This website uses cookies to ensure you get the best experience on our website.
- Table of Contents
Facts about Endothelial transcription factor GATA-2.
.
Human | |
---|---|
Gene Name: | GATA2 |
Uniprot: | P23769 |
Entrez: | 2624 |
Belongs to: |
---|
No superfamily |
endothelial transcription factor GATA-2; FLJ45948; GATA binding protein 2; GATA2; GATA-2; GATA-binding protein 2NFE1B; MGC2306
Mass (kDA):
50.5 kDA
Human | |
---|---|
Location: | 3q21.3 |
Sequence: | 3; NC_000003.12 (128479422..128493201, complement) |
Endothelial cells.
Nucleus.
This article will focus on the most effective uses for the GATA2 marker (Boster Bio). GATA2 is an element of the GATA transcription factor family, and its absence or decreased expression can cause a decrease in the development and differentiation of hematopoietic stem cells (HSCs). In turn, it is commonly used in stem cell transplantation because it increases the expression of the functionally distinct GATA1 transcription factor. The process is known as the GATA switch.
Patients with monosomy 7 and ASXL1 mutations have a greater chance of developing leukemia and MDS in the event that their GATA2 gene mutation is found. One study showed that 80percent of GATA2 haploinsufficiency patients developed myeloidleukemia before age 40. While the cause of GATA2 haploinsufficiency is still unclear It is believed to be a crucial regulator of the hematopoiesis.
The phenotypes associated with this disease are caused by the fact that GATA2 deficiency is a gene-based condition. Patients with GATA2 haploinsufficiency exhibit a broad range of symptoms that include bacterial and virus infections, cytopenias and myeloid leukemia, lymphedema, and alveolar proteinosis in the pulmonary apex.
While the exact role of GATA2 in the progression of MDS/AML remains unclear, it has been reported to deplete the HSC compartment in mice. It is unclear if a reduction in GATA2 levels in mice results in a reduced amount of HSCs within the patient. However clinical trials have demonstrated that a single transfer of two to five SSCs that have been corrected can alleviate symptoms of sickle cell disease in patients suffering from GATA2 haploinsufficiency.
GATA2 deficiency symptoms in humans are similar to those of other bone marrow failure disorders. The primary symptom of GATA2 deficiency is an infection. Sixty percent of patients have a diagnosis of an infection. Likewise, twenty percent are diagnosed of MDS/AML. GATA2 deficiency can also be due to high levels of Flt3-ligand and other oligoclonal cell receptors. Furthermore, patients with GATA2 mutations can experience hypocellularity in the bone marrow, which can result in anemia aplastic.
Although GATA2 expression is regulated by conserved cis-regulatory elements the onset of disease in GATA2 haploinsufficiencies is unpredictable. Mutations in GATA2 can affect the +9.5 cis regulator, which regulates GATA2 transcript. GATA2 haploinsufficiency can result by mutations in the region of the gene intron 4 which accounts for 10% of all cases.
In GATA2 haploinsufficiencies, the +9.5 enhancer WGATAR motif is insufficient for the emergence of HSCs. It leads to the loss of Ebox spacer GATA composite elements which disables the +9.5 function. The mutations are common in human patients with GATA-2 deficiency syndrome. It is possible to lose function due to disabling GATA2 binding.
A variety of autoimmune diseases could result from GATA2 mutations. MonoMAC is a condition that increases the risk of chronic myelomonocytic and acute myeloid leukemia. This genetic disorder is passed down autosomally. In severe cases, patients can develop myelodysplastic syndrome, lung alveolar proteinosis or NK-cell insufficiency.
In addition to the phenotype, Gata2 expression is induced in the BM LSK cell population in the course of regeneration. The RNA-Seq analyses of LSK cells from WT and +9.5 (Ets)and mice showed a similar pattern to mice that are WT. After treatment with 5-FU, Gata2 expression increased 15-fold in BM from WT mice. However it was found that the Ets motif was necessary to allow Gata2 expression to increase after myeloablation. This could be due to a defective regeneration or hypersensitivity to 5-FU.
A new study has revealed the possibility of using an RNA-guided system of CRISPR/Cas9 to correct an HBB gene mutation in iPSCs of patients suffering from sickle cell disease. In the past, correcting the HBB gene mutation in iPSCs needed the use of a donor-derived plasmid containing wild-type HBB gene and an antibiotic selection cassette for enrichment.
Cas9 gene correction has been proven to result in loss-of-function INELs. While ddPCR reveals an impressive rate of correction using this technique, the outcome of hHgbA analysis in secondary recipients is not as positive. The re-incorporation of mutant alleles is likely to contribute to lower hemoglobin levels in mice who were transplanted. Nevertheless, these experiments suggest that LT-HSCs are effective in repairing DNA damage caused by HiFi.
