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Masayuki Yamamoto - One of the best experts on this subject based on the ideXlab platform.
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gata2 and pu 1 collaborate to activate the expression of the mouse ms4a2 gene encoding fceriβ through distinct mechanisms
Molecular and Cellular Biology, 2019Co-Authors: Shin'ya Ohmori, Yasushi Ishijima, Masayuki Yamamoto, Suzuka Numata, Mai Takahashi, Masataka Sekita, Taichi Sato, Keisuke Chugun, Kinuko OhnedaAbstract:GATA factors GATA1 and GATA2 and ETS factor PU.1 are known to function antagonistically during hematopoietic development. In mouse mast cells, however, these factors are coexpressed and activate the expression of the Ms4a2 gene encoding the β chain of the high-affinity IgE receptor (FceRI). The present study showed that these factors cooperatively regulate Ms4a2 gene expression through distinct mechanisms. Although GATA2 and PU.1 contributed almost equally to Ms4a2 gene expression, gene ablation experiments revealed that simultaneous knockdown of both factors showed neither a synergistic nor an additive effect. A chromatin immunoprecipitation analysis showed that they shared DNA binding to the +10.4-kbp region downstream of the Ms4a2 gene with chromatin looping factor LDB1, whereas the proximal -60-bp region was exclusively bound by GATA2 in a mast cell-specific manner. Ablation of PU.1 significantly reduced the level of GATA2 binding to both the +10.4-kbp and -60-bp regions. Surprisingly, the deletion of the +10.4-kbp region by genome editing completely abolished the Ms4a2 gene expression as well as the cell surface expression of FceRI. These results suggest that PU.1 and LDB1 play central roles in the formation of active chromatin structure whereas GATA2 directly activates the Ms4a2 promoter.
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mouse tryptase gene expression is coordinately regulated by gata1 and gata2 in bone marrow derived mast cells
International Journal of Molecular Sciences, 2019Co-Authors: Kinuko Ohneda, Shin'ya Ohmori, Masayuki YamamotoAbstract:Mast cell tryptases have crucial roles in allergic and inflammatory diseases. The mouse tryptase genes represent a cluster of loci on chromosome 16p3.3. While their functional studies have been extensively performed, transcriptional regulation of tryptase genes is poorly understood. In this study, we examined the molecular basis of the tryptase gene expression in bone marrow-derived mast cells (BMMCs) of C57BL/6 mice and in MEDMC-BRC6 mast cells. The expression of the Tpsb2 and Tpsg1 genes, which reside at the 3′-end of the tryptase locus, is significantly decreased by the reduction of the GATA transcription factors GATA1 or GATA2. Chromatin immunoprecipitation assays have shown that the GATA factors bind at multiple regions within the locus, including 1.0 and 72.8 kb upstream of the Tpsb2 gene, and that GATA1 and GATA2 facilitate each other’s DNA binding activity to these regions. Deletion of the −72.8 kb region by genome editing significantly reduced the Tpsb2 and Tpsg1 mRNA levels in MEDMC-BRC6 cells. Furthermore, binding of CTCF and the cohesin subunit Rad21 was found upstream of the −72.8 kb region and was significantly reduced in the absence of GATA1. These results suggest that mouse tryptase gene expression is coordinately regulated by GATA1 and GATA2 in BMMCs.
