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Marjolein HFM Lentjes,1 Hanneke EC Niessen,1 Yoshimitsu Akiyama,2 Adriaan P de Bruïne,1 Veerle Melotte,1 and Manon van Engeland1,*
Contents
Marjolein HFM Lentjes
1Department of Pathology, GROW – School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
Hanneke EC Niessen
1Department of Pathology, GROW – School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
Yoshimitsu Akiyama
2Department of Molecular Oncology, Graduate School of Medicine and Dentistry, Tokyo Medical and Dental University, Tokyo, Japan
Adriaan P de Bruïne
1Department of Pathology, GROW – School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
Veerle Melotte
1Department of Pathology, GROW – School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
Manon van Engeland
1Department of Pathology, GROW – School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
1Department of Pathology, GROW – School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
2Department of Molecular Oncology, Graduate School of Medicine and Dentistry, Tokyo Medical and Dental University, Tokyo, Japan
*Corresponding author:Prof Dr Manon van Engeland, Department of Pathology, GROW – School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200 MD Maastricht, The Netherlands. Tel: +31-43-3885498; Fax: +31-43-3876613; E-mail: ln.cmum
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
Đang xem: Tai gata 1
The GATA family of transcription factors consists of six proteins (GATA1-6) which are involved in a variety of physiological and pathological processes. GATA1/2/3 are required for differentiation of mesoderm and ectoderm-derived tissues, including the haematopoietic and central nervous system. GATA4/5/6 are implicated in development and differentiation of endoderm- and mesoderm-derived tissues such as induction of differentiation of embryonic stem cells, cardiovascular embryogenesis and guidance of epithelial cell differentiation in the adult.
The importance of GATA factors for development is illustrated by the embryonic lethality of most single GATA knockout mice. Moreover, GATA gene mutations have been described in relation to several human diseases, such as hypoparathyroidism, sensorineural deafness and renal insufficiency (HDR) syndrome, congenital heart diseases (CHDs) and cancer. GATA family members are emerging as potential biomarkers, for instance for the risk prediction of developing acute megalokaryblastic leakemia in Down syndrome and for the detection of colorectal- and breast cancer.
The origin and molecular structure of the GATA family
In vertebrates, six GATA transcription factors have been identified. Based on phylogenetic analysis and tissue expression profiles, the GATA family can be divided into two subfamilies, GATA1/2/3 and GATA4/5/6 (Ref. 1). Although in non-vertebrates GATA genes are linked together onto chromosomes, in humans they are segregated onto six distinct chromosomal regions (Table 1 ), indicating segregation during evolution (Ref. 2). Most GATA genes encode for several transcripts and protein isoforms. GATA proteins have two zinc finger DNA binding domains, Cys-X2-C-X17-Cys-X2-Cys (ZNI and ZNII), which recognise the sequences (A/T)GATA(A/G) (Fig. 1 ) (Ref. 3). Amongst the six GATA binding proteins, the zinc finger domains are more than 70% conserved, while the sequences of the amino-terminal and carboxyl-terminal domains exhibit lower similarity (Ref. 4). In non-vertebrates GATA transcription factors have been identified that contain mostly one zinc finger, i.e. in Drosophila melanogaster and Caenorhabditis elegans (Ref. 3). The C-terminal zinc finger (ZNII) exists in both vertebrates and non-vertebrates indicating that ZNI was duplicated from ZNII (Ref. 2).
Overview of GATA1-6 proteins. The GATA proteins are depicted in the upper part of the figure. The GATA proteins are aligned according to the location of the zinc fingers (ZNI and ZNII). The exon boundaries are depicted above the protein structure. For GATA4 the TADI and TADII are shown. In the lower part of the figure the regions around the zinc fingers are enlarged, with the correspondingAA numbers written next to the GATA sequence. Posttranslational modification (post-transciptional modification) sites and disease-associated alterations are marked on top of the corresponding AA. AA, amino acid; TAD, transcriptional activation domains.
