; Cell cycle; Cyclin D3; Gene expression; Gon4-like; proliferation; Cell Anatomy; Cell Biology
• Online Access: https://ir.uiowa.edu/etd/1542; https://ir.uiowa.edu/cgi/viewcontent.cgi?article=5594&context=etd

B lymphopoiesis requires a network of transcription factors that orchestrate changes in gene expression amidst immunoglobulin gene rearrangement and periods of cell proliferation. Although proteins required for the function of this network have been identified, the precise mechanisms that coordinate these processes as hematopoietic progenitors differentiate into lineage-committed B cells remain unclear. Justy mice display a profound arrest of B cell development at the time of lineage commitment due to a point mutation that decreases expression of the protein Gon4-like. Previous studies suggested that Gon4-like functions to coordinate gene expression and cell division to determine cell fate, but the role of Gon4-like in B lymphopoiesis is largely unknown. Here we demonstrate that Gon4-like is required to regulate gene expression and cell cycle progression in B cell progenitors. Expression of genes required for B cell development is intact in Justy B cell progenitors, yet these cells fail to repress genes that promote the development of alternative lineages. In addition, Justy B cell progenitors are unable to upregulate genes that instruct cell cycle progression. Consistent with this, B cell progenitors from Justy mice show signs of impaired proliferation and undergo apoptosis despite containing elevated levels of activated STAT5, a transcription factor that promotes cell proliferation and survival. Genetic ablation of p53 or retroviral-mediated overexpression of pro-survival factors failed to rescue these defects. In contrast, overexpression of proteins that promote the G1/S transition of the cell cycle, including D-type cyclins, E2F2 and cyclin E, rescued pro-B cell development from Justy progenitors, an effect that was not observed upon overexpression of proteins that function during the S and G2M phases of the cell cycle. Further, overexpression of cyclin D3 led to partial restoration of gene repression in Justy pro-B cells. Notably, Gon4-like interacted with STAT5 when overexpressed in transformed cells, suggesting Gon4-like and STAT5 function together to activate expression of STAT5 target genes. Collectively, our data indicate that Gon4-like is required to coordinate gene repression and cell cycle progression during B lymphopoiesis.