Regulation of Gene Expression Dynamics during Developmental Transitions by the Ikaros Transcription Factor

The DNA-binding protein, Ikaros, functions as a potent tumor suppressor and hematopoietic regulator. However, the mechanisms by which Ikaros functions in the nucleus remain largely undefined, due in part to its atypical DNA-binding properties and partnership with the poorly understood Mi-2/NuRD complex. In this study, we extended our analysis of thymocyte development and lymphomagenesis in a mouse strain containing a specific deletion of Ikaros zinc finger 4, which exhibits a select subset of abnormalities observed in Ikaros null mice. By examining thymopoiesis in vivo and in vitro, numerous abnormalities were observed. RNA-sequencing revealed that each developmental stage is characterized by mis-regulation of a limited number of genes, with a strong preference for genes modulated in a stage-specific manner. Strikingly, individual genes and pathways rarely exhibited Ikaros-dependence at all developmental stages. Instead, the most consistent feature of aberrantly expressed genes was a reduced magnitude of expression level change during a developmental transition. These results and others suggest that Ikaros may not be a dedicated and consistent activator or repressor of a defined set of genes. Instead, its primary function may be to support the dynamic range of gene expression changes during developmental transitions via atypical molecular mechanisms that remain undefined. RNA-Seq of T cells at varying developmental stages and T cells expressing activated Notch in WT and Ikzf1-dF4/dF4 mutant backgrounds