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spiral ganglion cell degeneration induced deafness as a consequence of reduced gata factor activity
Genes to Cells, 2019Co-Authors: Masayuki Yamamoto, Jun Takai, Tomofumi Hoshino, Tsumoru Terunuma, Satoshi Uemura, Yasuhiro Nakamura, Michito Hamada, Satoru Takahashi, James Douglas EngelAbstract:Zinc-finger transcription factors GATA2 and GATA3 are both expressed in the developing inner ear, although their overlapping versus distinct activities in adult definitive inner ear are not well understood. We show here that GATA2 and GATA3 are co-expressed in cochlear spiral ganglion cells and redundantly function in the maintenance of spiral ganglion cells and auditory neural circuitry. Notably, Gata2 and GATA3 compound heterozygous mutant mice had a diminished number of spiral ganglion cells due to enhanced apoptosis, which resulted in progressive hearing loss. The decrease in spiral ganglion cellularity was associated with lowered expression of neurotrophin receptor TrkC that is an essential factor for spiral ganglion cell survival. We further show that Gata2 null mutants that additionally bear a Gata2 YAC (yeast artificial chromosome) that counteracts the lethal hematopoietic deficiency due to complete Gata2 loss nonetheless failed to complement the deficiency in neonatal spiral ganglion neurons. Furthermore, cochlea-specific Gata2 deletion mice also had fewer spiral ganglion cells and resultant hearing impairment. These results show that GATA2 and GATA3 redundantly function to maintain spiral ganglion cells and hearing. We propose possible mechanisms underlying hearing loss in human GATA2- or GATA3-related genetic disorders.
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Derepression of the DNA Methylation Machinery of the Gata1 Gene Triggers the Differentiation Cue for Erythropoiesis
Molecular and cellular biology, 2017Co-Authors: Jun Takai, James Douglas Engel, Takashi Moriguchi, Mikiko Suzuki, Akihito Otsuki, Fumiki Katsuoka, Saori Katayama, Masahiro Nezu, Masayuki YamamotoAbstract:GATA1 is a critical regulator of erythropoiesis. While the mechanisms underlying the high-level expression of GATA1 in maturing erythroid cells have been studied extensively, the initial activation of the Gata1 gene in early hematopoietic progenitors remains to be elucidated. We previously identified a hematopoietic stem and progenitor cell (HSPC)-specific silencer element (the Gata1 methylation-determining region [G1MDR]) that recruits DNA methyltransferase 1 (Dnmt1) and provokes methylation of the Gata1 gene enhancer. In the present study, we hypothesized that removal of the G1MDR-mediated silencing machinery is the molecular basis of the initial activation of the Gata1 gene and erythropoiesis. To address this hypothesis, we generated transgenic mouse lines harboring a Gata1 bacterial artificial chromosome in which the G1MDR was deleted. The mice exhibited abundant GATA1 expression in HSPCs, in a GATA2-dependent manner. The ectopic GATA1 expression repressed Gata2 transcription and induced erythropoiesis and apoptosis of HSPCs. Furthermore, genetic deletion of Dnmt1 in HSPCs activated Gata1 expression and depleted HSPCs, thus recapitulating the HSC phenotype associated with GATA1 gain of function. These results demonstrate that the G1MDR holds the key to HSPC maintenance and suggest that release from this suppressive mechanism is a fundamental requirement for subsequent initiation of erythroid differentiation.
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A regulatory network governing Gata1 and Gata2 gene transcription orchestrates erythroid lineage differentiation
International Journal of Hematology, 2014Co-Authors: Takashi Moriguchi, Masayuki YamamotoAbstract:GATA transcription factor family members GATA1 and GATA2 play crucial roles in the regulation of lineage-restricted genes during erythroid differentiation. GATA1 is indispensable for survival and terminal differentiation of erythroid, megakaryocytic and eosinophilic progenitors, whereas GATA2 regulates proliferation and maintenance of hematopoietic stem and progenitor cells. Expression levels of GATA1 and GATA2 are primarily regulated at the transcriptional level through auto- and reciprocal regulatory networks formed by these GATA factors. The dynamic and strictly controlled change of expression from GATA2 to GATA1 during erythropoiesis has been referred to as GATA factor switching, which plays a crucial role in erythropoiesis. The regulatory network comprising GATA1 and GATA2 gives rise to the stage-specific changes in Gata1 and Gata2 gene expression during erythroid differentiation, which ensures specific expression of early and late erythroid genes at each stage. Recent studies have also shed light on the genome-wide binding profiles of GATA1 and GATA2, and the significance of epigenetic modification of Gata1 gene during erythroid differentiation. This review summarizes the current understanding of network regulation underlying stage-dependent Gata1 and Gata2 gene expressions and the functional contribution of these GATA factors in erythroid differentiation.
