Changes in chromatin structure underlie the activation or silencing of genes during development. The chromatin remodeler Mi-2beta is highly expressed in thymocytes and is presumed to be a transcriptional repressor because of its presence in the nucleosome remodeling deacetylase (NuRD) complex. Using conditional inactivation, we show that Mi-2beta is required at several steps during T cell development: for differentiation of beta selected immature thymocytes, for developmental expression of CD4, and for cell divisions in mature T cells. We further show that Mi-2beta plays a direct role in promoting CD4 gene expression. Mi-2beta associates with the CD4 enhancer as well as the E box binding protein HEB and the histone acetyltransferase (HAT) p300, enabling their recruitment to the CD4 enhancer and causing histone H3-hyperacetylation to this regulatory region. 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.
Deletion of the Ikaros (Ikzf1) DNA-binding domain generates dominant-negative isoforms that interfere with Ikaros family activity and correlate with poor prognosis in human precursor B cell acute lymphoblastic leukemias (B-ALL). Here, we show that conditional inactivation of the Ikaros DNA binding domain in early pre-B cells arrests their differentiation at a stage where integrin-dependent niche adhesion augments mitogen-activated protein kinase signaling, proliferation, and self-renewal, and attenuates pre-B cell receptor signaling and differentiation. Transplantation of polyclonal Ikzf1 mutant pre-B cells results in long-latency oligoclonal pre-B-ALL, demonstrating that loss of Ikaros contributes to multistep B-leukemogenesis. These results explain how normal pre-B cells transit from a highly proliferative and stromal-dependent to a stromal-independent phase where differentiation is enabled, providing potential therapeutic strategies for IKZF1 mutant B-ALL.
The ability of somatic stem cells to self-renew and differentiate into downstream lineages is dependent on specialized chromatin environments that keep stem cell-specific genes active and key differentiation factors repressed but poised for activation. The epigenetic factors that provide this type of regulation remain ill-defined. Here we provide the first evidence that the SNF2-like ATPase Mi-2 of the Nucleosome Remodeling Deacetylase (NuRD) complex is required for maintenance of and multilineage differentiation in the early hematopoietic hierarchy. Shortly after conditional inactivation of Mi-2, there is an increase in cycling and a decrease in quiescence in an HSC (hematopoietic stem cell)-enriched bone marrow population. These cycling mutant cells readily differentiate into the erythroid lineage but not into the myeloid and lymphoid lineages. Together, these effects result in an initial expansion of mutant HSC and erythroid progenitors that are later depleted as more differentiated proerythroblasts accumulate at hematopoietic sites exhibiting features of erythroid leukemia. Examination of gene expression in the mutant HSC reveals changes in the expression of genes associated with self-renewal and lineage priming and a pivotal role of Mi-2 in their regulation. Thus, Mi-2 provides the hematopoietic system with immune cell capabilities as well as with an extensive regenerative capacity.[Keywords: Mi-2; chromatin; HSC; multipotency; self-renewal; lineage priming] Supplemental material is available at http://www.genesdev.org. Received December 13, 2007; revised version accepted March 4, 2008. The defining properties of somatic stem cells, their ability to self-renew and to progress through available differentiation pathways, are critical for the life-long tissue integrity of multicellular organisms (Weissman 2000;Lemischka and Moore 2003). A balance between stem cell quiescence and activation is required to sustain the stem cell pool and to provide adequate numbers of mature cells to meet normal homeostatic conditions. Both the self-renewal and differentiation properties of stem cells can be altered dramatically in order to meet demands imposed by stress conditions.In hematopoietic tissue, the most primitive stem cells are thought to be in a comparatively quiescent state. They cycle with slow kinetics that strongly correlate with their long-term self-renewing potential (LT-HSC) (Morrison and Weissman 1994;Cheshier et al. 1999). Thus, maintenance of hematopoietic stem cell (HSC) activity can be compromised in two ways. On the one hand, a cell cycle block can prevent self-renewing divisions. On the other hand, prolonged cell cycle activation can lead to HSC exhaustion. This has been corroborated by studies on components of the cell cycle machinery and on signaling pathways that modulate their activity. An increase in expression of the cell cycle inhibitors p16 Ink4A, p19Ink4D/Arf , or p18Ink4C has an adverse effect on the HSC's self-renewal, presumably by restricting its entry into the cell cycle (Park et a...
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