Ikaros represses and activates PU.1 cell-type-specifically through the multifunctional Sfpi1 URE and a myeloid specific enhancer

Generation of myeloid and lymphoid cells from progenitors involves dynamic changes in transcription factor expression and use, and disruption of hematopoietic transcription factor function and expression can contribute to leukemic transformation. PU.1 and Ikaros are pivotal factors whose expression and utilization are dynamically altered during hematopoietic development. Here, we demonstrate that expression of PU.1, encoded by the Sfpi1 gene, is divergently regulated by Ikaros in distinct cell type-specific contexts. Chromatin immune precipitation analysis and functional perturbations revealed that Ikaros can directly repress or activate Sfpi1 transcription via different PU.1 cis-elements, with PU.1 and Ikaros collaborating at myeloid-specific elements but not at other elements. Our results thus shed light on how PU.1 and Ikaros can act as lineage competency factors to facilitate both myeloid and lymphoid developmental programs.