Massachusetts General Hospital/East
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In many developmental systems, nuclear regulators have been implicated in coupling key events in gene expression with specific cell fate and lineage decisions. Focusing on this topic in the hemo-lymphoid system,we identified and shown in a series of genetic studies, that the family of zinc finger DNA binding proteins encoded by Ikaros (1), are key to lymphocyte specification (2) and function (3, 4, 10) working from the level of the hemopoietic stem cell (5). These investigations have provided evidence for the postulated distinct lymphoid progenitors of fetal and adult origin and continue to contribute insight into the earliest steps of the B and T cell differentiation pathways and the progenitors involved. Studies are also underway to determine the gene expression differences between Ikaros-deficient and normal HSC and to delineate which of these are responsible for the described developmental defects.
Ikaros and family members were also shown to associate with functionally distinct chromatin remodeling complexes and to target them into different nuclear compartments (6). Thus these lineage -potentiating factors can direct changes in the structure of chromatin, and possibly in its organization into nuclear subdomains. Such local changes in chromatin may alter the transcription status of associated genes, expression of which may be a prerequisite for lineage commitment and progression (7, 8, 11). The role and regulation of these Ikaros-based chromatin remodeling complexes during hemo-lymphopoiesis is under study in a series of biochemical and genetic approaches.
In line with our original goal to work our way back to the regulatory mechanisms that confer HSC identity on a mesodermal precursor, we have also made significant progress in understanding the transcriptional regulation of Ikaros (9). We have exploited this information to target cells at the very rare and poorly understood stages of hemopoiesis by generating expression cassettes based on Ikaros regulatory elements. These are being used to differentiate between these highly controversial cell types.
Georgopoulos K. Haematopoietic cell fate decisions, chromatin regulation and Ikaros Nature-Reviews- Immunology. 2002; 2(3): 162-174.
Harker N, Naito T, Cortes M, Hostert A, Hirschberg S, Tolaini M, Roderick K, Georgopoulos K and Kioussis D. The CD8 Gene locus is regulated by the Ikaros Family of Proteins. Molecular Cell. 2002; 10: 1403-1415.
Kaufmann C, YoshidaT, Perotti LA, Landhuis E, Wu P and Georgopoulos K.A complex network of regulatory elements in the Ikaros locus and their activity during hemo-lymphopoiesis. EMBO J. 2003; 22: 1-13.
Gomez del Arco P, Maki K and Georgopoulos K. Phosphorylation controls Ikaros' s ability to negatively regulate the G1-S transition. MCB 2004; 24(7):2797-2807.
Williams C, Naito T, G—mez-del Arco P, Seavitt J, Cashman S, De Souza B, Qi X, Keables P, Von Andrian U and Georgopoulos K. The Chromatin Remodeler Mi-2§ is Required for CD4 Expression and T Cell Development. Immunity 2004; 20:719-733.
Last Update: 1/6/2014