Journal
CELL CYCLE
Volume 10, Issue 13, Pages 2129-2139Publisher
LANDES BIOSCIENCE
DOI: 10.4161/cc.10.13.16045
Keywords
ZNF521; EBF1; transcription; B-lymphocytes; hematopoietic stem cells; differentiation
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Funding
- Italian Ministry for University and Research
- Italian Association for Cancer Research (AIRC)
- Leukemia and Lymphoma Society Specialized Center of Research Program and Gar Reichman Cancer Research Institute
- Leukemia Research Foundation
- Dutch Cancer Foundation (KWF)
- Netherlands Organization for Scientific Research (NWO-VIDI)
- Medical School of the University of Catanzaro
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Zinc finger protein 521 (EHZF/ZNF521) is a multi-functional transcription co-factor containing 30 zinc fingers and an N-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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