Abstract
Ikaros is essential for the normal development and regulated proliferation of lymphoid cells. In lymphocytes, Ikaros exists as an integral component of chromatin-remodeling complexes, including the Mi-2beta/nucleosome remodeling and deacetylation complex (NuRD) complex. It is expected that Ikaros, together with these associated activities effects repression, but here we show that they may also potentiate gene expression in cycling cells. Ikaros cannot activate transcription by itself; instead, it enhances the activity of both weak and strong activators. For this role in potentiation, Ikaros requires its DNA binding and dimerization domains. The DNA binding and dimerization properties of Ikaros are also responsible for its targeting to pericentromeric heterochromatin (PC-HC). Significantly, Ikaros mutants with altered specificity for DNA binding that are unable to localize to PC-HC are incapable of stimulating transcription from reporters bearing their cognate sites. 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.
Highlights
Lineage commitment and differentiation along the hemolymphoid pathway rely heavily on Ikaros, which encodes a number of Kruppel-type zinc finger proteins [1,2,3,4]
In actively cycling primary lymphocytes, Ikaros concentrates in distinctive toroidal structures, which are found in apposition to pericentromeric heterochromatin and a variety of transcriptionally silent genes [20]
It is well established that Ikaros plays a critical role at many distinct steps of the hemolymphoid pathway, but the mechanisms involved remain under investigation
Summary
NuRD, nucleosome remodeling and deacetylation complex; PC-HC, pericentromeric heterochromatin; DBD, DNA binding domain; CAT, chloramphenicol acetyl transferase; Ik, Ikaros; GH, growth hormone; CTF, CCAAT-binding factor. We report that Ikaros is capable of enhancing gene expression as a potentiator of bona fide transcriptional activators and not by functioning as a classical activator. We show that there is an unexpected correlation between Ikaros localization to these heterochromatin-associated sites and its ability to activate gene expression These studies indicate that the presence of Ikaros in this nuclear compartment provide a “landing pad” for its chromatin remodeling partner Mi-2 and presumably the NuRD complex.
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