GATA1

 GATA transcription factors comprise a family of zinc finger proteins that bind the consensus DNA sequence (T/A)GATA(A/G). There are six known members of the GATA family in vertebrates. GATA1, GATA2, and GATA3 play roles predominantly, although not exclusively, within the hematopoietic system. GATA4, GATA5, and GATA6 are expressed in nonhematopoietic tissues and play diverse developmental roles within the cardiac, gastrointestinal, endocrine, and gonadal systems. Functionally important binding sites for GATA factors have been identified in cis-acting regulatory elements of essentially every megakaryocytic and erythroid gene that has been studied. GATA1, the founding member of this family, is highly expressed in erythroid and megakaryocytic cells and, to a lesser extent, in eosinophils and mast cells. GATA1 plays an essential role in erythroid development, with loss of function resulting in blocked erythroid maturation and apoptosis of erythroid progenitor cells. GATA1 is also required for megakaryocyte maturation and growth control. Lineage-selective loss of GATA1 in megakaryocytes results in marked thrombocytopenia in mice with platelet counts of only ≈15% of WT littermates. Megakaryocytes are present in the mutant animals but have a disorganized DMS, paucity of platelet-specific granules, reduced expression of multiple megakaryocyte-specific genes (including GPIbα, GPIbβ, PF4, c-Mpl, and p45 NF-E2), and marked hyperproliferation as compared with WT mice. Gene expression studies of GATA1-deficient versus WT murine megakaryocytes have revealed a large number of potential GATA1 target genes, and many of these have been found to be bound by GATA1 in genome wide chromatin occupancy studies. Mice containing a reduced mega karyocyte-specific expression of GATA1 (GATA1low) develop MF as they age, a frequent finding with disorders of MkP hyperproliferation. A GATA binding site mutation in the GPIbβ promoter has been described in a patient with Bernard-Soulier syndrome, which is characterized by a deficiency of the GPIb/IX/V complex and a bleeding diathesis. Taken together, these findings suggest that GATA1 acts as a master regulator of megakaryocyte maturation and proliferative control.

Friend of GATA (ZFPM1)

All vertebrate GATA factors contain two zinc fingers. The carboxyl zinc finger mediates high-affinity DNA binding, whereas the amino zinc finger stabilizes the DNA interaction at certain double GATA sites. The amino zinc finger also interacts with a friend of GATA (FOG) proteins, a family of large multitype zinc finger transcriptional cofactors. This interaction occurs on the surface of the zinc finger opposite to its DNA binding surface. FOG-1 (also called zfpm1), the founding member, is expressed predominantly within erythroid and megakaryocytic cells. Knockout of FOG-1 in mice results in embryonic lethality caused by severe anemia from a block in erythroid maturation similar to that observed in GATA1− mice. In addition, FOG-1−/− mice have a complete failure of megakaryocytopoiesis, establishing FOG-1 as the first identified transcription-associated factor selectively required to generate the entire megakaryocyte lineage. FOG-1’s role in megakaryocyte and erythroid development requires direct physical interaction with GATA factors. The discrepancy between the relatively late block in megakaryocyte development seen in GATA1-deficient animals and the complete loss of megakaryocytopoiesis in FOG-1−/− mice is explained by overlapping FOG-dependent roles of GATA1 and GATA2 during the early stages of megakaryocytopoiesis.

X-Linked Dyserythropoietic Anemia and Thrombocytopenia Caused by GATA1 Mutations

 Germline GATA1 mutations that impair binding to FOG-1 and/ or DNA have been identified in several families with X-linked macrothrombocytopenia and/or anemia (GATA1 is located on the X chromosome in both humans and mice). The first case, reported by Nichols et al., involved a woman with mild chronic thrombocytopenia who had two pregnancies with male offspring that were both complicated by severe fetal anemia and thrombocytopenia requiring in utero transfusions. BM examination after birth revealed marked dyserythropoiesis and an overabundance of immature appearing, dysplastic megakaryocytes that share many of the features of GATA1^low murine megakaryocytes. Remarkably, sequencing of the GATA1 gene from affected family members identified a substitution of valine by methionine at codon 205 within the amino zinc finger. This mutation (GATA1^V205M) significantly impairs FOG-1 binding but retains normal DNA affinity based on electromobility shift assays using synthetic oligonucleotides. This is consistent with the location of this residue on the surface of the zinc finger opposite the DNA binding face.

