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ZNF143 protein is an important regulator of the myeloid transcription factor C/EBP?.

ABSTRACT: The transcription factor C/EBP? is essential for myeloid differentiation and is frequently dysregulated in acute myeloid leukemia. Although studied extensively, the precise regulation of its gene by upstream factors has remained largely elusive. Here, we investigated its transcriptional activation during myeloid differentiation. We identified an evolutionarily conserved octameric sequence, CCCAGCAG, ?100 bases upstream of the CEBPA transcription start site, and demonstrated through mutational analysis that this sequence is crucial for C/EBP? expression. This sequence is present in the genes encoding C/EBP? in humans, rodents, chickens, and frogs and is also present in the promoters of other C/EBP family members. We identified that ZNF143, the human homolog of the Xenopus transcriptional activator STAF, specifically binds to this 8-bp sequence to activate C/EBP? expression in myeloid cells through a mechanism that is distinct from that observed in liver cells and adipocytes. Altogether, our data suggest that ZNF143 plays an important role in the expression of C/EBP? in myeloid cells.

SUBMITTER: Gonzalez D

PROVIDER: S-EPMC5704476 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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ZNF143 protein is an important regulator of the myeloid transcription factor C/EBPα.

Gonzalez David D Luyten Annouck A Bartholdy Boris B Zhou Qiling Q Kardosova Miroslava M Ebralidze Alex A Swanson Kenneth D KD Radomska Hanna S HS Zhang Pu P Kobayashi Susumu S SS Welner Robert S RS Levantini Elena E Steidl Ulrich U Chong Gilbert G Collombet Samuel S Choi Min Hee MH Friedman Alan D AD Scott Linda M LM Alberich-Jorda Meritxell M Tenen Daniel G DG

The Journal of biological chemistry 20170912 46

The transcription factor C/EBPα is essential for myeloid differentiation and is frequently dysregulated in acute myeloid leukemia. Although studied extensively, the precise regulation of its gene by upstream factors has remained largely elusive. Here, we investigated its transcriptional activation during myeloid differentiation. We identified an evolutionarily conserved octameric sequence, CCCAGCAG, ∼100 bases upstream of the <i>CEBPA</i> transcription start site, and demonstrated through mutati ...[more]

PMID: 28900037

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Project description:Chicken NF-M transcription factor, in cooperation with either c-Myb or v-Myb, is active in the combinatorial activation of myeloid-cell-specific genes in heterologous cell types, such as embryonic fibroblasts. In humans, similar effects were observed with homologous members of the CCAAT/enhancer-binding protein (C/EBP) family of transcriptional regulators, especially the human homolog of chicken NF-M, C/EBP-beta (NF-IL6). However, the NF-IL6 gene is expressed in a variety of nonmyeloid cell types and is strongly inducible in response to inflammatory stimuli, making it an unlikely candidate to have an exclusive role as a combinatorial differentiation switch during myelopoiesis in human cells. By using a reverse transcription-PCR-based approach and a set of primers specific for the DNA-binding domains of highly homologous members of the C/EBP family of transcriptional regulators, we have cloned a novel human gene encoding a member of the C/EBP gene family, identified as the human homolog of CRP1, C/EBP-epsilon. A 1.2-kb cDNA encoding full-length human C/EBP-epsilon was cloned from a promyelocyte-late myeloblast-derived lambda gt11 library. Molecular analysis of the cDNA and genomic clones indicated the presence of two exons encoding a protein with an apparent molecular mass of 32 kDa and a pI of 9.5. Primer extension analysis of C/EBP-epsilon mRNA detected a single major transcription start site approximately 200 bp upstream of the start codon. The putative promoter area is similar to those of several other myeloid-cell-specific genes in that it contains no TATAAA box but has a number of purine-rich stretches with multiple sites for the factors of the Ets family of transcriptional regulators. Northern blot analyses indicated a highly restricted mRNA expression pattern, with the strongest expression occurring in promyelocyte and late-myeloblast-like cell lines. Western blot and immunoprecipitation studies using rabbit anti-C/EBP-epsilon antibodies raised against the N-terminal portion of C/EBP-epsilon (amino acids 1 to 115) showed that C/EBP-epsilon is a 32-kDa nuclear phosphoprotein. The human C/EBP-epsilon protein exhibited strong and specific binding to double-stranded DNA containing consensus C/EBP sites. Cotransfection of the C/EBP-epsilon sense and antisense expression constructs together with chloramphenicol acetyltransferase reporter vectors containing myeloid-cell-specific c-mim and human myeloperoxidase promoters suggested a role for C/EBP-epsilon transcription factor in the regulation of a subset of myeloid-cell-specific genes. Transient tranfection of a promyelocyte cell line (NB4) with a C/EBP-epsilon expression plasmid increased cell growth by sevenfold, while antisense C/EBP-epsilon caused a fivefold decrease in clonal growth of these cells.

Project description:Transcription factor C/EBP-beta regulates a number of physiological responses. During an investigation of the growth-suppressive effects of interferons (IFNs), we noticed that cebpb(-/-) cells fail to undergo apoptosis upon gamma IFN (IFN-gamma) treatment, compared to wild-type controls. To examine the basis for this response, we have performed gene expression profiling of isogenic wild-type and cebpb(-/-) bone marrow macrophages and identified a number of IFN-gamma-regulated genes that are dependent on C/EBP-beta for their expression. These genes are distinct from those regulated by the JAK-STAT pathways. Genes identified in this screen appear to participate in various cellular pathways. Thus, we identify a new pathway through which the IFNs exert their effects on cellular genes through C/EBP-beta. One of these genes is death-associated protein kinase 1 (dapk1). DAPK1 is critical for regulating the cell cycle, apoptosis, and metastasis. Using site-directed mutagenesis, RNA interference, and chromatin immunoprecipitation assays, we show that C/EBP-beta binds to the promoter of dapk1 and is required for the regulation of dapk1. Both mouse dapk1 and human dapk1 exhibited similar dependences on C/EBP-beta for their expression. The expression of the other members of the DAPK family occurred independently of C/EBP-beta. Members of the C/EBP family of transcription factors other than C/EBP-beta did not significantly affect dapk1 expression. We identified two elements in this promoter that respond to C/EBP-beta. One of these is a consensus C/EBP-beta-binding site that constitutively binds to C/EBP-beta. The other element exhibits homology to the cyclic AMP response element/activating transcription factor binding sites. C/EBP-beta binds to this site in an IFN-gamma-dependent manner. Inhibition of ERK1/2 or mutation of an ERK1/2 site in the C/EBP-beta protein suppressed the IFN-gamma-induced response of this promoter. Together, our data show a critical role for C/EBP-beta in a novel IFN-induced cell growth-suppressive pathway via DAPK1.

Dataset Information

ZNF143 protein is an important regulator of the myeloid transcription factor C/EBP?.

Publications

ZNF143 protein is an important regulator of the myeloid transcription factor C/EBPα.

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