Zinc finger protein 521 antagonizes early B-cell factor 1 and modulates the B-lymphoid differentiation of primary hematopoietic progenitors

Laboratory of Molecular Hematopoiesis, University of Catanzaro Magna Græcia, Catanzaro, Italy.
Cell cycle (Georgetown, Tex.) (Impact Factor: 4.57). 07/2011; 10(13):2129-39. DOI: 10.4161/cc.10.13.16045
Source: PubMed


Zinc finger protein 521 (EHZF/ZNF521) is a multi-functional transcription co-factor containing 30 zinc fingers and an amino-terminal motif that binds to the nucleosome remodelling and histone deacetylase (NuRD) complex. ZNF521 is believed to be a relevant player in the regulation of the homeostasis of the hematopoietic stem/progenitor cell compartment, however the underlying molecular mechanisms are still largely unknown. Here, we show that this protein plays an important role in the control of B-cell development by inhibiting the activity of early B-cell factor-1 (EBF1), a master factor in B-lineage specification. In particular, our data demonstrate that: (1) ZNF521 binds to EBF1 via its carboxyl-terminal portion and this interaction is required for EBF1 inhibition; (2) NuRD complex recruitment by ZNF521 is not essential for the inhibition of transactivation of EBF1-dependent promoters; (3) ZNF521 represses EBF1 target genes in a human B-lymphoid molecular context; and (4) RNAi-mediated silencing of ZNF521/Zfp521 in primary human and murine hematopoietic progenitors strongly enhances the generation of B-lymphocytes in vitro. Taken together, our data indicate that ZNF521 can antagonize B-cell development and lend support to the notion that it may contribute to conserve the multipotency of primitive lympho-myeloid progenitors by preventing or delaying their EBF1-driven commitment toward the B-cell lineage.

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Available from: Nicola Amodio, Jun 03, 2014
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    • "By applying multistability analysis methods, we are able to assess the capability of the model to capture the experimentally observed switch-like commitment behavior in B-lymphoid commitment of LMPPs into LRPS. These methods allow us to confirm the role of zinc finger protein 521 (ZNF521) in this process, as it provides a key regulator as recently proved in experimental studies from our group [2], and to identify a novel putative functional interaction for ZNF521, which is essential to realize such characteristic behavior. Furthermore , rigorously analyzing the devised model we are able to understand the machinery guaranteeing irreversibility of the switch and to devise a possible reprogramming strategy of LRPs into LMPPs, tuning different expression levels of ZNF521 and EBF1. "
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    ABSTRACT: Cellular differentiation is continuously orchestrated by complex networks of transcription factors, signaling molecules and genetic and epigenetic events, a fundamental prerequisite for the design of strategies for reprogramming differentiated cells to immature stem/progenitor cells is a thorough understanding of such complex regulatory machinery. Therefore, mathematical models, along with the associated analysis and control methods, are highly needed in this research field. In the present work, we provide a first model of the genetic regulatory network driving the cellular fate determination at the stage of lymphoid lineage commitment, in particular during lineage restriction of multipotent progenitors to early B-cell committed precursors.
    IEEE EMBC 2015, Milan, ITALY; 08/2015
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    • "ZNF521/EHZF is a large multifunctional protein with 30 zinc fingers, identified in our laboratory for its selective abundance in immature hematopoietic progenitors compared to mature leukocytes [5] [6]. ZNF521 shows features of a transcriptional corepressor and has been found to modulate the transcriptional induction of erythroid and B-lymphoid differentiation by GATA1 and EBF1 [7] [8]. In addition to the hematopoietic system, ZNF521 has recently been demonstrated to drive the generation of neuroectodermal precursors from embryonic stem cells [9] and to contribute to the growth, clonogenicity, and tumorigenicity of medulloblastoma cells [10]. "
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    ABSTRACT: Comment on: Mega T, et al. Cell Cycle 2011; 10:1853-60.
    Cell cycle (Georgetown, Tex.) 09/2011; 10(18):3054. DOI:10.4161/cc.10.18.16999 · 4.57 Impact Factor
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