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Klaus H. Kaestner - One of the best experts on this subject based on the ideXlab platform.
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foxa1 and FOXA2 drive gastric differentiation and suppress squamous identity in nkx2 1 negative lung cancer
eLife, 2018Co-Authors: Soledad A Camolotto, Shrivatsav Pattabiraman, Timothy L Mosbruger, Alex Jones, Veronika K Belova, Grace Orstad, Mitchell Streiff, Lydia Salmond, Chris Stubben, Klaus H. KaestnerAbstract:Changes in cancer cell identity can alter malignant potential and therapeutic response. Loss of the pulmonary lineage specifier NKX2-1 augments the growth of KRAS-driven lung adenocarcinoma and causes pulmonary to gastric transdifferentiation. Here, we show that the transcription factors FoxA1 and FOXA2 are required for initiation of mucinous NKX2-1-negative lung adenocarcinomas in the mouse and for activation of their gastric differentiation program. Foxa1/2 deletion severely impairs tumor initiation and causes a proximal shift in cellular identity, yielding tumors expressing markers of the squamocolumnar junction of the gastrointestinal tract. In contrast, we observe downregulation of FoxA1/2 expression in the squamous component of both murine and human lung adenosquamous carcinoma. Using sequential in vivo recombination, we find that FoxA1/2 loss in established KRAS-driven neoplasia originating from SPC-positive alveolar cells induces keratinizing squamous cell carcinomas. Thus, NKX2-1, FoxA1 and FOXA2 coordinately regulate the growth and identity of lung cancer in a context-specific manner.
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foxa1 and FOXA2 are required for the maintenance of dopaminergic properties in ventral midbrain neurons at late embryonic stages
The Journal of Neuroscience, 2013Co-Authors: Simon R W Stott, Klaus H. Kaestner, Wei Lin, Emmanouil Metzakopian, Rene Hen, Siewlan AngAbstract:The maintained expression of transcription factors throughout the development of mesodiencephalic dopaminergic (mDA) neurons suggests multiple roles at various stages in development. Two members of the forkhead/winged helix transcription factor family, Foxa1 and FOXA2, have been recently shown to have an important influence in the early development of mDA neurons. Here we present data demonstrating that these genes are also involved in the later maintenance of the mDA system. We conditionally removed both genes in postmitotic mDA neurons using the dopamine transporter-cre mouse. Deletion of both Foxa1 and FOXA2 resulted in a significant reduction in the number of tyrosine hydroxylase (TH)-positive mDA neurons. The decrease was predominantly observed in the substantia nigra region of the mDA system, which led to a loss of TH+ fibers innervating the striatum. Further analysis demonstrated that the reduction in the number of TH+ cells in the mutant mice was not due to apoptosis or cell-fate change. Using reporter mouse lines, we found that the mDA neurons were still present in the ventral midbrain, but that they had lost much of their dopaminergic phenotype. The majority of these neurons remained in the ventral mesencephalon until at least 18 months of age. Chromatin immunoprecipitation suggested that the loss of the mDA phenotype is due to a reduction in the binding of the nuclear orphan receptor, Nurr-1 to the promoter region of TH. These results extend previous findings and demonstrate a later role for Foxa genes in regulating the maintenance of dopaminergic phenotype in mDA neurons.
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genome wide location analysis reveals distinct transcriptional circuitry by paralogous regulators foxa1 and FOXA2
PLOS Genetics, 2012Co-Authors: Irina M Bochkis, Jonathan Schug, Svitlana Kurinna, Sabrina A Stratton, Michelle Craig Barton, Klaus H. KaestnerAbstract:Gene duplication is a powerful driver of evolution. Newly duplicated genes acquire new roles that are relevant to fitness, or they will be lost over time. A potential path to functional relevance is mutation of the coding sequence leading to the acquisition of novel biochemical properties, as analyzed here for the highly homologous paralogs Foxa1 and FOXA2 transcriptional regulators. We determine by genome-wide location analysis (ChIP-Seq) that, although Foxa1 and FOXA2 share a large fraction of binding sites in the liver, each protein also occupies distinct regulatory elements in vivo. Foxa1-only sites are enriched for p53 binding sites and are frequently found near genes important to cell cycle regulation, while FOXA2-restricted sites show only a limited match to the forkhead consensus and are found in genes involved in steroid and lipid metabolism. Thus, Foxa1 and FOXA2, while redundant during development, have evolved divergent roles in the adult liver, ensuring the maintenance of both genes during evolution.
