X-linked thrombocytopenia caused by a novel mutation ofGATA-1

Blood ◽  
2001 ◽  
Vol 98 (9) ◽  
pp. 2681-2688 ◽  
Author(s):  
Michele G. Mehaffey ◽  
Anthea L. Newton ◽  
Manish J. Gandhi ◽  
Merlin Crossley ◽  
Jonathan G. Drachman
Keyword(s):  
Transcription Factor ◽  
Zinc Finger ◽  
Novel Mutation ◽  
Direct Interaction ◽  
Vital Role ◽  
Single Amino Acid ◽  
Female Carrier ◽  
Coding Region ◽  
Erythroid Development

Abstract A family with recessive X-linked thrombocytopenia affecting 4 males in 2 generations, characterized by macrothrombocytopenia, profound bleeding, and mild dyserythropoiesis, is described. Microsatellite linkage analysis identified a region of the X chromosome including theGATA-1 gene, which encodes a critical transcription factor involved in erythrocyte and megakaryocyte development. By sequencing the entire coding region of GATA-1, a 2-base mutation was detected that results in a single amino acid substitution (glycine 208 to serine) within a highly conserved portion of the N-terminal zinc finger domain. Restriction fragment length polymorphism confirmed that this novel mutation segregated with the affected males and female carrier. Although not required for DNA binding, Gly208 of GATA-1 is involved in direct interaction with Friend of GATA-1 (FOG), a cofactor required for normal megakaryocytic and erythroid development. These results demonstrate that the GATA-1–FOG interaction is partially disrupted by the mutation and that the greatest effect involves contact with the FOG zinc finger 9. These findings help describe a novel mutation of GATA-1 in humans as a cause of X-linked thrombocytopenia, and they confirm the vital role played by this transcription factor during in vivo megakaryocyte development.

A Drosophila doublesex-related gene, terra, is involved in somitogenesis in vertebrates

Development ◽  
1999 ◽  
Vol 126 (6) ◽  
pp. 1259-1268 ◽  
Author(s):  
A. Meng ◽  
B. Moore ◽  
H. Tang ◽  
B. Yuan ◽  
S. Lin
Keyword(s):  
Transcription Factor ◽  
Zinc Finger ◽  
Dna Binding Domain ◽  
Related Gene ◽  
Presomitic Mesoderm ◽  
Zinc Finger Gene ◽  
Human And Mouse

The Drosophila doublesex (dsx) gene encodes a transcription factor that mediates sex determination. We describe the characterization of a novel zebrafish zinc-finger gene, terra, which contains a DNA binding domain similar to that of the Drosophila dsx gene. However, unlike dsx, terra is transiently expressed in the presomitic mesoderm and newly formed somites. Expression of terra in presomitic mesoderm is restricted to cells that lack expression of MyoD. In vivo, terra expression is reduced by hedgehog but enhanced by BMP signals. Overexpression of terra induces rapid apoptosis both in vitro and in vivo, suggesting that a tight regulation of terra expression is required during embryogenesis. Terra has both human and mouse homologs and is specifically expressed in mouse somites. Taken together, our findings suggest that terra is a highly conserved protein that plays specific roles in early somitogenesis of vertebrates.

scholarly journals Transcription factor Krüppel-like factor 2 plays a vital role in endothelial colony forming cells differentiation

2013 ◽  
Vol 99 (3) ◽  
pp. 514-524 ◽  
Author(s):  
Yimeng Song ◽  
Xiaoxia Li ◽  
Dawei Wang ◽  
Chenglai Fu ◽  
Zhenjiu Zhu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Tube Formation ◽  
Vital Role ◽  
Ampk Activation ◽  
Cell Markers ◽  
Endothelial Colony Forming Cells ◽  
Angiogenesis Assay

