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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
7F32HL082448-02
Application #
7163345
Study Section
Special Emphasis Panel (ZRG1-DIG-B (21))
Program Officer
Mondoro, Traci
Project Start
2005-07-01
Project End
2008-06-30
Budget Start
2005-12-01
Budget End
2006-06-30
Support Year
2
Fiscal Year
2005
Total Cost
$28,361
Indirect Cost
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
120989983
City
Cambridge
State
MA
Country
United States
Zip Code
02142
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Novershtern, Noa; Subramanian, Aravind; Lawton, Lee N et al. (2011) Densely interconnected transcriptional circuits control cell states in human hematopoiesis. Cell 144:296-309
Guenther, Matthew G; Lawton, Lee N; Rozovskaia, Tatiana et al. (2008) Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia. Genes Dev 22:3403-8