Genomic sequencemRNA sequenceProtein sequenceNameChromosomal locationEnsembl acession no.CpG island in the promoter regionTranscriptsEnsembl transcript ID a Coding exonsUniprot accession no.IsoformProtein length (AA)GATA1Xp11.23ENSG00000102145None3ENST000003766705} P15976141323303335GATA23q21.3ENSG00000179348+6ENST000003411055} P2376914802466GATA310p15ENSG00000107485+5ENST000003462085} P2377114432444GATA48p23.1-p22ENSG00000136574++9ENST000003351356} P43694442GATA520q13.33ENSG00000130700++4ENST000002529976} Q9BWX5397GATA618q11.1-q11.2ENSG00000141448++1ENST000002692166} Q9290815952449
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NamePhenotype (embryonic day)AbnormalityReferenceGATA1die (11.5–12.5 dpc)Defective erythroid cell maturation(Ref. 5)GATA2die (12.5 dpc)Severe anaemia(Ref. 6)GATA3die (11–12 dpc)Massive internal bleeding and severe deformities of the brain and spinal cord(Ref. 7)GATA4die (9.5 dpc)Defects of heart morphogenesis and ventral closure of the forgut(Ref. 8)GATA5Viable and fertileFemales exhibited pronounced genitourinary abnormalities that included vaginal and uterine defects and hypospadias(Ref. 9)GATA6die (5.5–7.5 dpc)defects of visceral endoderm function and subsequent extra-embryonic endoderm(Ref. 10)
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GATA1, the first recognised member of the GATA family, is specifically expressed during haematopoietic development of erythroid, and megakaryocytic cell lineages (Fig. 2 ) (Ref. 11). Loss of GATA1 in mouse embryo-derived stem cells results in a complete lack of primitive erythroid precursor production (Ref. 5). Definitive erythroid precursors, on the other hand, are normally produced, but undergo a maturation arrest at the proerythroblast stage followed by apoptosis (Ref. 12). Ablation of GATA1 in adult mice also results in a maturation arrest at the same proerythroblast stage (Ref. 13). The requirement of the different GATA1 functional domains during primitive and definitive erythropoiesis has been investigated in vivo, showing that both zinc fingers are needed to rescue GATA1 germline mutant mice (Ref. 14). In haematopoietic stem cells (HSCs), GATA1 gene expression is suppressed, which is indispensable for the maintenance of these stem cells. The mechanism behind this suppression is not fully understood yet. Recently, it was shown that decreased DNA methylation of the GATA1 locus leads to increased GATA2 binding and that increased GATA2 binding results in GATA1 gene transactivation. According to these study results, Takai et al. proposed a mechanism in which GATA1 hypomethylation results in an accessible locus for GATA2 binding which enables transactivation of GATA1 gene expression to initiate erythropoiesis in megakaryo-erythroid progenitors (Ref. 15). Loss of GATA1 results in a marked increase of GATA2 expression, indicating not only that GATA2 partially compensates for GATA1 but also that GATA1 suppresses GATA2 transcription during normal erythropoiesis (Ref. 16). This suppression is mediated by the displacement of GATA2 from its upstream enhancer by increasing levels of GATA1 referred to as the ‘GATA switch’ (Ref. 17). The combined loss of GATA1 and GATA2 in double-knockout embryos leads to an almost complete absence of primitive erythroid cells, suggesting functional overlap between these transcription factors early in the primitive erythropoiesis (Ref. 18).