Abstract Aims Endothelial colony forming cells (ECFCs) participate in post-natal vasculogenesis. We previously reported that vascular endothelial growth factor (VEGF) promotes human ECFC differentiation through AMP-activated protein kinase (AMPK) activation. However, the mechanisms underlying transcriptional regulation of ECFC differentiation still remain largely elusive. Here, we investigated the role of transcription factor Krüppel-like factor 2 (KLF2) in the regulation of ECFC function. Methods and results Human ECFCs were isolated from cord blood and cultured. Treatment with VEGF significantly increased endothelial markers in ECFCs and their capacity for migration and tube formation. The mRNA and protein levels of KLF2 were also significantly up-regulated. This up-regulation was abrogated by AMPK inhibition or by knockdown of KLF2 with siRNA. Furthermore, adenovirus-mediated overexpression of KLF2 promoted ECFC differentiation by enhancing expression of endothelial cell markers, reducing expression of progenitor cell markers, and increasing the capacity for tube formation in vitro, indicating the important role of KLF2 in ECFC-mediated angiogenesis. Histone deacetylase 5 (HDAC5) was phosphorylated by AMPK activity induced by VEGF and the AMPK agonist AICAR (5-amino-1-β-d-ribofuranosyl-imidazole-4-carboxamide). In vivo angiogenesis assay revealed that overexpression of KLF2 in bone-marrow-derived pro-angiogenic progenitor cells promoted vessel formation when the cells were implanted in C57BL/6 mice. Conclusion Up-regulation of KLF2 by AMPK activation constitutes a novel mechanism of ECFC differentiation, and may have therapeutic value in the treatment of ischaemic heart disease.

scholarly journals Transcriptional regulation of the fad regulon genes of Escherichia coli by ArcA

Microbiology ◽  
2006 ◽  
Vol 152 (8) ◽  
pp. 2207-2219 ◽  
Author(s):  
Byung-Kwan Cho ◽  
Eric M. Knight ◽  
Bernhard Ø. Palsson
Keyword(s):  
Escherichia Coli ◽  
Transcription Factor ◽  
Transcriptional Regulation ◽  
Expression Profiles ◽  
Direct Interaction ◽  
Anaerobic Growth ◽  
Binding Motif ◽  
Promoter Regions ◽  
Chip Analysis

ArcA is a global transcription factor required for optimal growth of Escherichia coli during anaerobic growth. In this study, the role of ArcA on the transcriptional regulatory subnetwork of the fad regulon was investigated. Gene expression profiles of deletion mutants (ΔarcA, ΔfadR and ΔarcA/ΔfadR) indicated that (i) ArcA is a major transcription factor for the transcriptional regulation of fatty acid metabolism in the absence of oxygen, and (ii) ArcA and FadR cooperatively regulate the fad regulon under anaerobic conditions. To determine the direct interaction between ArcA and the promoters of the fad regulon genes, chromatin immunoprecipitation (ChIP) analysis was performed. ChIP analysis suggested that ArcA directly binds to the promoter regions of the fad regulon genes in vivo. An ArcA-binding motif was identified from known binding sequences and predicted putative binding sites in the promoter regions of the fad regulon genes. These results indicate that ArcA directly represses the expression of fad regulon genes during anaerobic growth.

scholarly journals ZEB1 Mediates Bone Marrow Mesenchymal Stem Cell Osteogenic Differentiation Partly via Wnt/β-Catenin Signaling

2021 ◽  
Vol 8 ◽  
Author(s):  
Cuidi Xu ◽  
Hongli Shi ◽  
Xin Jiang ◽  
Yongqian Fan ◽  
Donghui Huang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transcription Factor ◽  
Osteogenic Differentiation ◽  
Zinc Finger ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Marrow Mesenchymal Stem Cells ◽  
Zeb1 Expression

Zinc finger E-box-binding homebox 1 (ZEB1) is a zinc-finger transcription factor best known for its role in promoting the epithelial-mesenchymal transition, which is also related to osteogenesis. Here, ZEB1 was investigated for its role in the commitment of bone marrow mesenchymal stem cells (BMSCs) to osteoblasts. In vitro, ZEB1 expression decreased following osteogenic differentiation. Furthermore, silencing of ZEB1 in BMSCs promoted osteogenic activity and mineralization. The increase in osteogenic differentiation induced by si-ZEB1 could be partly rescued by the inhibition of Wnt/β-catenin (si-β-catenin). In vivo, knockdown of ZEB1 in BMSCs inhibited the rapid bone loss of ovariectomized (OVX) mice. ZEB1 expression has also been negatively associated with bone mass and bone formation in postmenopausal women. In conclusion, ZEB1 is an essential transcription factor in BMSC differentiation and may serve as a potential anabolic strategy for treating and preventing postmenopausal osteoporosis (PMOP).