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genome wide location analysis reveals distinct transcriptional circuitry by paralogous regulators foxa1 and FOXA2
PLoS, 2012Co-Authors: Irina M Bochkis, Jonathan Schug, Svitlana Kurinna, Sabrina A Stratton, Michelle Craig Barton, Klaus H. KaestnerAbstract:Institute for Diabetes, Obesity and Metabolism. Diabetes Research Center (Functional Genomics Core P30-DK19525)
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foxa family members are crucial regulators of the hypertrophic chondrocyte differentiation program
Developmental Cell, 2012Co-Authors: Andreia M Ionescu, Klaus H. Kaestner, Elena Kozhemyakina, Claudia Nicolae, Bjorn Olsen, Andrew B LassarAbstract:Summary During endochondral ossification, small, immature chondrocytes enlarge to form hypertrophic chondrocytes, which express collagen X. In this work, we demonstrate that FoxA factors are induced during chondrogenesis, bind to conserved binding sites in the collagen X enhancer, and can promote the expression of a collagen X-luciferase reporter in both chondrocytes and fibroblasts. In addition, we demonstrate by both gain- and loss-of-function analyses that FoxA factors play a crucial role in driving the expression of both endogenous collagen X and other hypertrophic chondrocyte-specific genes. Mice engineered to lack expression of both FOXA2 and FoxA3 in their chondrocytes display defects in chondrocyte hypertrophy, alkaline phosphatase expression, and mineralization in their sternebrae and, in addition, exhibit postnatal dwarfism that is coupled to significantly decreased expression of both collagen X and MMP13 in their growth plates. Our findings indicate that FoxA family members are crucial regulators of the hypertrophic chondrocyte differentiation program.
Irina M Bochkis - One of the best experts on this subject based on the ideXlab platform.
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pioneer factor FOXA2 enables ligand dependent activation of type ii nuclear receptors fxr and lxrα
Molecular metabolism, 2021Co-Authors: Jessica Kain, Xiaolong Wei, Andrew J Price, Claire Woods, Nihal A Reddy, Irina M BochkisAbstract:ABSTRACT Objective Type II nuclear hormone receptors, including farnesoid X receptors (FXR), liver X receptors (LXR), and peroxisome proliferator-activated receptors (PPAR), which serve as drug targets for metabolic diseases, are permanently positioned in the nucleus and thought to be bound to DNA regardless of the ligand status. However, recent genome-wide location analysis showed that LXRα and PPARα binding in the liver is largely ligand-dependent. We hypothesized that pioneer factor FOXA2 evicts nucleosomes to enable ligand-dependent binding of type II nuclear receptors and performed genome-wide studies to test this hypothesis. Methods ATAC-Seq was used to profile chromatin accessibility, ChIP-Seq was performed to assess transcription factor (FOXA2, FXR, LXRα, and PPARα) binding, and RNA-Seq analysis determined differentially expressed genes in wildtype and FOXA2 mutants treated with a ligand (GW4064 for FXR, GW3965 and T09 for LXRα). Results We show that chromatin accessibility, FXR binding and LXRα occupancy, and ligand-responsive activation of gene expression by FXR and LXRα require FOXA2. Unexpectedly, FOXA2 occupancy is drastically increased when either receptor, FXR or LXRα, is bound by an agonist. In addition, co-immunoprecipitation experiments demonstrate that FOXA2 interacts with either receptor in a ligand-dependent manner, suggesting that FOXA2 and the receptor bind DNA as an interdependent complex during ligand activation. Furthermore, PPARα binding is induced in FOXA2 mutants treated with FXR and LXR ligands, leading to activation of PPARα targets. Conclusions Our model requiring pioneering activity for ligand activation challenges the existing ligand-independent binding mechanism. We also demonstrate that FOXA2 is required to achieve activation of the proper receptor, one that binds the added ligand, by repressing the activity of a competing receptor.
