Figure 6. Model of IKAROS dosage effect for formation and recruitment of the NuRD-P-TEFb complex and transcription elongation control of IKAROS-target genes.

Productive elongation: when expressed at high levels, as in lineage negative hematopoietic progenitor cells, IKAROS (Ik) associates Mi2/NuRD and CDK9/P-TEFb activities into one complex at gene transcription start site (TSS) and throughout the ORF of IKAROS-target genes. IKAROS dependent enrichment of PP1α at TSS provides a control to P-TEFb activation by the dephosphorylation of CDK9. Once activated, CDK9/P-TEFb phosphorylates Ser-2 on POL II CTD as well as NELF and DSIF, two negative regulators of POL II elongation and thereby, releases the promoter-proximal paused POL II. Then, IKAROS and the NuRD-P-TEFb complex assist POL II during elongation. Based on results obtained by LC-MS/MS analysis, the latter might occurs along with SEC subunits. Paused transcription: the gradual decrease of IKAROS protein concentration, such as normally observed at defined stages of hematopoietic cell differentiation, still allows Mi2/NuRD loading at gene regulatory regions as well as PIC formation at gene promoters. However, lack of P-TEFb and PP1α recruitment results in promoter-proximal pausing of POL II. Gene silencing: in absence of IKAROS, as observed in lymphoma and leukemia clones carrying mutated and/or deleted alleles of IKAROS, the IKAROS-target genes are embedded in inactive chromatin conformation (not depicted) and they are characterized by the absence of PIC formation. To simplify the model, some of the proteins or complexes mentioned are not indicated.