Katia Georgopoulos

..We conclude that Ikaros regulates T cell differentiation, selection, and homeostasis by providing signaling thresholds for pre-TCR and TCR...

..Regulation of expression of the gene encoding interleukin 10 by the histone deacetylase HDAC11 emphasizes the ability of an antigen-presenting cell to induce immunity or tolerance in CD4+ T cells...

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..Thus, Mi-2beta provides the hematopoietic system with immune cell capabilities as well as with an extensive regenerative capacity...

..Thus, concomitant interactions between functionally opposing chromatin-regulating machineries are an important mode of gene regulation during lineage determination...

..Taken together, our studies provide new insight into the priming and restriction of lineage potentials during early hematopoiesis and identify Ikaros as a key bivalent regulator of this process...

..These studies reveal a new dynamic way by which Ikaros-mediated gene repression is controlled by SUMOylation...

..Using this approach, we identify previously unknown pivotal functions for Ikaros in distinct fate 'decisions' in the early hematopoietic hierarchy...

..Finally, we show that, barring CtBP, the Ikaros family members Aiolos, Helios, and Eos can associate with all of the identified corepressors of Ikaros including its newly identified interactors, Class II HDACs...

..These findings provide important insights into the regulation of CD4 expression during T cell development and define a role for Mi-2beta in gene activation...

..Genetic studies of this family of nuclear factors are now providing unique insight into the functional molecular signatures that bestow plasticity to the hematopoietic stem cell and its early progeny...

..Finally, we show that CtIP and CtBP can interact with the general transcription factors, TATA binding protein and transcription factor IIB, which suggests a possible mechanism for their deacetylase-independent mode of repression...

..Loss of Ikaros removes the lymphoid leg of the immune system and may confer aberrant self-renewing properties to myeloid progenitors...

..Mi-2beta is however essential for the reprogramming of basal cells to the follicular and, subsequently, hair matrix fates...

..These data extend the role of ILK to immune-cell trafficking and survival via modulation of Akt- and Rac-dependent substrates, and have implications for cell recruitment in both homeostatic and pathological processes...

..We thus propose that Ikaros's activity as a regulator of the G(1)-S transition is controlled by phosphorylation in response to signaling events that down-modulate its DNA binding activity...

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..These mutant mice will be useful for further elucidation of the pathogenic and molecular mechanisms underlying ICF syndrome...

..Thus, we have identified a module in the transcriptional program of T(H)17 cells that actively limits IL-2 production and promotes their differentiation...

..These studies support a model by which the high affinity plasma cell population in the BM undergoes a unique differentiation program that is dependent on Aiolos...

..Thus, potentiation of gene expression by Ikaros correlates strongly with its ability to localize to PC-HC in combination with the chromatin remodeler Mi-2beta...

..These results demonstrate that Ik-1 and Ik-2 proteins through their DNA binding act as positive regulators of ENK gene expression in the developing striatum and participate in regulating enkephalinergic differentiation...

..Our results indicate that B cells play a crucial role in the development of SLE in Aiolos mutant mice and might be useful for the strategy of SLE treatment...

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..Aiolos expression was controlled by pre-BCR signals via the adaptor protein SLP-65. Thus, pre-BCR signaling regulates Aiolos and the silencing of Igll1 via a developmental-stage-specific feedback loop...

..These data are consistent with the hypothesis that the Ikaros-binding sites in the U3 region of MCF 247 are functional and cooperate with other DNA elements for optimal enhancer function in vivo...

..We hypothesize that achieving some of these goals would dramatically increase our ability to analyze and manipulate development of the hemopoietic stem cell in vivo and in vitro with important therapeutic implications. ..

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..This investigation may also identify molecular targets for intervention in immune disease, characterized by inappropriate lymphocyte proliferation such as autoimmunity, leukemia and lymphoma. ..

..These studies will provide us with new important and far-reaching paradigms that will impact our understanding of normal development and cancer. ..

..e immuno-deficiency, autoimmunity and neoplastic transformation. An important outcome of these studies will be an increase in our ability to apply molecular intervention to these differentiation processes. ..

..Finally, target genes for the Ikaros proteins, important in the development and maturation of lymphoid progenitors, will be investigated by studying differential mRNA expression in the Ikaros C-/mutant lymphoid and HSC populations. ..

..In the long run, these studies on the role of Aiolos in B-cell differentiation and function, we will have a great impact on our ability to apply molecular intervention to our immune system. ..

..The molecular and genetic approaches described in this proposal will unravel the biological function of de novo methylation in development and cancer. ..

..These studies will provide us with new important and far-reaching paradigms that will impact our understanding of normal development and cancer. ..