DiseaseAbberationLocationConsequence GATA1 XLTMS mutZnF1FOG1 interaction ↓XLTTMS mutZnF1DNA binding ↓Anaemia (e.g. Diamond-Blackfan anaemia)Splice site mutation, mutation initiation codonexon 2Only short for or loss of the full length GATA1 isoformCongenital erythropoietic porphyriaMS mutZnF1UnknownTMD and AMKL in DSFS INS and DEL, NS mut and splice site mutationIntron 1, exon 2 and 3Protein truncation, transcriptional activation ↓AMKL without DSINSexon 2Protein truncation GATA2 Chronic myeloid leukaemiaMS mut, FS DELZnF2DNA binding ↑, transcriptional activation ↓DCML / MonoMAC / Emberger syndromeFS INS and DEL, MS and NS mut, full gene DELZnF2, 5′UTR, intron 5Nonfunctional protein, nonsense-mediated decayMyelodysplastic syndromeFS INS and DEL, MS and NS mut, full gene DELexon, intron, 5′UTRProtein truncation, DNA binding ↓Acute myeloid leukaemiaMS mut, FS INS, full gene DELZnF1, ZnF2, exonsNonfunctional protein GATA3 HDR syndromeMS and NS mut, FS INS and DEL, splice site mutation,partial and full gene DELZnF1, ZnF2, exonsProtein truncation, FOG2 interaction ↓, DNA binding/affinity ↓Breast cancerMS and NS mut, FS INS and DELZnF2, exonsProtein truncation, nonfunctional proteinT-ALLMS mut, FS DEL, in-frame DELZnF1, ZnF2Likely loss of functionB-ALLSNPIntron 3UnknownUCC and RCCCpG methylationPromoterTranscriptional activation ↓ GATA4 CHDMS and NS mut, FS INS and DEL, SNP, full gene DEL, gene duplicationZnF1, ZnF2, exons, 3″-UTR, introns, promoterProtein truncation, DNA binding/affinity ↓, transcriptional activation ↓, TBX5 interaction ↓, changed RNA foldingPancreatic agenesisMS mut, intragenic and full gene deletionZnF2Transcriptional activation ↓, DNA binding ↓GI cancerCpG methylation, amplificationPromoter, 8pTranscriptional activation ↓/↑Glioblastoma multiformeCpG methylation, FS INS and DELPromoter, ZnF domains, C terminal regionTranscriptional activation ↓Ovarian cancerHypoacetylation, loss trimethylation, CpG methylationHistone 3 and 4, lysine 4Transcriptional activation ↓Other cancers (e.g. lung, DLBCL)CpG methylationPromoterTranscriptional activation ↓ GATA5 CHDMS and NS mutZnF1, ZnF2Transcriptional activation ↓Cancer (e.g. GI cancer, RCC)CpG methylationPromoterTranscriptional activation ↓ GATA6 CHDMS and NS mut, duplication and DELZnF1, ZnF2, exonsTranscriptional activation ↓Pancreatic agenesisMS and NS mut, FS INS and DELZnf2, exonsTranscriptional activation ↓Ovarian cancerHypoacetylation, loss trimethylation, upregulationHistone 3 and 4, lysine 4Transcriptional activation ↓/↑GI cancerAmplification, CpG methylation18q, promoterTranscriptional activation ↓/↑Pancreatobiliary cancerAmplification18q11.2Transcriptional activation ↑Pediatric rhabdomyosarcomaCpG methylationPromoterTranscriptional activation ↓
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AMK, acute megakaryoblastic leukaemia; B-ALL, B-cell acute lymphoblastic leukaemia; CHD, congenital heart disease; CML, chronic myeloid leukaemia; DCML, dendritic cell, monocyte, B-lymphocyte and natural killer lymphocyte deficiency; DEL, deletion; DLBCL, diffuse large B-cell lymphoma; DS, Down syndrome; GI, cancer gastrointestinal cance; FS, frameshift; HDR, hypoparathyreoidism, sensorineural deafness and renal disease; INS, insertion; MS, mut missense mutation; MonoMAC, syndrome associated with monocytopenia, B and NK, cell lymphopenia and mycobacterial, fungal and viral infections; NS, mut nonsense mutation; RCC, renal cell carcinoma; SNP, single nucleotide polymorphism; T-ALL, T-cell acute lymphoblastic leukaemia; TMD, transient myeoloproliferative disorder; UCC, urothelial cell carcinoma; XLT, X-linked thrombocytopenia; XLTT, X-linked thrombocytopenia with thalassemia.
