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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    • "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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