Deficiency in the Ikaros gene causes a reduction in hematopoietic stem cells (HSCs) and specific defects in lymphocyte differentiation including the development of leukemias and lymphomas. Ikaros, the founding member of a transcription factor family, is capable of directing sequence-specific DNA binding to regulatory elements in lymphoid specific genes in vitro. Gene regulation by Ikaros may be mediated by its associated with 2 functionally distinct chromatin remodeling complexes. However, few gene targets have been identified in vivo. This proposal seeks to identify Ikaros targets in the HSC compartment, which are vital for proper differentiation. 2 parallel approaches are being employed to identify the regulatory network controlled by Ikaros that is required for proper lineage specification. First, a comparison of gene expression profiles from hematopoietic precursors in adult bone marrow of wild-type and mutant animals is being performed to identify the hierarchy of genes regulated by Ikaros. Second, a global set of cis-regulatory elements bound by Ikaros will be identified in progenitor cell lines. Candidate target genes will be identified from gene expression changes in Aim 1. Taken together these studies may uncover molecular mechanisms of transcriptional repression and activation required for lineage specification by Ikaros. The proposed studies on Ikaros target genes in HSCs will provide us with an instructive entry point into the transcriptional programs that specify hematopoietic lineages and prevent leukemogenesis.
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