Conditional megakaryocytic lineage specific GATA1 knockout mice show excessive marrow megakaryocyte proliferation whereas the platelet numbers are decreased. The maturation of these hyperproliferated megakaryocytes is severely impaired and the produced platelets are structurally and functionally abnormal (Ref. 21). Additionally, megakaryocyte-expressed genes with functional GATA1-binding sites (e.g. STAT1) are downregulated in GATA1−/− megakaryocytes (Ref. 22). Loss of GATA1 leads to overexpression of GATA2 in megakaryocytes. However GATA1-deficient megakaryocytes still show abnormal megakaryocytic proliferation and differentiation, establishing no functional redundancy of these transcription factors in megakaryopoiesis (Ref. 23). In contrast to erythropoiesis, GATA2 remains to be expressed after the GATA switch in late megakaryopoiesis, suggesting a divergent function for both GATA proteins (Ref. 24).
Children with trisomy 21 are at risk of developing leukaemia, in particular acute megakaryoblastic leukaemia (AMKL). Nearly all Down syndrome patients with AMKL harbour somatic mutations in the GATA1 gene (Table 3 ) (Ref. 25), predominantly leading to an N-terminal truncated ‘short’ GATA1 protein (GATA1s) (Ref. 26). Inadequate GATA1 mediated repression of specific oncogenic factors contributes to megakaryocytic abnormalities (Ref. 27). Analysis of Down syndrome children with transient myeloproliferative disorder (TMD), which is considered a potential precursor to AMKL, also revealed GATA1 mutations (Ref. 28). Noticeable the GATA1 mutation in TMD and subsequent AMKL is identical, suggesting that GATA1 mutations are early events in the development of AMKL in trisomy 21-children (Ref. 29). Not all TMD Down syndrome neonates with a GATA1 mutation progress to AMKL, indicating the need for more molecular events contributing to the pathogenesis of AMKL. Recently, Yoshida et al. reported newly acquired driver mutations, which lead to the development from TMD to Down syndrome-AMKL (Refs 30, 31).
The mechanism behind the leukaemogenesis remains elusive. Based on mutational spectrum analysis of the GATA1 locus in Down syndrome AMKL, Cabelof et al. hypothesised that increased oxidative stress because of trisomy 21, uracil accumulation and reduced DNA repair together driving leukaemogenesis in Down syndrome (Ref. 32). Recently it was shown that GATA1 mutations protect megakaryocytes from activated AKT-induced apoptosis (Ref. 33). Additionally, trisomy 21 itself increases HSC frequency, clonogenicity and megakaryocyte-erythroid output with associated megakaryocyte-erythroid progenitor expansion (Refs 34, 35, 36). Another hypothesis is that upregulation of runt-related transcription factor 1 (RUNX1), which physically interacts with GATA1, due to trisomy 21 leads to the induction of GATA1 transcription during embryogenesis, thereby leading to transcription-associated mutagenesis (Ref. 37). Recently it is shown that loss of type I interferon (IFN) signalling contributes to GATA1s-induced megakaryocyte hyperproliferation, suggesting AMKL-treatment with IFN-α administration (Ref. 38).
GATA1 mutations are also detected in a specific form of X-linked hereditary thrombocytopenia and are described with and without thalassemia (Table 3 and Supplemental Table 1). Hereditary thrombocytopenia without thalassemia has been associated with GATA1 missense mutations that are located in the N-terminal zinc finger region. These mutations lead to loss or inhibition of GATA1 interaction with friend-of-GATA(FOG)1-cofactor (Ref. 39). The degree of disrupted GATA1–FOG1 interaction depends on the mutation, explaining different clinical presentations (Ref. 40). The only GATA1 mutation reported in hereditary X-linked thrombocytopenia with thalassemia is the missense mutation R216Q which is located in the DNA binding surface of the GATA1 N-terminal zinc finger and results in reduced DNA binding rather than affecting GATA1–FOG1 interaction (Ref. 41).
