Regulation of B lymphopoiesis by Zinc Finger Protein 521 (ZFP521) (111.9)

Abstract

Abstract The ZFP521 (Evi3/ZNF521/EHZF) transcription factor has been identified as an inhibitor of Early B cell factor 1 (EBF1), which is essential for B cell lineage specification and commitment. ZFP521 contains 30-zinc finger (ZF) domains, including C-terminal ZF’s that bind to EBF1. However, whether ZFP521 is required for appropriate B cell development and function has not been addressed. We demonstrated that Zfp521 transcripts correlate inversely with Ebf1 transcripts. Zfp521 transcripts are expressed at the highest levels in pre-pro-B and pro-B cells and decrease progressively with differentiation. In contrast, Ebf1 transcripts are detected only weakly in pre-pro-B cells and are increased at later stages in the bone marrow. In 3-wk old Zfp521 knockout (KO) mice, pre-pro-B and pro-B cells are increased substantially, while late pro-B, pre-B and immature B cells are reduced significantly. Re-circulating mature B cells accumulate prematurely in the bone marrow of Zfp521 KO mice relative to WT mice. We are addressing two possible models in these mice. ZFP521 may modulate EBF1 function through direct protein:protein interactions. Alternatively, because ZFP521 is itself a DNA-binding protein, ZFP521 may direct transcription of cognate target genes independently of EBF1. We obtained evidence that ZFP521 co-occupies functional promoters with EBF1 in pro-B cells. This indicates that ZFP521 regulates B cell development through interactions with EBF1 on target genes.