Differentiation of macrophages from precursor cells is accompanied by irreversible growth arrest, inducedby stable transcriptional repression of cell cycle-associated genes. Inhibition of the mechanisms that causeGO arrest plays a central role in leukemogenesis. Growth arrest induced by mitogenic ets transcriptionalsuppressor (METS), which is upregulated during macrophage differentiation requires the DEAD box proteinDP103 (DP103). DP103 also acts as a corepressor for a number of other, divergent transcription factors,which suggests a broad functional role for DP103 as a corepressor. Studies are proposed to define thedevelopmental functions, transcriptional targets and repression mechanisms of DP103. Its possible role asa corepressor for a larger number of transcription factors will be asessed by identifying new interaction part-ners in a yeast two-hybrid screen of a macrophage cDNA library. To assess its function in embryonicdevelopment, in controlling proliferation during hematopoiesis, DP103 knockout mice will be generated andthe proliferative potential of macrophages and macrophage precursors analyzed. Finally, the potentiallyepigenetic repression mechanism of DP103 will be analyzed by genome-wide location analysis.
|Lin, Yin C; Jhunjhunwala, Suchit; Benner, Christopher et al. (2010) A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates B cell fate. Nat Immunol 11:635-43
|Heinz, Sven; Benner, Christopher; Spann, Nathanael et al. (2010) Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell 38:576-89