In the study of the past edited cells were implanted into immunodeficient NOD scid gamma mice. The edited cells were able of correcting an HBB gene mutation in around 40% of patients and could be detected 16-17 weeks after transplant. TALGlobin01 cleavage activity also was detected at a single site that was located at the HBD gene locus.
The results of this study suggest autologous hematopoietic transplantation can be used to correct an HBB gene variation. While this treatment might not be appropriate for all patients, it has significantly improved the outlook for many patients with Thalassemia. If the procedure is provided in a timely manner, patients suffering from this mutation could benefit. This will also assist to avoid any end-organ damage. However, this procedure is restricted because it cannot be match-up with any donor.
There are numerous advantages to autologous HSCs (including those that could be used for cancer prevention) However, the clinical trials currently in progress have been conducted on mice. The use of Cas9-based editing techniques in humans has opened the door to the correction of HBB gene mutations by using patient-derived HSCs. In addition, the CRISPR/Cas9 gene editing technology has given an innovative approach to the correction of HBB gene mutations in human HSPCs.
Another option is to use human bone marrow or other stem cells of hematopoietic origin to create HBB cells that have been corrected. This method has been demonstrated not to diminish the total engraftment of donors. However, HSCSs targeted by genes have not shown a significant reduction after the first transplantation in humans.
In the past, gene-editing to human zygotes aimed at modifying human b-globin genes was controversial, however, today it is being widely used to treat hemoglobinopathies that affect adults. These cells can also be used to correct autologous HBB genes and are highly suitable for allogeneous HSPC transplantation.
The aim of autologous hematopoietic cell transplantation for the correction of a HBB gene mutation is to replace the altered B-globin by an a-globin-like G-globin from the fetus. This procedure is not without the potential for risk, since the HBB gene is extremely similar to the gene d-globin.
The GATA transcription factor family is comprised of many members of which is GATA2. These proteins bind DNA and control a range of biological processes, such as development and cell differentiation. GATA is vital for the growth of the hematopoietic stem cells (HSCs) during the fetal stage as well as in adulthood. While the precise mechanisms behind GATA deficiency remain unclear changes to the gene alter its interaction with DNA.
GATA1 and GATA2 share a similar mutation that can result in leukemia. The mutation in GATA2 affects the gene's n-terminal activation domain and its zinc finger. Both genes have been implicated in leukemogenesis. However, mutations in GATA1 are associated with abnormal myelopoiesis that is transiently present.
Hsu and colleagues discovered the heterozygous C–to–T transition in the gene that encodes GATA2 which causes a decrease in GATA2 expression in the vivo. In addition to these mutations, the GATA2 gene also has the T354M mutation in the zinc finger-2 domain that is extremely conserved. These findings highlight the importance of GATA2 in the fight against cancer.
Six members comprise the GATA transcription factor family. GATA-1 to GATA-2and GATA-4 to GATA-5 are important players in the endocrine and gastrointestinal systems. All six members can bind to FOG proteins through their amino acids sequences that they have conserved. FOG binding happens on the zinc finger's surface, which is opposite to DNA's contact sites.
GATA1 is crucial in the growth of megakaryocytes and erythroids. GATA2 is created to compensate for the loss in megakaryocytes of GATA-1 in the late stage of megakaryopoiesis. Both proteins have a small homology in their sequences, which means they can perform their functions independently. GATA1 is crucial for megakaryocyte development, while FOG1 is necessary for megakaryopoiesis.
Three members of the GATA family are involved in the the development of certain kinds of blood clotting cells. GATA1 is crucial for the development of granulocyte-monocytes and mast cells' expression prevents it. GATA2 expression could also play a part in the point of terminal differentiation. Mutations of GATA1 and GATA2 affect cysteine residues located at positions A318 and G321.
Genetic studies have proven that mutations and transgenes that are not properly regulated are linked to the outcome de novo acutemyeloid leukemia in children (AML). GATA2 is an essential transcription element for the determination myeloid lineages. Therefore it was imperative that patients with GATA2 mutations were screened. The results showed a significant relationship between GATA2 mutants and the overall survival in de novo AML.
Recent studies have revealed that GATA2 can covalently be modified by SUMOs using the kinase inhibitor, PIASY. PIASY is a preferred way to enhance SUMO2 conjugation to GATA2. The inhibition of GATA2 activity in endothelial cells requires a GATA-binding site in the ET1 promoter. GATA2 and Tal1 were also identified as components of the gene regulatory network during the specification of mouse hematopoietic stem cells in the aorta-gonal-mesonephrose region.
PMID: 1714909 by Lee M.-E., et al. Cloning of the GATA-binding protein that regulates endothelin-1 gene expression in endothelial cells.
PMID: 1370462 by Dorfman D.M., et al. Human transcription factor GATA-2. Evidence for regulation of preproendothelin-1 gene expression in endothelial cells.