Takuya Yashiro - One of the best experts on this subject based on the ideXlab platform.
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cooperative regulation of the mucosal mast cell specific protease genes mcpt1 and mcpt2 by gata and smad transcription factors
Journal of Immunology, 2020Co-Authors: Kazumi Kasakura, Kazuki Nagata, Ryosuke Miura, Mayu Iida, Hikaru Nakaya, Hikaru Okada, Takahiro Arai, Yuko Kawakami, Toshiaki Kawakami, Takuya YashiroAbstract:Mouse mast cell proteases (mMCP)-1 and -2 are specifically expressed in mucosal mast cells (MCs). However, the transcriptional regulation mechanism of the Mcpt1 and Mcpt2 genes induced in mucosal MCs is largely unknown. In the current study, we found that TGF-β stimulation drastically induced upregulation of Mcpt1 and Mcpt2 mRNA in mouse bone marrow-derived MCs (BMMCs). TGF-β-induced expression of Mcpt1 and Mcpt2 was markedly suppressed by transfection with small interfering RNA targeting Smad2 or Smad4 and moderately reduced by Smad3 small interfering RNA. We next examined the roles of the hematopoietic cell-specific transcription factors GATA1 and GATA2 in the expression of Mcpt1 and Mcpt2 and demonstrated that knockdown of GATA1 and GATA2 reduced the mRNA levels of Mcpt1 and Mcpt2 in BMMCs. The recruitment of GATA2 and acetylation of histone H4 of the highly conserved GATA-Smad motifs, which were localized in the distal regions of the Mcpt1 and Mcpt2 genes, were markedly increased by TGF-β stimulation, whereas the level of GATA2 binding to the proximal GATA motif was not affected by TGF-β. A reporter assay showed that TGF-β stimulation upregulated GATA2-mediated transactivation activity in a GATA-Smad motif-dependent manner. We also observed that GATA2 and Smad4 interacted in TGF-β-stimulated BMMCs via immunoprecipitation and Western blotting analysis. Taken together, these results demonstrate that TGF-β induced mMCP-1 and -2 expression by accelerating the recruitment of GATA2 to the proximal regions of the Mcpt1 and Mcpt2 genes in mucosal MCs.
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critical roles for pu 1 gata1 and gata2 in the expression of human fceri on mast cells pu 1 and gata1 transactivate fcer1a and gata2 transactivates fcer1a and ms4a2
Journal of Immunology, 2014Co-Authors: Eisuke Inage, Yosuke Baba, Takuya Yashiro, Kazumi Kasakura, Ryuyo Suzuki, Mutsuko Hara, Nobuhiro Nakano, Atsushi TanabeAbstract:The high-affinity IgE receptor, FceRI, which is composed of α-, β-, and γ-chains, plays an important role in IgE-mediated allergic responses. In the current study, involvement of the transcription factors, PU.1, GATA1, and GATA2, in the expression of FceRI on human mast cells was investigated. Transfection of small interfering RNAs (siRNAs) against PU.1, GATA1, and GATA2 into the human mast cell line, LAD2, caused significant downregulation of cell surface expression of FceRI. Quantification of the mRNA levels revealed that PU.1, GATA1, and GATA2 siRNAs suppressed the α transcript, whereas the amount of β mRNA was reduced in only GATA2 siRNA transfectants. In contrast, γ mRNA levels were not affected by any of the knockdowns. Chromatin immunoprecipitation assay showed that significant amounts of PU.1, GATA1, and GATA2 bind to the promoter region of FCER1A (encoding FceRIα) and that GATA2 binds to the promoter of MS4A2 (encoding FceRIβ). Luciferase assay and EMSA showed that GATA2 transactivates the MS4A2 promoter via direct binding. These knockdowns of transcription factors also suppressed the IgE-mediated degranulation activity of LAD2. Similarly, all three knockdowns suppressed FceRI expression in primary mast cells, especially PU.1 siRNA and GATA2 siRNA, which target FceRIα and FceRIβ, respectively. From these results, we conclude that PU.1 and GATA1 are involved in FceRIα transcription through recruitment to its promoter, whereas GATA2 positively regulates FceRIβ transcription. Suppression of these transcription factors leads to downregulation of FceRI expression and IgE-mediated degranulation activity. Our findings will contribute to the development of new therapeutic approaches for FceRI-mediated allergic diseases.
