Description
Cell fate decisions depend on the interplay between chromatin regulators and transcription factors. Here we show that activity of the Mi-2u Nucleosome Remodeling and Deacetylase (NuRD) complex is controlled by the Ikaros family of lymphoid-lineage determining proteins. Ikaros, an integral component of the NuRD complex in lymphocytes, tethers this complex to active lymphoid differentiation genes, but keeps it in a functionally-poised state. Loss in Ikaros DNA binding activity causes a local increase in Mi-2u chromatin remodeling, histone deacetylation and suppression of lymphoid gene expression. The NuRD complex also redistributes to transcriptionally-poised non-Ikaros gene targets, involved in proliferation and metabolism, inducing their re-activation. Thus release of NuRD from Ikaros regulation blocks lymphocyte maturation and mediates progression to a leukemic state by engaging functionally-opposing epigenetic mechanisms and genetic networks.