In vertebrates, GATA2 is expressed in haematopoietic progenitor cells (HPCs), early erythroid cells, mast cells and megakaryocytes, closely resembling the cellular distribution of GATA1 (Fig. 2 ). A deficit in primitive erythropoiesis is apparent in GATA2−/− mice since the total number of blood cells during embryonic development is markedly reduced, leading to lethality because of severe anaemia (Table 2 ) (Ref. 6). In GATA2+/− mice haematopoietic defects are seen within HSCs and granulocyte-macrophage progenitor cells. Moreover, the loss of GATA2 in adult mice leads to profound abnormalities in definitive haematopoiesis, also directing to a defect at the level of HSCs (Refs 6, 42, 43). The function of GATA2 in haematopoietic development has recently been reviewed by Bresnick et al. (Ref. 44), describing GATA2 as one of the key components establishing the transcriptional program for early haematopoietic development.
Two different GATA2 alterations have been reported in patients with chronic myeloid leukemia (CML) during blast crisis formation (Table 3 ). In contrast to the in-frame deletion Δ341-346, which leads to decreased transcriptional activation, GATA2 L359V is a gain-of-function mutation and leads to increased DNA binding. Transduction of GATA2 L359V (in vitro and in vivo) resulted in disturbed myelomonocytic differentiation/proliferation, suggesting GATA2 mutations are involved in the acute myeloid transformation of CML (Ref. 45).
GATA2 gene mutations that predisposed to myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) were reported (Supplemental Table 1). This occurred either in the absence (non-syndromic) or presence of certain syndromes, including Emberger syndrome and monoMAC syndrome (Ref. 46). Most mutations affect the C-terminal zinc finger or result in N-terminal frameshift mutations (Ref. 47).
Similar expression patterns of GATA1, GATA2 and GATA3 in human, murine and avian erythroid cells indicate a conserved role for these GATA transcription factors in vertebrate erythropoiesis (Ref. 48). Beyond its expression in erythroid lineages, GATA3 is also expressed in T lymphocytes (Ref. 49). During haematopoiesis vertebrate GATA3 is expressed in HSCs and in developing T lymphocytes. Murine GATA3−/− embryos are predominantly affected during definitive haematopoiesis in the fetal liver. Although later than GATA2−/− mice, these embryos appear also anaemic and die in utero, probably owing to massive internal bleeding (Table 2 ) (Ref. 7). Frelin et al. demonstrated that GATA3 regulates the self-renewal and differentiation of bone marrow long-term HSCs (Ref. 50). During embryogenesis, GATA3 deficiency leads to a marked reduction in the production of HSCs in the aorta-gonads-mesonephros region. It was shown that GATA3 regulates HSC emergence during embryogenenis via the production of catecholamines linking the haematopoietic system development to the development of the sympathetic nervous system (SNS) (Ref. 51).
In T cell development, GATA3 has a pivotal role from the generation of early T lineage progenitors to CD4+ specification
GATA3 dysregulation is described in leukaemia. Together with T-cell acute lymphocytic leukemia 1 (TAL1) and RUNX1, GATA3 forms an autoregulatory loop that positively regulates the v-myb avian myeloblastosis viral oncogene (MYB) oncogene, which in turn controls the gene expression program in T-cell acute lymphoblastic leukaemia (T-ALL) (Ref. 56). Thereby, whole-genome sequencing of patients with early T-cell precursor ALL, an aggressive subtype of T-ALL, revealed GATA3 inactivating mutations (Supplemental Table 1) (Ref. 57).
In summary, GATA1/2/3 are essential regulators in the development of erythroid and megakaryocytic cell lineages and in the molecular pathogenesis of different haematopoietic diseases.
Cardiovascular system
The mesoderm gives rise to numerous organs, including the heart and genitourinary tract. GATA4/5/6 proteins are expressed in the mesodermal precursors that develop into the heart (Ref. 58).