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gata2 is a critical transactivator for the human il1rl1 st2 promoter in mast cells basophils opposing roles for gata2 and gata1 in human il1rl1 st2 gene expression
Journal of Biological Chemistry, 2012Co-Authors: Yosuke Baba, Keiko Maeda, Takuya Yashiro, Eisuke Inage, Kazumi Kasakura, Ryuyo Suzuki, Francois Niyonsaba, Mutsuko Hara, Atsushi Tanabe, Hideoki OgawaAbstract:The IL1RL1/ST2 gene encodes a receptor for IL-33. Signaling from IL1RL1/ST2 induced by IL-33 binding was recently identified as a modulator of the Th2 response. The target cells for IL-33 are restricted in some hematopoietic lineages, including mast cells, basophils, eosinophils, Th2 cells, natural killer cells, and dendritic cells. To clarify the molecular mechanisms of cell type-specific IL1RL1/ST2 expression in mast cells and basophils, transcriptional regulation of the human IL1RL1/ST2 promoter was investigated using the mast cell line LAD2 and the basophilic cell line KU812. Reporter assays suggested that two GATA motifs just upstream of the transcription start site in the ST2 promoter are critical for transcriptional activity. These two GATA motifs possess the capacity to bind GATA1 and GATA2 in EMSA. ChIP assay showed that GATA2, but not GATA1, bound to the ST2 promoter in LAD2 cells and that histone H3 at the ST2 promoter was acetylated in LAD2 cells, whereas binding of GATA1 and GATA2 to the ST2 promoter was detected in KU812 cells. Knockdown of GATA2 mRNA by siRNA reduced ST2 mRNA levels in KU812 and LAD2 cells and ST2 protein levels in LAD2 cells; in contrast, GATA1 siRNA transfection up-regulated ST2 mRNA levels in KU812 cells. The ST2 promoter was transactivated by GATA2 and repressed by GATA1 in coexpression analysis. When these siRNAs were introduced into human peripheral blood basophils, GATA2 siRNA reduced ST2 mRNA, whereas GATA1 siRNA up-regulated ST2 mRNA. These results indicate that GATA2 and GATA1 positively and negatively control human ST2 gene transcription, respectively.
Kazumi Kasakura - One of the best experts on this subject based on the ideXlab platform.
