Ikaros isoforms: The saga continues

Through alternate splicing, the Ikaros gene produces multiple proteins. Ikaros is essential for normal hematopoiesis and possesses tumor suppressor activity. Ikaros isoforms interact to form dimers and potentially multimeric complexes. Diverse Ikaros complexes produced by the presence of different Ikaros isoforms are hypothesized to confer distinct functions. Small dominant-negative Ikaros isoforms have been shown to inhibit the tumor suppressor activity of full-length Ikaros. Here, we describe how Ikaros activity is regulated by the coordinated expression of the largest Ikaros isoforms IK-1 and IK-H. Although IK-1 is described as full-length Ikaros, IK-H is the longest Ikaros isoform. IK-H, which includes residues coded by exon 3B (60 bp that lie between exons 3 and 4), is abundant in human but not murine hematopoietic cells. Specific residues that lie within the 20 amino acids encoded by exon 3B give IK-H DNA-binding characteristics that are distinct from those of IK-1. Moreover, IK-H can potentiate or inhibit the ability of IK-1 to bind DNA. IK-H binds to the regulatory regions of genes that are upregulated by Ikaros, but not genes that are repressed by Ikaros. Although IK-1 localizes to pericentromeric heterochromatin, IK-H can be found in both pericentromeric and non-pericentromeric locations. Anti-silencing activity of gamma satellite DNA has been shown to depend on the binding of IK-H, but not other Ikaros isoforms. The unique features of IK-H, its influence on Ikaros activity, and the lack of IK-H expression in mice suggest that Ikaros function in humans may be more complex and possibly distinct from that in mice.