Zfp281 (ZBP-99) plays a functionally redundant role with Zfp148 (ZBP-89) during erythroid development

Abstract

Erythroid maturation requires the concerted action of a core set of transcription factors. We previously identified the Krüppel-type zinc finger transcription factor Zfp148 (also called ZBP-89) as an interacting partner of the master erythroid transcription factor GATA1. Here we report the conditional knockout of Zfp148 in mice. Global loss of Zfp148 results in perinatal lethality from nonhematologic causes. Selective Zfp148 loss within the hematopoietic system results in a mild microcytic and hypochromic anemia, mildly impaired erythroid maturation, and delayed recovery from phenylhydrazine-induced hemolysis. Based on the mild erythroid phenotype of these mice compared with GATA1-deficient mice, we hypothesized that additional factor(s) may complement Zfp148 function during erythropoiesis. We show that Zfp281 (also called ZBP-99), another member of the Zfp148 transcription factor family, is highly expressed in murine and human erythroid cells. Zfp281 knockdown by itself results in partial erythroid defects. However, combined deficiency of Zfp148 and Zfp281 causes a marked erythroid maturation block. Zfp281 physically associates with GATA1, occupies many common chromatin sites with GATA1 and Zfp148, and regulates a common set of genes required for erythroid cell differentiation. These findings uncover a previously unknown role for Zfp281 in erythroid development and suggest that it functionally overlaps with that of Zfp148 during erythropoiesis.

Identification of the transcription factor MAZ as a regulator of erythropoiesis

“…A small group of lineage-restricted TFs, including GATA binding protein 1 (GATA1), T-cell acute lymphocytic leukemia 1 protein (TAL1), and erythroid Kr€ uppel-like factor (EKLF; henceforth referred to as KLF1), act as erythroid master regulators 3 by binding to both promoters and enhancers of the globin genes as well as to other genes important for erythropoiesis (reviewed in Philipsen et al, 2 Perkins et al, 4 and Katsumura et al 5 ), where they usually act together with other widely expressed TFs. [6][7][8][9][10][11][12][13][14] However, despite the enormous advances that have been achieved in our understanding of the molecular mechanisms controlling globin gene expression, this research area keeps progressing.…”

A MYC-ZNF148-ID1/3 regulatory axis modulating cancer stem cell traits in aggressive breast cancer

“…BioChIP was performed broadly as previously described [ 22 ]. MCF7 and MDA-MB-231 cells were grown to 60–80% confluence and cross-linked with 1% formaldehyde (methanol-free) for 10 min at room temperature and quenched with 125 mM glycine.…”

“…Quantitative PCR was performed on a Rotor-Gene 6000 thermocycler (Qiagen) using SensiMixPlus SYBR (Bioline). The expression levels of genes quantified by RT-PCR (RT-qPCR) are presented relative to that of GAPDH; while the enrichments of regulatory regions assayed by quantitative ChIP-PCR (ChIP-qPCR) were calculated relative to an unrelated region in exon 6 of the ACTB locus, as previously described [ 20 , 22 , 39 ].…”

“…We found zinc finger protein 148 (ZNF148, also called Zfp148 and ZBP-89), a ubiquitously expressed Krüppel-like zinc finger protein, as a target of MYC-regulatory network in mouse ES cells [ 20 ]. Partial deletion of the ZNF148 locus causes defective primordial germ cell development in mice [ 21 ], though a complete deletion in the C57BL/6 mouse strain leads to postnatal lethality [ 22 ]. In malignant tumors, ZNF148 has been reported to be a suppressive [ 23 – 25 ] or oncogenic [ 26 – 28 ] factor, depending on the tumor cell of origins and tissue types.…”

3136 – Identification of the Transcription Factor Maz as a Regulator of Erythropoiesis

“…A small group of lineage-restricted TFs, including GATA binding protein 1 (GATA1), T-cell acute lymphocytic leukemia 1 protein (TAL1), and erythroid Kr€ uppel-like factor (EKLF; henceforth referred to as KLF1), act as erythroid master regulators 3 by binding to both promoters and enhancers of the globin genes as well as to other genes important for erythropoiesis (reviewed in Philipsen et al, 2 Perkins et al, 4 and Katsumura et al 5 ), where they usually act together with other widely expressed TFs. [6][7][8][9][10][11][12][13][14] However, despite the enormous advances that have been achieved in our understanding of the molecular mechanisms controlling globin gene expression, this research area keeps progressing.…”