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changes at the nuclear lamina alter binding of pioneer factor FOXA2 in aged liver
Aging Cell, 2018Co-Authors: Holly Whitton, Andrew J Price, Irina M Bochkis, Larry N Singh, Marissa A Patrick, Fernando G Osorio, Carlos LopezotinAbstract:Increasing evidence suggests that regulation of heterochromatin at the nuclear envelope underlies metabolic disease susceptibility and age-dependent metabolic changes, but the mechanism is unknown. Here, we profile lamina-associated domains (LADs) using lamin B1 ChIP-Seq in young and old hepatocytes and find that, although lamin B1 resides at a large fraction of domains at both ages, a third of lamin B1-associated regions are bound exclusively at each age in vivo. Regions occupied by lamin B1 solely in young livers are enriched for the forkhead motif, bound by Foxa pioneer factors. We also show that FOXA2 binds more sites in Zmpste24 mutant mice, a progeroid laminopathy model, similar to increased FOXA2 occupancy in old livers. Aged and Zmpste24-deficient livers share several features, including nuclear lamina abnormalities, increased FOXA2 binding, de-repression of PPAR- and LXR-dependent gene expression, and fatty liver. In old livers, additional FOXA2 binding is correlated to loss of lamin B1 and heterochromatin (H3K9me3 occupancy) at these loci. Our observations suggest that changes at the nuclear lamina are linked to altered FOXA2 binding, enabling opening of chromatin and de-repression of genes encoding lipid synthesis and storage targets that contribute to etiology of hepatic steatosis.
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genome wide location analysis reveals distinct transcriptional circuitry by paralogous regulators foxa1 and FOXA2
PLOS Genetics, 2012Co-Authors: Irina M Bochkis, Jonathan Schug, Svitlana Kurinna, Sabrina A Stratton, Michelle Craig Barton, Klaus H. KaestnerAbstract:Gene duplication is a powerful driver of evolution. Newly duplicated genes acquire new roles that are relevant to fitness, or they will be lost over time. A potential path to functional relevance is mutation of the coding sequence leading to the acquisition of novel biochemical properties, as analyzed here for the highly homologous paralogs Foxa1 and FOXA2 transcriptional regulators. We determine by genome-wide location analysis (ChIP-Seq) that, although Foxa1 and FOXA2 share a large fraction of binding sites in the liver, each protein also occupies distinct regulatory elements in vivo. Foxa1-only sites are enriched for p53 binding sites and are frequently found near genes important to cell cycle regulation, while FOXA2-restricted sites show only a limited match to the forkhead consensus and are found in genes involved in steroid and lipid metabolism. Thus, Foxa1 and FOXA2, while redundant during development, have evolved divergent roles in the adult liver, ensuring the maintenance of both genes during evolution.