Persistence of GATA1+ Erythroid Progenitors In Vivo in Absence of Zebrafish SCL.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1615-1615
Author(s):  
Marianne A. Juarez ◽  
Fengyun Su ◽  
Mark J. Kiel ◽  
Susan E. Lyons
Keyword(s):  
Initiation Site ◽  
Vital Role ◽  
Translation Initiation Site ◽  
Bhlh Transcription Factor ◽  
Erythroid Progenitors ◽  
Functional Conservation ◽  
Myeloid Development ◽  
Lateral Mesoderm ◽  
Erythroid Development

Abstract The stem cell leukemia (SCL) gene encodes a bHLH transcription factor essential to the primitive and definitive hematopoietic systems in vertebrates. In the zebrafish, studies of hematopoiesis have shown significant functional conservation with mammals. In order to assess the functions of scl in zebrafish primitive hematopoiesis, zebrafish embryos were analyzed after ablation of Scl protein by morpholino-modified antisense RNA injection. Embryos injected with morpholinos targeting the scl translation initiation site or two independent splice donor sites lacked circulating blood and exhibited cardiac edema by 28 hours post fertilization. RNA in situ hybridization analysis with a panel of hematopoietic-specific genes showed that myeloid lineage development in the anterior lateral mesoderm was absent upstream of draculin and pu.1 expression. In contrast, erythroid development in the posterior lateral mesoderm occurred with little or no functional Scl, as shown by expression of draculin, pu.1, and gata1 in this PLM region. Primitive erythroid cells failed to mature, as evidenced by the absence of circulating cells after 24 hpf. Only upon titration of scl morpholinos to near toxic levels was gata1 reduced or absent in embryos at 21 somites. These findings show that scl plays a vital role in development of all hematopoietic lineages in zebrafish. However, these data reveal differential effects of reduction or loss of Scl on hematopoietic development in the anterior lateral mesoderm versus the posterior lateral mesoderm. The results reveal that reduction or loss of Scl affects erythroid development in the posterior lateral mesoderm or ICM at a progenitor stage of erythroid development, after initiation of gata1 and embryonic globin expression. These data suggest that early erythroid development in the zebrafish requires little or no Scl, while maturation of erythroid progenitors cannot occur in the absence of Scl. Myeloid development in the anterior lateral mesoderm is dependent upon Scl. This embryonic analysis in the zebrafish is the first to demonstrate a transient, in vivo population of erythroid precursors in embryos with severely reduced or absent expression of Scl.

scholarly journals Regions outside the DNA-binding domain are critical for proper in vivo specificity of an archetypal zinc finger transcription factor

2013 ◽  
Vol 42 (1) ◽  
pp. 276-289 ◽  
Author(s):  
J. Burdach ◽  
A. P. W. Funnell ◽  
K. S. Mak ◽  
C. M. Artuz ◽  
B. Wienert ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Dna Binding ◽  
Zinc Finger ◽  
Binding Domain ◽  
Dna Binding Domain ◽  
Zinc Finger Transcription Factor

scholarly journals Novel Antifungal Drug Discovery Based on Targeting Pathways Regulating the Fungus-Conserved Upc2 Transcription Factor

2013 ◽  
Vol 58 (1) ◽  
pp. 258-266 ◽  
Author(s):  
Christina Gallo-Ebert ◽  
Melissa Donigan ◽  
Ilana L. Stroke ◽  
Robert N. Swanson ◽  
Melissa T. Manners ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Dna Binding ◽  
Fungal Pathogens ◽  
Direct Interaction ◽  
Antifungal Drugs ◽  
Sterol Biosynthesis ◽  
Content Type ◽  
Stressed Cells