Several other GATA1 mutations have been linked to cases of familial X-linked macrothrombocytopenia with or without anemia. All of these substitutions impair FOG-1 binding, although to different degrees. Substitution of glycine by serine at codon 208 (GATA1^G208S) results in moderate to severe thrombocytopenia and mild dyserythropoiesis, but no anemia. Substitution of the same residue by arginine (GATA1^G208R) results in thrombocytopenia with anemia and severe dyserythropoiesis. Similarly, the substitution of aspartic acid by glycine at codon 218 (GATA1D218G) leads only to thrombocytopenia, whereas substitution of this same codon by tyrosine (GATA1^D218Y) leads to severe thrombocytopenia, moderate anemia, and marked dyserythropoiesis. The severity of the phenotype appears to correlate with the degree of FOG-1 binding impairment, suggesting that megakaryocytic development is more sensitive to affinity changes in GATA1–FOG-1 interactions than is erythroid development.

X-Linked Thrombocytopenia and Thalassemia Caused by GATA1 Mutations

Mutations mapping to the DNA binding surface of the amino zinc finger of GATA1 have also been described (GATA1^R216Q). As expected, this reduces DNA affinity to double (palindromic) GATA sites but not to single GATA sites. FOG-1 binding is not substantially altered. Affected family members exhibit an X-linked β-thalassemia syndrome characterized by an imbalance of alpha- and beta-globin chain synthesis, reticulocytosis, and hemolysis. They also have mild to moderate thrombocytopenia. In vitro plate let aggregation studies are normal, but there is a prolonged bleeding time. Substitution of the same residue by tryptophan (R216W) produces thrombocytopenia, β-thalassemia intermedia, and con genital erythropoietic porphyria (CEP). The CEP is likely caused by dysregulation of the GATA1 target gene uroporphyrinogen III synthase.

X-Linked Gray Platelet–Like Syndrome

 GPS refers to a disorder of large platelets with absent or markedly reduced α-granules and/or α-granule proteins. Platelets from individuals with GATA1^R261Q share some features with classical GPS. Ultrastructural studies of platelets from a different family with GATA1-related X-linked macrothrombocytopenia (GATA1^G208S) also demonstrate hypogranular platelets that contain small vacuoles, likely representing membranes of empty α-granules. However, the GATA1 mutant platelets also possess unique features such as masses of dense tubular system channels, dense double membranes, and platelets within platelets, not seen in classical GPS, suggesting a more general disorder of platelet biogenesis. GPS is characterized by the release of proteins normally contained in α granules into the mar row, causing MF. GPS is primarily inherited in an autosomal recessive manner, and the mutated gene has been mapped to chromosome 3p and identified as NBEAL2.

GATA1 Mutations in Down Syndrome Transient Myeloproliferative Disorders and Acute Megakaryoblastic Leukemia

About 10% of children with DS (trisomy 21) are born with a transient myeloproliferative disorder (also termed “Down Syndrome—Transient Abnormal Myelopoiesis [DS-TAM]”), which is characterized by an abundance of circulating erythromegakaryocytic precursor cells, pancytopenia, and in some cases, severe liver fibrosis. Remarkably, this myeloproliferation resolves spontaneously over the first few months of life. In about 20% to 30% of cases, DS-associated acute megakaryocytic leukemia (DS-AMKL, also termed “Myeloid Leukemia of Down Syndrome [ML-DS]”) devel ops within a few years, sometimes preceded by a myelodysplastic phase. In 2002, Wechsler et al. reported that DS-AMKL cells harbor acquired mutations in their GATA1 gene. Since then, many groups have identified similar mutations in DS-TMD cells. Although a wide spectrum of mutations has been found, including missense, deletion, insertion, and splice-site mutations, they all involve exon 2 (or rarely exon 3) and result in the same outcome: generation of an amino-terminal truncated protein (loss of amino acids 1 to 83) because of translation initiation from a downstream ATG codon. This removes a region that functions as a transcriptional activation domain in transient transfection reporter assays. The mutations are detectable in BM from DS-AMKL patients but disappear when patients enter remission, indicating a strong correlation between the mutated clone and the leukemic phenotype. Mutations involving exon 2 of GATA1 are highly specific for DS-AMKL and DS-TMD, or AMKL with acquired trisomy 21. There is only one reported case of such a mutation in AMKL without trisomy 21, and mutations have not been detected in DS-acute lymphoblastic leukemia or a large number of healthy individuals.