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cooperative regulation of the mucosal mast cell specific protease genes mcpt1 and mcpt2 by gata and smad transcription factors
Journal of Immunology, 2020Co-Authors: Kazumi Kasakura, Kazuki Nagata, Ryosuke Miura, Mayu Iida, Hikaru Nakaya, Hikaru Okada, Takahiro Arai, Yuko Kawakami, Toshiaki Kawakami, Takuya YashiroAbstract:Mouse mast cell proteases (mMCP)-1 and -2 are specifically expressed in mucosal mast cells (MCs). However, the transcriptional regulation mechanism of the Mcpt1 and Mcpt2 genes induced in mucosal MCs is largely unknown. In the current study, we found that TGF-β stimulation drastically induced upregulation of Mcpt1 and Mcpt2 mRNA in mouse bone marrow-derived MCs (BMMCs). TGF-β-induced expression of Mcpt1 and Mcpt2 was markedly suppressed by transfection with small interfering RNA targeting Smad2 or Smad4 and moderately reduced by Smad3 small interfering RNA. We next examined the roles of the hematopoietic cell-specific transcription factors GATA1 and GATA2 in the expression of Mcpt1 and Mcpt2 and demonstrated that knockdown of GATA1 and GATA2 reduced the mRNA levels of Mcpt1 and Mcpt2 in BMMCs. The recruitment of GATA2 and acetylation of histone H4 of the highly conserved GATA-Smad motifs, which were localized in the distal regions of the Mcpt1 and Mcpt2 genes, were markedly increased by TGF-β stimulation, whereas the level of GATA2 binding to the proximal GATA motif was not affected by TGF-β. A reporter assay showed that TGF-β stimulation upregulated GATA2-mediated transactivation activity in a GATA-Smad motif-dependent manner. We also observed that GATA2 and Smad4 interacted in TGF-β-stimulated BMMCs via immunoprecipitation and Western blotting analysis. Taken together, these results demonstrate that TGF-β induced mMCP-1 and -2 expression by accelerating the recruitment of GATA2 to the proximal regions of the Mcpt1 and Mcpt2 genes in mucosal MCs.
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critical roles for pu 1 gata1 and gata2 in the expression of human fceri on mast cells pu 1 and gata1 transactivate fcer1a and gata2 transactivates fcer1a and ms4a2
Journal of Immunology, 2014Co-Authors: Eisuke Inage, Yosuke Baba, Takuya Yashiro, Kazumi Kasakura, Ryuyo Suzuki, Mutsuko Hara, Nobuhiro Nakano, Atsushi TanabeAbstract:The high-affinity IgE receptor, FceRI, which is composed of α-, β-, and γ-chains, plays an important role in IgE-mediated allergic responses. In the current study, involvement of the transcription factors, PU.1, GATA1, and GATA2, in the expression of FceRI on human mast cells was investigated. Transfection of small interfering RNAs (siRNAs) against PU.1, GATA1, and GATA2 into the human mast cell line, LAD2, caused significant downregulation of cell surface expression of FceRI. Quantification of the mRNA levels revealed that PU.1, GATA1, and GATA2 siRNAs suppressed the α transcript, whereas the amount of β mRNA was reduced in only GATA2 siRNA transfectants. In contrast, γ mRNA levels were not affected by any of the knockdowns. Chromatin immunoprecipitation assay showed that significant amounts of PU.1, GATA1, and GATA2 bind to the promoter region of FCER1A (encoding FceRIα) and that GATA2 binds to the promoter of MS4A2 (encoding FceRIβ). Luciferase assay and EMSA showed that GATA2 transactivates the MS4A2 promoter via direct binding. These knockdowns of transcription factors also suppressed the IgE-mediated degranulation activity of LAD2. Similarly, all three knockdowns suppressed FceRI expression in primary mast cells, especially PU.1 siRNA and GATA2 siRNA, which target FceRIα and FceRIβ, respectively. From these results, we conclude that PU.1 and GATA1 are involved in FceRIα transcription through recruitment to its promoter, whereas GATA2 positively regulates FceRIβ transcription. Suppression of these transcription factors leads to downregulation of FceRI expression and IgE-mediated degranulation activity. Our findings will contribute to the development of new therapeutic approaches for FceRI-mediated allergic diseases.