GATA4 is one of the earliest transcription factors expressed in developing cardiac cells, already detectable in murine precardiac splanchnic mesoderm and associated endoderm (Ref. 8). GATA4−/− mice display severe defects in ventral foregut closure and heart morphogenesis, resulting in embryonic lethality at embryonic day 8 (Table 2 ). These deformities result from a general loss in ventral folding throughout the embryo and implicate GATA4 requirement for the migration or folding morphogenesis of the precardiogenic splanchic mesodermal cells (Ref. 8). Mice harbouring a knock-in mutation that abrogates the interaction with FOG-cofactors (GATA4Ki/Ki) lack coronary vessels (Ref. 59). In addition, murine GATA4 regulates cardiac angiogenesis by inducing angiogenic factors such as VEGF, facilitating compensation following injury (Ref. 60). Yamak et al. have suggested that GATA4 and Cyclin D2 are part of a forward reinforcing loop in which Cyclin D2 feeds back to enhance cardiogenic activity of GATA4 through direct interaction. GATA4 mutations that abrogate Cyclin D2 interactions are associated with human CHD (Ref. 61).
A variety of GATA4 mutations have been detected in patients with various forms of CHD such as Tetralogy of Fallot, ventricular septal defect and atrial fibrillation as reviewed by McCulley et al and summarised in Table 3 and Supplemental Table 1 (Ref. 62).
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Within the developing heart, GATA5 is expressed in the myocardium as well as in the endocardium and derived endocardial cushions in mouse embryos (Ref. 63). Depending on how GATA5 is inactivated in several mouse models, different cardiac phenotypes are described. Deletion of both GATA5 isoforms leads to hypoplastic hearts and partially penetrant bicuspid aortic valve formation (Ref. 64). When a GATA5 mutant allele was established that lacked the two zinc finger domains, cardiovascular defects were only detectable in a GATA4+/− background (Ref. 65). Although little is known about GATA5 in human heart conditions, three heterozygous GATA5 mutations have been associated with familial atrial fibrillation (Ref. 66) and four heterozygous GATA5 mutations with CHD (Ref. 67).
GATA6 is abundantly expressed in vascular smooth muscle cells during murine embryonic and postnatal development (Ref. 68). GATA6−/− mice die at the embryonic stage due to defects of the extra-embryonic endoderm (Table 2 ) (Ref. 10). Tissue-specific deletion of GATA6 in neural crest-derived smooth muscle cells results in an interrupted aortic arch and persistent truncus arteriosus (PTA). These results suggest that GATA6 is required for proper patterning of the aortic arch arteries. This phenotype is associated with severely attenuated expression of semaphorin 3C, a signalling molecule critical for both neuronal and vascular patterning (Ref. 69). Other GATA6 target genes, e.g. Wnt2, in vascular smooth muscle cells and cardiac cells have been identified by microarray analysis after transient GATA6 over-expression. Interestingly, GATA6 is also a target of Wnt2 and together they form a feedforward transcriptional loop to regulate posterior cardiac development (Ref. 70).
A number of mutations have been described for GATA6 in the aetiology of CHD (Table 3 ; Supplemental Table 1). For example, two GATA6 mutations were found in patients with PTA disrupting the transcriptional activity of the GATA6 protein on downstream genes involved in the development of the cardiac outflow tract (Ref. 71).
Thus, the GATA4/5/6 transcription factors have closely related functions during cardiovascular development, and defects lead to CHD and other heart conditions.
Gastrointestinal tract
The endoderm gives rise to the respiratory and gastrointestinal tract as well as the associated organs such as pancreas and liver. Differentiation of embryonic stem cells towards the extra-embryonic endoderm can be induced by forced expression of either GATA4 or GATA6 (Ref. 72). Targeted mutagenesis of GATA4 in mouse embryonic stem cells results in disturbed differentiation of the visceral endoderm, suggesting that GATA4 has a role in yolk sac formation (Ref. 73).
Murine GATA4 is expressed in the proximal but not in the distal small intestine and has an important role in the maintenance of jejunal-ileal identities (Ref. 74). Furthermore, GATA4 is essential for jejunal functions such as fat and cholesterol absorption (Ref. 75). Beuling et al. found that reduction of GATA4 activity in the intestine induces bile acid absorption in the proximal ileum, which can restore bile acid homeostasis in mice with an ileocaecal resection (Ref. 76).