Analysis of stored neonatal blood spots shows the coexistence of several different GATA1 mutations (all resulting in the generation of GATA1s) in patients who subsequently developed DS-AMKL, suggesting an oligoclonal expansion. In a few cases in which mate rial was available, identical GATA1 mutations have been found in both the DS-TMD and DS-AMKL cells from the same patient. DS-AMKL cells often harbor additional genetic abnormalities, such as trisomy 8 or tetrasomy 21, not observed in DS-TMD cells. Acquisition of secondary loss-of-function mutations in members of the cohesion complex, and other epigenetic factors, is also common. Taken together, these findings support a clonal evolution model of DS-AMKL, with GATA1 mutations associated with an early initiating event.

Generation of knock-in mice that recapitulate these truncating GATA1 mutations show unexpected stage-specific effects on mega karyocytopoiesis. During fetal liver hematopoiesis, the mutant mega karyocytes markedly hyperproliferate, similar to what is observed for GATA1-deficient megakaryocytes. However, during adult-stage BM hematopoiesis, megakaryocytopoiesis and thrombocytopoiesis appear normal. This suggests that the fetal liver and BM cellular contexts interact differentially with the GATA1 truncated molecule. This may also explain the restriction of TMD to the neonatal period. A family has been described with members containing a germline GATA1 gene splice site mutation (G332C) that results in the exclusive production of the GATA1s protein product. Affected individuals exhibit a unique phenotype characterized by trilineage BM dysplasia, macrocytic anemia, and neutropenia. None of the family members has developed leukemia, suggesting that trisomy 21 plays a role in DS-TMD progression to DS-AMKL.

Of note, Calligaris et al., previously reported that GATA1s is produced naturally at low levels in erythroid cells. They proposed that this might serve a regulatory role during normal hematopoiesis by acting as a dominant-negative molecule at specific times/environmental stimuli. Endogenous GATA1s have also been detected in normal mouse fetal liver megakaryocytes and adult human BM megakaryocytes. Thus, it has been proposed that the ratio of GATA1 to GATA1s plays a role in developmental aspects of megakaryocytopoiesis and that acquired GATA1 mutations observed in DS-TMD and DS-AMKL, or germline mutations in the family described earlier, perturb hematopoiesis by altering this ratio.

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مواضيع ذات صلة

Cellular and Molecular Mechanisms in Development: Gene Regulation by Transcription Factors

The Polymerase Chain Reaction Amplifies a Specific DNA Sequence from a Complex Mixture

Role of Developmentally Important Neutrophil-Specific Genes in Disease

Genes Can Be Identified by Their Map Position on the Chromosome

Homologous Recombination Can Repair DNA Damage and Generate Genetic Diversity

During Chain Elongation Each Incoming Aminoacyl-tRNA Moves Through Three Ribosomal Sites

Eukaryotic Translation Initiation Usually Occurs at the First AUG Downstream from the 5′ End of an mRNA

Ribosomes Are Protein-Synthesizing Machines

The Amyloid Precursor Protein Gives Rise to the β-Amyloid Peptide

Nonstandard Base Pairing Often Occurs Between Codons and Anticodons

The Folded Structure of tRNA Promotes Its Decoding Functions

Messenger RNA Carries Information from DNA in a Three-Letter Genetic Code