Figure 1. Schematic representation of the Ikaros isoforms, DNA binding motifs and of the Ikaros-NuRD complex and its mode of action in lymphocytes.

(a) Exon composition containing Zn finger motifs involved in DNA binding and protein dimerization is shown for Ikaros isoforms and Ikaros family members (Aiolos, Helios and Eos). Exons are shown as light blue boxes. Dark blue bars indicate zinc fingers. (b) Transcription factor binding motifs identified in the vicinity of Ikaros enrichment peaks at enhancer regions in thymocytes. Two highly enriched Ikaros binding motifs identified by de novo motif search on its chromatin binding sites. (c) Structure of the Ikaros-NuRD complex and of Mi-2β. The NuRD complex contains Class I histone deacetylases (HDAC1/2) and the ATP-dependent chromatin remodeler Mi-2β (and α). (d) A model of negative and positive regulation by the NuRD complex. Targeting of the Mi-2β–NuRD complex to permissive chromatin (H3K4me3, H3K9Ac) is restricted to lymphoid genes by the Ikaros family proteins. Our hypothesis is that NuRD’s repressive activities are poised by Ikaros extensive DNA binding at its target sites. Upon reduction in Ikaros activity either through posttranslational modification of the protein or through Ikaros inactivating mutations increases chromatin access of the Mi-2β–NuRD complex and loss of lymphoid gene expression. Upon loss of Ikaros, the NuRD complex also re-distributes to new sites associated with promoters of transcriptionally poised genes that support cell growth, proliferation and metabolism causing their activation in part by displacing the PRC2 complex. Ik, Ikaros; Aio, Aiolos; polII, RNA polymerase II; PRC, polycomb repressive complex.