Whereas GATA4 expression is absent from the distal ileum, GATA6 is expressed throughout the entire small intestine. Conditional deletion of GATA6 in the ileum results in a decrease of crypt cell proliferation and numbers of enteroendocrine and Paneth cells, an increase in numbers of goblet-like cells in crypts and altered expression of genes specific to absorptive enterocytes. GATA4/6 factors are therefore required for proliferation, differentiation and gene expression in the small intestine (Ref. 77).
In humans, GATA4 and GATA5 are expressed in normal gastric and colon mucosa (Refs 78, 79). In gastric and colorectal cancer (CRC) these genes are frequently transcriptionally silenced by methylation (Refs 80, 78). In addition, we reported that GATA4 and GATA5 exhibit tumour suppressive properties in human CRC cells in vitro (Ref. 80). The potential biomarker capacities of GATA4 are discussed below.
Liver and pancreas
In the mouse, the ventral foregut endoderm differentiates to form the parenchymal components of the liver and ventral pancreas. Although GATA4 has an essential function in embryonic liver development, the protein seems to be dispensable in the adult liver function (Refs 81, 82). GATA6−/− murine embryos have defects in endoderm differentiation, and show severely attenuated GATA4 expression levels and complete absence of hepatocyte nuclear factor 4 (HNF4) expression in the visceral endoderm, parietal endoderm and liver bud (Ref. 83). HNF4 is a key regulator for complete differentiation of visceral endoderm, hepatocyte differentiation and the epithelial transformation of the liver (Ref. 84). Tetraploid rescue experiments with GATA6 null mice show that GATA6 is a key regulator for liver bud growth and commitment of the endoderm to a hepatic cell fate (Ref. 83).
Development of the ventral pancreas was, in contrast to the dorsal pancreas, impaired in GATA4−/− murine embryos using tetraploid rescue experiments. GATA6−/− embryos show a similar phenotype, although not as severe as that observed in GATA4−/− embryos (Ref. 81). In humans, the role of GATA6 in pancreatic development became apparent in a group of patients with pancreatic agenesis, in which Allen et al. identified 15 de novo heterozygous inactivating mutations in GATA6 (Supplemental Table 1). In addition, these patients suffered from CHD, biliary tract abnormalities, gut developmental disorders, neurocognitive abnormalities and other endocrine abnormalities (Ref. 85). In contrast to these results, Martinelli et al. described that GATA6 is dispendable for pancreas development. However, GATA6 is essential for acinar differentiation and maintenance of adult exocrine homeostasis in mice (Ref. 86). An explanation for this contradiction might be the timepoint of GATA6 inactivation which is earlier in agenesis patients compared with the mouse model used by Martinelli et al. Together these data show the need for further research to unravel the role of GATA6 in pancreatic development.
In pancreatic cancer, GATA6 is often overexpressed, which correlates with GATA6 amplification (Table 3 ) (Ref. 87). Retained GATA6 expression has been shown in gastric, colorectal, esophageal, ovarian and pulmonary cancer cell lines (Refs 78, 88, 89, 90). Additionally, intestinal GATA6 expression is higher in proliferating progenitor cells compared with differentiated cells (Ref. 91). In primary gastric cancer, the pro-oncogenic effects of GATA6 are recently confirmed, in vitro and in vivo (Ref. 92).
Urogenital tract and kidney
GATA1 is abundantly expressed in the Sertoli cells of the testis during murine prepubertal testis development (Fig. 2 ). GATA1 expression decreases thereafter and is in the adult mouse testis only found in the Sertoli cells during different stages of the spermatogenesis (Ref. 93). Surprisingly, Sertoli-specific GATA1 knockout mice show no alterations in testis development, spermatogenesis, male fertility and expression of putative testis-specific GATA1 target genes (Ref. 94). Further research has to clarify whether there is a functional redundancy between GATA factors in the testis.