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gata2 is a critical transactivator for the human il1rl1 st2 promoter in mast cells basophils opposing roles for gata2 and gata1 in human il1rl1 st2 gene expression
Journal of Biological Chemistry, 2012Co-Authors: Yosuke Baba, Keiko Maeda, Takuya Yashiro, Eisuke Inage, Kazumi Kasakura, Ryuyo Suzuki, Francois Niyonsaba, Mutsuko Hara, Atsushi Tanabe, Hideoki OgawaAbstract:The IL1RL1/ST2 gene encodes a receptor for IL-33. Signaling from IL1RL1/ST2 induced by IL-33 binding was recently identified as a modulator of the Th2 response. The target cells for IL-33 are restricted in some hematopoietic lineages, including mast cells, basophils, eosinophils, Th2 cells, natural killer cells, and dendritic cells. To clarify the molecular mechanisms of cell type-specific IL1RL1/ST2 expression in mast cells and basophils, transcriptional regulation of the human IL1RL1/ST2 promoter was investigated using the mast cell line LAD2 and the basophilic cell line KU812. Reporter assays suggested that two GATA motifs just upstream of the transcription start site in the ST2 promoter are critical for transcriptional activity. These two GATA motifs possess the capacity to bind GATA1 and GATA2 in EMSA. ChIP assay showed that GATA2, but not GATA1, bound to the ST2 promoter in LAD2 cells and that histone H3 at the ST2 promoter was acetylated in LAD2 cells, whereas binding of GATA1 and GATA2 to the ST2 promoter was detected in KU812 cells. Knockdown of GATA2 mRNA by siRNA reduced ST2 mRNA levels in KU812 and LAD2 cells and ST2 protein levels in LAD2 cells; in contrast, GATA1 siRNA transfection up-regulated ST2 mRNA levels in KU812 cells. The ST2 promoter was transactivated by GATA2 and repressed by GATA1 in coexpression analysis. When these siRNAs were introduced into human peripheral blood basophils, GATA2 siRNA reduced ST2 mRNA, whereas GATA1 siRNA up-regulated ST2 mRNA. These results indicate that GATA2 and GATA1 positively and negatively control human ST2 gene transcription, respectively.
James Douglas Engel - One of the best experts on this subject based on the ideXlab platform.
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spiral ganglion cell degeneration induced deafness as a consequence of reduced gata factor activity
Genes to Cells, 2019Co-Authors: Masayuki Yamamoto, Jun Takai, Tomofumi Hoshino, Tsumoru Terunuma, Satoshi Uemura, Yasuhiro Nakamura, Michito Hamada, Satoru Takahashi, James Douglas EngelAbstract:Zinc-finger transcription factors GATA2 and GATA3 are both expressed in the developing inner ear, although their overlapping versus distinct activities in adult definitive inner ear are not well understood. We show here that GATA2 and GATA3 are co-expressed in cochlear spiral ganglion cells and redundantly function in the maintenance of spiral ganglion cells and auditory neural circuitry. Notably, Gata2 and GATA3 compound heterozygous mutant mice had a diminished number of spiral ganglion cells due to enhanced apoptosis, which resulted in progressive hearing loss. The decrease in spiral ganglion cellularity was associated with lowered expression of neurotrophin receptor TrkC that is an essential factor for spiral ganglion cell survival. We further show that Gata2 null mutants that additionally bear a Gata2 YAC (yeast artificial chromosome) that counteracts the lethal hematopoietic deficiency due to complete Gata2 loss nonetheless failed to complement the deficiency in neonatal spiral ganglion neurons. Furthermore, cochlea-specific Gata2 deletion mice also had fewer spiral ganglion cells and resultant hearing impairment. These results show that GATA2 and GATA3 redundantly function to maintain spiral ganglion cells and hearing. We propose possible mechanisms underlying hearing loss in human GATA2- or GATA3-related genetic disorders.