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genome wide location analysis reveals distinct transcriptional circuitry by paralogous regulators foxa1 and FOXA2
PLoS, 2012Co-Authors: Irina M Bochkis, Jonathan Schug, Svitlana Kurinna, Sabrina A Stratton, Michelle Craig Barton, Klaus H. KaestnerAbstract:Institute for Diabetes, Obesity and Metabolism. Diabetes Research Center (Functional Genomics Core P30-DK19525)
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impaired male fertility and atrophy of seminiferous tubules caused by haploinsufficiency for foxa3
Developmental Biology, 2007Co-Authors: Rudiger Behr, Sara D Sackett, Irina M Bochkis, Klaus H. KaestnerAbstract:Foxa1, 2 and 3 (formerly HNF-3α, -β and -γ) constitute a sub-family of winged helix transcription factors with multiple roles in mammalian organ development. While all three Foxa mRNAs are present in endoderm derivatives including liver and pancreas, only Foxa3 is expressed in the testis. Here we demonstrate by genetic lineage tracing that Foxa3 is expressed in postmeiotic germ and interstitial Leydig cells. The germinal epithelium of Foxa3-deficient testes is characterized by a loss of germ cells secondary to an increase in germ cell apoptosis that ultimately leads to a Sertoli cell-only syndrome. Remarkably, not only the Foxa3−/− mice but also Foxa3+/− mice exhibited loss of germ cells. This cellular phenotype caused significantly reduced fertility and testis weight of both Foxa3−/− and Foxa3+/− mice. Using microarray analysis, we found a dramatic downregulation of the zinc finger protein 93 and the testicular tumor-associated paraneoplastic Ma antigen (PNMA) and increased expression of a number of genes including zinc finger protein 94 and several kallikrein 1-related peptidases which could account for at least part of the observed phenotype. In summary, we have identified Foxa3 as a transcriptional regulator with a dominant phenotype in germ cell maintenance and suggest FOXA3 as a potential candidate gene for subfertility in man.
Jonathan Schug - One of the best experts on this subject based on the ideXlab platform.
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genome wide location analysis reveals distinct transcriptional circuitry by paralogous regulators foxa1 and FOXA2
PLOS Genetics, 2012Co-Authors: Irina M Bochkis, Jonathan Schug, Svitlana Kurinna, Sabrina A Stratton, Michelle Craig Barton, Klaus H. KaestnerAbstract:Gene duplication is a powerful driver of evolution. Newly duplicated genes acquire new roles that are relevant to fitness, or they will be lost over time. A potential path to functional relevance is mutation of the coding sequence leading to the acquisition of novel biochemical properties, as analyzed here for the highly homologous paralogs Foxa1 and FOXA2 transcriptional regulators. We determine by genome-wide location analysis (ChIP-Seq) that, although Foxa1 and FOXA2 share a large fraction of binding sites in the liver, each protein also occupies distinct regulatory elements in vivo. Foxa1-only sites are enriched for p53 binding sites and are frequently found near genes important to cell cycle regulation, while FOXA2-restricted sites show only a limited match to the forkhead consensus and are found in genes involved in steroid and lipid metabolism. Thus, Foxa1 and FOXA2, while redundant during development, have evolved divergent roles in the adult liver, ensuring the maintenance of both genes during evolution.
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genome wide location analysis reveals distinct transcriptional circuitry by paralogous regulators foxa1 and FOXA2
PLoS, 2012Co-Authors: Irina M Bochkis, Jonathan Schug, Svitlana Kurinna, Sabrina A Stratton, Michelle Craig Barton, Klaus H. KaestnerAbstract:Institute for Diabetes, Obesity and Metabolism. Diabetes Research Center (Functional Genomics Core P30-DK19525)
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foxa1 and FOXA2 are essential for sexual dimorphism in liver cancer
Cell, 2012Co-Authors: Zhaoyu Li, Jonathan Schug, Geetu Tuteja, Klaus H. KaestnerAbstract:Summary Hepatocellular carcinoma (HCC) is sexually dimorphic in both rodents and humans, with significantly higher incidence in males, an effect that is dependent on sex hormones. The molecular mechanisms by which estrogens prevent and androgens promote liver cancer remain unclear. Here, we discover that sexually dimorphic HCC is completely reversed in Foxa1- and FOXA2-deficient mice after diethylnitrosamine-induced hepatocarcinogenesis. Coregulation of target genes by Foxa1/a2 and either the estrogen receptor (ERα) or the androgen receptor (AR) was increased during hepatocarcinogenesis in normal female or male mice, respectively, but was lost in Foxa1/2-deficient mice. Thus, both estrogen-dependent resistance to and androgen-mediated facilitation of HCC depend on Foxa1/2. Strikingly, single nucleotide polymorphisms at FOXA2 binding sites reduce binding of both FOXA2 and ERα to their targets in human liver and correlate with HCC development in women. Thus, Foxa factors and their targets are central for the sexual dimorphism of HCC.