During urogenital development, GATA4 is expressed in somatic ovarian and testicular cell lineages, and is suggested to have an important regulatory role in gonadal gene expression (Fig. 2 ) (Ref. 95). Mouse embryos conditionally deficient in GATA4 show no formation of the genital ridge, the structure which differentiates into either testis or ovary (Ref. 96). GATA4ki/ki mice and FOG2−/− mice display defects in the gonadogenesis in both sexes (Ref. 97). SRY (Y chromosome-linked testis-determining gene), MIS (Mullerian inhibiting substance) and SOX9 expression, which is critical for testis formation, are dependent on GATA4 × FOG2 interaction (Ref. 98). Recently, a signalling cascade was suggested describing transduction of the p38 mitogen-activated protein kinase (MAPK) pathway by MAP3K4 and GADD45G which leads to GATA4 phosphorylation and thereby activation. Phosphorylated GATA4 then binds and activates the SRY promoter (Ref. 99).
The GATA4 gene has also been implicated in a disorder of sex development (DSD). A GATA4 mutation, which abrogates the binding with FOG2, was discovered in a family with both CHD and 46,XY DSD (Table 3 ) (Ref. 100). The phenotype closely resembles that of the mouse GATA4ki/ki model (Ref. 97). The data described above indicate that GATA4, in combination with FOG2, is necessary for proper mammalian sex differentiation.
Murine GATA5 is expressed in the urogenital ridge during foetal development (Ref. 63). GATA5−/− female mice exhibit abnormalities of the genitourinary tract including malpositioning of the urogenital sinus, vagina and urethra, whereas males are unaffected (Table 2 ). These defects suggest that early morphogenic movements in the lower genitourinary tract are disrupted in the absence of GATA5. GATA5 and GATA6 are coexpressed in the developing urogenital ridge but do not seem to have entirely overlapping functions during development of the female genitourinary system (Ref. 9).
GATA6 is expressed during both testicular and ovarian fetal development (Fig. 2 ) (Ref. 63). In the developing gonads, GATA4 and GATA6 have overlapping, but distinct expression patterns, which suggest different roles for these transcription factors. In addition, it is also possible that these factors complement each other”s functions because GATA4 and GATA6 are expressed in similar cell types in the testis and ovary (Refs 101, 102).
Loss of GATA6 expression has been found in ovarian cancer and has been associated with hypoacetylation of histones H3 and H4 and loss of H3K4me3 at the promoter region (Ref. 90). Downregulation of GATA6 expression results in nuclear deformation and aneuploidy of ovarian surface epithelial cells (Ref. 103). In contrast to other cancers, these data indicate a tumour suppressor role for GATA6 in ovarian cancer. Tumour suppressing activities are also suggested for GATA4 and GATA5 whereas introduction of these genes into ovarian tumour cell lines greatly inhibits cell growth and survival (Ref. 104).
During pronephros formation human GATA3 expression is already detected in the nephric duct (Fig. 2 ) (Ref. 105). Subsequently, ureter tips and the collecting duct system of the metanephros are formed, which both show GATA3 expression (Ref. 106). Inactivation of the murine GATA3 locus results in a morphologically abnormal nephric duct with an aberrant elongation path, loss of ureteric bud and a severe growth disturbance of de mesonephros due to the disturbance of a regulatory cascade consisting of GATA3 with β-catenin as upstream regulator and Ret as downstream target (Ref. 107).
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In humans, GATA3 haploinsufficiency leads to the HDR syndrome, a rare and complex disease characterised by the combination of HDR, associated with GATA3 mutations (Table 3 , Supplemental Table 1) (Ref. 108). The majority of these mutations leads to loss of DNA binding caused by a disrupted ZnF2, or altered FOG2 interaction and/or DNA binding affinity by a disrupted ZnF1 (Table 3 ). Most of the HDR probands without GATA3 mutations do not have renal abnormalities and no GATA3 mutations are found in patients with isolated hypoparathyreoidism (Ref. 109). This suggests that GATA3 mutations are highly penetrant and result in the HDR phenotype. In addition, GATA3+/− mice show small size parathyroids resulting in failure to correct hypocalcaemia similar to HDR patients (Ref. 110). When GATA3 is specifically deleted in the developing inner ear, defective formation of the cochlear prosensory domain and loss of spiral ganglion neurons is shown (Ref. 111). However, the exact mechanisms leading to the HDR phenotype remain to be elucidated.