Ikaros: linking dimer state to function – IKAROS

The Ikaros family of transcription factors (TFs) comprises related zinc finger proteins that are differentially expressed in hematopoietic cells and essential for immunity. In humans, polymorphisms in the genes encoding Ikaros family members are linked to autoimmune and inflammatory diseases, while loss-of-function mutations are implicated in common variable immunodeficiency (CVID) and cancers like B cell precursor-acute lymphoblastic leukemias (BCP-ALL). In mice, Ikaros factors are key regulators of cell fate decisions, differentiation and inflammation. These studies have revealed that individual Ikaros proteins are required in numerous cell types and differentiation stages. However, much less is understood about how these TFs work at the molecular level. Ikaros TFs have homologous DNA-binding and dimerization domains, and current data suggest that they bind to core GGAA motifs as homo- or heterodimers. They have not been shown to exist as monomers, or to dimerize with TFs outside of the Ikaros family. Ikaros proteins bind largely overlapping repertoires of target genes, and binding results in gene repression or activation. Further, Ikaros TFs have been shown to recruit different chromatin remodeling complexes, by mechanisms that remain unclear. It is currently unknown how different Ikaros proteins might dimerize to recognize their targets and what transcriptional properties could ensue. It is unknown what rules govern the choice of targets (motif polarity, spacing, flanking nucleotides), and if target sequence architecture promotes repression or activation. Determining the precise functions of Ikaros family proteins is essential for understanding their role in physiology and disease. We propose to: 1) determine how dimeric partners of Ikaros dictate its ability to regulate gene expression; 2) evaluate the potential function of Ikaros monomers; 3) model Ikaros family binding and their effects on transcription through machine learning and biophysics.