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foxa1 and FOXA2 maintain the metabolic and secretory features of the mature β cell
The Journal of Clinical Endocrinology and Metabolism, 2010Co-Authors: Nan Gao, Nicolai M Doliba, Jonathan Schug, Olga Smirnova, Franz M Matschinsky, John Le Lay, Wei Qin, Alan J Fox, Klaus H. KaestnerAbstract:Foxa1 and FOXA2 play both redundant and distinct roles in early pancreas development. We demonstrate here that inducible ablation of both transcription factors in mature mouse beta-cells leads to impaired glucose homeostasis and insulin secretion. The defects in both glucose-stimulated insulin secretion and intracellular calcium oscillation are more pronounced than those in beta-cells lacking only FOXA2. Unexpectedly, in contrast to the severe reduction of beta-cell-enriched factors contributing to metabolic and secretory pathways, expression of a large number of genes that are involved in neural differentiation and function is significantly elevated. We further demonstrate that expression of carbohydrate response element-binding protein (ChREBP or Mlxipl), an important transcriptional regulator of carbohydrate metabolism, is significantly affected in compound Foxa1/a2 mutant beta-cells. ChREBP expression is directly controlled by Foxa1 and FOXA2 in both the fetal endocrine pancreas as well as mature islets. These data demonstrate that Foxa1 and FOXA2 play crucial roles in the development and maintenance of beta-cell-specific secretory and metabolic pathways.
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foxa1 and FOXA2 maintain the metabolic and secretory features of the mature β cell
Molecular Endocrinology, 2010Co-Authors: Nicolai M Doliba, Jonathan Schug, Olga Smirnova, Franz M Matschinsky, Klaus H. KaestnerAbstract:Foxa1 and FOXA2 play both redundant and distinct roles in early pancreas development. We demonstrate here that inducible ablation of both transcription factors in mature mouse β-cells leads to impaired glucose homeostasis and insulin secretion. The defects in both glucose-stimulated insulin secretion and intracellular calcium oscillation are more pronounced than those in β-cells lacking only FOXA2. Unexpectedly, in contrast to the severe reduction of β-cell-enriched factors contributing to metabolic and secretory pathways, expression of a large number of genes that are involved in neural differentiation and function is significantly elevated. We further demonstrate that expression of carbohydrate response element-binding protein (ChREBP or Mlxipl), an important transcriptional regulator of carbohydrate metabolism, is significantly affected in compound Foxa1/a2 mutant β-cells. ChREBP expression is directly controlled by Foxa1 and FOXA2 in both the fetal endocrine pancreas as well as mature islets. These data demonstrate that Foxa1 and FOXA2 play crucial roles in the development and maintenance of β-cell-specific secretory and metabolic pathways.
Xin Xie - One of the best experts on this subject based on the ideXlab platform.
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chemical cocktails enable hepatic reprogramming of mouse fibroblasts with a single transcription factor
Stem cell reports, 2017Co-Authors: Ren Guo, Xin Wang, Wei Tang, Qianting Yuan, Lijian Hui, Xin XieAbstract:Summary Liver or hepatocytes transplantation is limited by the availability of donor organs. Functional hepatocytes independent of the donor sources may have wide applications in regenerative medicine and the drug industry. Recent studies have demonstrated that chemical cocktails may induce reprogramming of fibroblasts into a range of functional somatic cells. Here, we show that mouse fibroblasts can be transdifferentiated into the hepatocyte-like cells (iHeps) using only one transcription factor (TF) ( Foxa1 , FOXA2 , or Foxa3 ) plus a chemical cocktail. These iHeps show typical epithelial morphology, express multiple hepatocyte-specific genes, and acquire hepatocyte functions. Genetic lineage tracing confirms the fibroblast origin of these iHeps. More interestingly, these iHeps are expandable in vitro and can reconstitute the damaged hepatic tissues of the fumarylacetoacetate hydrolase-deficient ( Fah − / − ) mice. Our study provides a strategy to generate functional hepatocyte-like cells by using a single TF plus a chemical cocktail and is one step closer to generate the full-chemical iHeps.