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Derepression of the DNA Methylation Machinery of the Gata1 Gene Triggers the Differentiation Cue for Erythropoiesis
Molecular and cellular biology, 2017Co-Authors: Jun Takai, James Douglas Engel, Takashi Moriguchi, Mikiko Suzuki, Akihito Otsuki, Fumiki Katsuoka, Saori Katayama, Masahiro Nezu, Masayuki YamamotoAbstract:GATA1 is a critical regulator of erythropoiesis. While the mechanisms underlying the high-level expression of GATA1 in maturing erythroid cells have been studied extensively, the initial activation of the Gata1 gene in early hematopoietic progenitors remains to be elucidated. We previously identified a hematopoietic stem and progenitor cell (HSPC)-specific silencer element (the Gata1 methylation-determining region [G1MDR]) that recruits DNA methyltransferase 1 (Dnmt1) and provokes methylation of the Gata1 gene enhancer. In the present study, we hypothesized that removal of the G1MDR-mediated silencing machinery is the molecular basis of the initial activation of the Gata1 gene and erythropoiesis. To address this hypothesis, we generated transgenic mouse lines harboring a Gata1 bacterial artificial chromosome in which the G1MDR was deleted. The mice exhibited abundant GATA1 expression in HSPCs, in a GATA2-dependent manner. The ectopic GATA1 expression repressed Gata2 transcription and induced erythropoiesis and apoptosis of HSPCs. Furthermore, genetic deletion of Dnmt1 in HSPCs activated Gata1 expression and depleted HSPCs, thus recapitulating the HSC phenotype associated with GATA1 gain of function. These results demonstrate that the G1MDR holds the key to HSPC maintenance and suggest that release from this suppressive mechanism is a fundamental requirement for subsequent initiation of erythroid differentiation.
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gata2 specifies serotonergic neurons downstream of sonic hedgehog
Development, 2004Co-Authors: Sarah E Craven, James Douglas Engel, Kim Chew Lim, Frederic J De Sauvage, Arnon RosenthalAbstract:Distinct classes of serotonergic (5-HT) neurons develop along the ventral midline of the vertebrate hindbrain. Here, we identify a Sonic hedgehog (Shh)-regulated cascade of transcription factors that acts to generate a specific subset of 5-HT neurons. This transcriptional cascade is sufficient for the induction of rostral 5-HT neurons within rhombomere 1 (r1), which project to the forebrain, but not for the induction of caudal 5-HT neurons, which largely terminate in the spinal cord. Within the rostral hindbrain, the Shh-activated homeodomain proteins Nkx2.2 and Nkx6.1 cooperate to induce the closely related zinc-finger transcription factors Gata2 and GATA3. Gata2 in turn is necessary and sufficient to activate the transcription factors Lmx1b and Pet1, and to induce 5-HT neurons within r1. In contrast to Gata2, GATA3 is not required for the specification of rostral 5-HT neurons and appears unable to substitute for the loss of Gata2 . Our findings reveal that the identity of closely related 5-HT subclasses occurs through distinct responses of adjacent rostrocaudal progenitor domains to broad ventral inducers.
Crystal Y Chia - One of the best experts on this subject based on the ideXlab platform.
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gata6 cooperates with eomes smad2 3 to deploy the gene regulatory network governing human definitive endoderm and pancreas formation
Stem cell reports, 2019Co-Authors: Crystal Y Chia, Pedro Madrigal, Simon Denil, Iker Martinez, Jose Garciabernardo, Ranna Elkhairi, Mariya Chhatriwala, Maggie Shepherd, Andrew T HattersleyAbstract:Heterozygous de novo mutations in GATA6 are the most frequent cause of pancreatic agenesis in humans. In mice, however, a similar phenotype requires the biallelic loss of Gata6 and its paralog Gata4. To elaborate the human-specific requirements for GATA6, we chose to model GATA6 loss in vitro by combining both gene-edited and patient-derived pluripotent stem cells (hPSCs) and directed differentiation toward β-like cells. We find that GATA6 heterozygous hPSCs show a modest reduction in definitive endoderm (DE) formation, while GATA6-null hPSCs fail to enter the DE lineage. Consistent with these results, genome-wide studies show that GATA6 binds and cooperates with EOMES/SMAD2/3 to regulate the expression of cardinal endoderm genes. The early deficit in DE is accompanied by a significant reduction in PDX1+ pancreatic progenitors and C-PEPTIDE+ β-like cells. Taken together, our data position GATA6 as a gatekeeper to early human, but not murine, pancreatic ontogeny.