ABSTRACTInfections byCandida albicansand related fungal pathogens pose a serious health problem for immunocompromised patients. Azole drugs, the most common agents used to combat infections, target the sterol biosynthetic pathway. Adaptation to azole therapy develops as drug-stressed cells compensate by upregulating several genes in the pathway, a process mediated in part by the Upc2 transcription factor. We have implemented a cell-based high-throughput screen to identify small-molecule inhibitors of Upc2-dependent induction of sterol gene expression in response to azole drug treatment. The assay is designed to identify not only Upc2 DNA binding inhibitors but also compounds impeding the activation of gene expression by Upc2. An AlphaScreen assay was developed to determine whether the compounds identified interact directly with Upc2 and inhibit DNA binding. Three compounds identified by the cell-based assay inhibited Upc2 protein level andUPC2-LacZgene expression in response to a block in sterol biosynthesis. The compounds were growth inhibitory and attenuated antifungal-induced sterol gene expressionin vivo. They did so by reducing the level of Upc2 protein and Upc2 DNA binding in the presence of drug. The mechanism by which the compounds restrict Upc2 DNA binding is not through a direct interaction, as demonstrated by a lack of DNA binding inhibitory activity using the AlphaScreen assay. Rather, they likely inhibit a novel pathway activating Upc2 in response to a block in sterol biosynthesis. We suggest that the compounds identified represent potential precursors for the synthesis of novel antifungal drugs.

scholarly journals Inhibition of red blood cell development by arsenic-induced disruption of GATA-1

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Xixi Zhou ◽  
Sebastian Medina ◽  
Alicia M. Bolt ◽  
Haikun Zhang ◽  
Guanghua Wan ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Zinc Finger ◽  
Zinc Fingers ◽  
Arsenic Exposure ◽  
In Vivo Studies ◽  
Regulatory Factor ◽  
Zinc Finger Motifs ◽  
First Time

Abstract Anemia is a hematological disorder that adversely affects the health of millions of people worldwide. Although many variables influence the development and exacerbation of anemia, one major contributing factor is the impairment of erythropoiesis. Normal erythropoiesis is highly regulated by the zinc finger transcription factor GATA-1. Disruption of the zinc finger motifs in GATA-1, such as produced by germline mutations, compromises the function of this critical transcription factor and causes dyserythropoietic anemia. Herein, we utilize a combination of in vitro and in vivo studies to provide evidence that arsenic, a widespread environmental toxicant, inhibits erythropoiesis likely through replacing zinc within the zinc fingers of the critical transcription factor GATA-1. We found that arsenic interacts with the N- and C-terminal zinc finger motifs of GATA-1, causing zinc loss and inhibition of DNA and protein binding activities, leading to dyserythropoiesis and an imbalance of hematopoietic differentiation. For the first time, we show that exposures to a prevalent environmental contaminant compromises the function of a key regulatory factor in erythropoiesis, producing effects functionally similar to inherited GATA-1 mutations. These findings highlight a novel molecular mechanism by which arsenic exposure may cause anemia and provide critical insights into potential prevention and intervention for arsenic-related anemias.

scholarly journals Differential regulation of target genes by different alleles of the segmentation gene hunchback in Drosophila.

Genetics ◽  
1994 ◽  
Vol 138 (1) ◽  
pp. 125-134 ◽  
Author(s):  
M Hülskamp ◽  
W Lukowitz ◽  
A Beermann ◽  
G Glaser ◽  
D Tautz
Keyword(s):  
Transcription Factor ◽  
Zinc Finger ◽  
Target Genes ◽  
Regulatory Gene ◽  
Differential Regulation ◽  
Coding Region ◽  
Segmentation Gene ◽  
Zinc Finger Domains ◽  
Morphogenetic Gradient ◽  
Blastoderm Stage

Abstract hunchback (hb) is a key regulatory gene in the early segmentation gene hierarchy of Drosophila. It codes for a transcription factor of the Cys2-His2 zinc finger type and shows two separate zinc finger domains in its coding region. hb forms a morphogenetic gradient in the middle of the embryo that is required for setting the spatial boundaries of several target genes. We have analyzed the molecular lesions found in the different hb alleles and have studied the differential effects of these alleles on a number of such target genes. We find that in mutants in which the HB protein lacks a functional second finger domain, the regulation of the target genes Krüppel (Kr) and knirps (kni) is differentially affected. While this domain is required for the correct regulation of Kr, it is not necessary for the repression of kni. Furthermore, mutations affecting this domain lead to a decreased protein stability. The integration of the expression pattern of target genes was found to be distorted in a second class of mutants between the two finger domains which lead to gain of function or neomorphic phenotypes. The effects of these mutations were studied in detail and it was found that they fall into two classes, the first one interfering with the function of the maternal hb product, the second leading to a delayed segmentation. The function of the latter class appears to be linked to the secondary expression of hb in the parasegment 4 (PS4) stripe at blastoderm stage.

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