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Chemical Cocktails Enable Hepatic Reprogramming of Mouse Fibroblasts with a Single Transcription Factor
Elsevier, 2017Co-Authors: Ren Guo, Xin Wang, Wei Tang, Qianting Yuan, Lijian Hui, Xin XieAbstract:Summary: Liver or hepatocytes transplantation is limited by the availability of donor organs. Functional hepatocytes independent of the donor sources may have wide applications in regenerative medicine and the drug industry. Recent studies have demonstrated that chemical cocktails may induce reprogramming of fibroblasts into a range of functional somatic cells. Here, we show that mouse fibroblasts can be transdifferentiated into the hepatocyte-like cells (iHeps) using only one transcription factor (TF) (Foxa1, FOXA2, or Foxa3) plus a chemical cocktail. These iHeps show typical epithelial morphology, express multiple hepatocyte-specific genes, and acquire hepatocyte functions. Genetic lineage tracing confirms the fibroblast origin of these iHeps. More interestingly, these iHeps are expandable in vitro and can reconstitute the damaged hepatic tissues of the fumarylacetoacetate hydrolase-deficient (Fah−/−) mice. Our study provides a strategy to generate functional hepatocyte-like cells by using a single TF plus a chemical cocktail and is one step closer to generate the full-chemical iHeps. : In this article, Xie and colleagues show that mouse fibroblasts can be transdifferentiated into the hepatocyte-like cells (iHeps) using only one transcription factor plus a chemical cocktail. Genetic lineage tracing confirms the fibroblast origin of these iHeps. These iHeps are expandable in vitro and can reconstitute the damaged hepatic tissues of the fumarylacetoacetate hydrolase-deficient mice. Keywords: reprogramming, hepatic transdifferentiation, hepatocyte, induced hepatocyte, chemically induced hepatocyte, fibroblast, chemical cocktail, regenerative medicin
Michelle Craig Barton - One of the best experts on this subject based on the ideXlab platform.
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genome wide location analysis reveals distinct transcriptional circuitry by paralogous regulators foxa1 and FOXA2
PLOS Genetics, 2012Co-Authors: Irina M Bochkis, Jonathan Schug, Svitlana Kurinna, Sabrina A Stratton, Michelle Craig Barton, Klaus H. KaestnerAbstract:Gene duplication is a powerful driver of evolution. Newly duplicated genes acquire new roles that are relevant to fitness, or they will be lost over time. A potential path to functional relevance is mutation of the coding sequence leading to the acquisition of novel biochemical properties, as analyzed here for the highly homologous paralogs Foxa1 and FOXA2 transcriptional regulators. We determine by genome-wide location analysis (ChIP-Seq) that, although Foxa1 and FOXA2 share a large fraction of binding sites in the liver, each protein also occupies distinct regulatory elements in vivo. Foxa1-only sites are enriched for p53 binding sites and are frequently found near genes important to cell cycle regulation, while FOXA2-restricted sites show only a limited match to the forkhead consensus and are found in genes involved in steroid and lipid metabolism. Thus, Foxa1 and FOXA2, while redundant during development, have evolved divergent roles in the adult liver, ensuring the maintenance of both genes during evolution.
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genome wide location analysis reveals distinct transcriptional circuitry by paralogous regulators foxa1 and FOXA2
PLoS, 2012Co-Authors: Irina M Bochkis, Jonathan Schug, Svitlana Kurinna, Sabrina A Stratton, Michelle Craig Barton, Klaus H. KaestnerAbstract:Institute for Diabetes, Obesity and Metabolism. Diabetes Research Center (Functional Genomics Core P30-DK19525)
