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Global Developmental Gene Programing Involves a Nuclear Form of Fibroblast Growth Factor Receptor-1 (FGFR1).

Terranova C, Narla ST, Lee YW, Bard J, Parikh A, Stachowiak EK, Tzanakakis ES, Buck MJ, Birkaya B, Stachowiak MK - PLoS ONE (2015)

Bottom Line: Nuclear FGFR1 targets genes in developmental pathways represented by Wnt/β-catenin, CREB, BMP, the cell cycle and cancer-related TP53 pathway, neuroectodermal and mesodermal programing networks, axonal growth and synaptic plasticity pathways.Nuclear FGFR1 targets the consensus sequences of transcription factors known to engage CREB-binding protein, a common coregulator of transcription and established binding partner of nuclear FGFR1.This investigation reveals the role of nuclear FGFR1 as a global genomic programmer of cell, neural and muscle development.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Anatomical Sciences, Western New York Stem Cell Culture and Analysis Center, State University of New York at Buffalo, Buffalo, New York, United States of America.

ABSTRACT
Genetic studies have placed the Fgfr1 gene at the top of major ontogenic pathways that enable gastrulation, tissue development and organogenesis. Using genome-wide sequencing and loss and gain of function experiments the present investigation reveals a mechanism that underlies global and direct gene regulation by the nuclear form of FGFR1, ensuring that pluripotent Embryonic Stem Cells differentiate into Neuronal Cells in response to Retinoic Acid. Nuclear FGFR1, both alone and with its partner nuclear receptors RXR and Nur77, targets thousands of active genes and controls the expression of pluripotency, homeobox, neuronal and mesodermal genes. Nuclear FGFR1 targets genes in developmental pathways represented by Wnt/β-catenin, CREB, BMP, the cell cycle and cancer-related TP53 pathway, neuroectodermal and mesodermal programing networks, axonal growth and synaptic plasticity pathways. Nuclear FGFR1 targets the consensus sequences of transcription factors known to engage CREB-binding protein, a common coregulator of transcription and established binding partner of nuclear FGFR1. This investigation reveals the role of nuclear FGFR1 as a global genomic programmer of cell, neural and muscle development.

No MeSH data available.


Related in: MedlinePlus

nFGFR1 regulates the expression of Homeobox genes in RA-treated NCs.(A) Heatmap illustrating the expression patterns of genes within the Hoxa-Hoxd clusters (left), and the associated binding of nFGFR1, RXR and Nur77 to the proximal promoter (right). (B) Expression of Hoxa genes in the presence of dominant-negative nuclear FGFR1(SP-/NLS)(TK-). mRNA expression was measured by RT-qPCR, in extracts from ESCs that had been transfected with either β-gal (control) or FGFR1(SP-/NLS)(TK-) and were then maintained in the presence of +LIF or +RA for 48 hours. In the presence of LIF, blocking nFGFR1 increased the levels of expression of the Hoxa1, 4 and 7 mRNAs. In RA-treated ESC, blocking nFGFR1 significantly reduced the RA-induced expression of all genes of the Hoxa cluster other than Hoxa5. * p-value <0.05; * relative to Bgal+LIF; + relative to β-gal+RA. (C) Expression of Hoxa genes in the presence of nFGFR1. nFGFR1 activates Hoxa gene expression to an extent similar to RA treatment. In the presence of LIF, FGFR1(SP-/NLS) induced significant upregulation of Hoxa1 and Hoxa2. * p value <0.05; * relative to Bgal+LIF; (D) RA-induced expression of Hoxa cluster genes in the presence of nuclear FGFR1(SP-/NLS). In the presence of RA, transfection of FGFR1(SP-/NLS) led to a marked increase in the expression of all Hoxa cluster genes. P-value <0.05; * relative to β-gal+LIF; + relative to β-gal +RA.
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pone.0123380.g006: nFGFR1 regulates the expression of Homeobox genes in RA-treated NCs.(A) Heatmap illustrating the expression patterns of genes within the Hoxa-Hoxd clusters (left), and the associated binding of nFGFR1, RXR and Nur77 to the proximal promoter (right). (B) Expression of Hoxa genes in the presence of dominant-negative nuclear FGFR1(SP-/NLS)(TK-). mRNA expression was measured by RT-qPCR, in extracts from ESCs that had been transfected with either β-gal (control) or FGFR1(SP-/NLS)(TK-) and were then maintained in the presence of +LIF or +RA for 48 hours. In the presence of LIF, blocking nFGFR1 increased the levels of expression of the Hoxa1, 4 and 7 mRNAs. In RA-treated ESC, blocking nFGFR1 significantly reduced the RA-induced expression of all genes of the Hoxa cluster other than Hoxa5. * p-value <0.05; * relative to Bgal+LIF; + relative to β-gal+RA. (C) Expression of Hoxa genes in the presence of nFGFR1. nFGFR1 activates Hoxa gene expression to an extent similar to RA treatment. In the presence of LIF, FGFR1(SP-/NLS) induced significant upregulation of Hoxa1 and Hoxa2. * p value <0.05; * relative to Bgal+LIF; (D) RA-induced expression of Hoxa cluster genes in the presence of nuclear FGFR1(SP-/NLS). In the presence of RA, transfection of FGFR1(SP-/NLS) led to a marked increase in the expression of all Hoxa cluster genes. P-value <0.05; * relative to β-gal+LIF; + relative to β-gal +RA.

Mentions: Whereas in ESCs nFGFR1 binding was detected only at the Hoxd1 and Hoxd13 genes, in NCs it bound at Hoxa1, 2 and 4, as determined by both ChIP-seq experiments (Fig 6A and S8A Fig) and independent ChIP assays (S8B Fig). nFGFR1 also bound to genes in downstream Hox clusters: Hoxb9, Hoxc6, Hoxc8, Hoxd1, and Hoxd9 (Fig 6A and S8A Fig). RXR, in contrast, bound to the promoters in ESCs and vacated them in NCs, particularly within the Hoxa cluster (Fig 6A and S8A Fig), suggesting that RXR acts as a repressor and nFGFR1 as an activator of the same Hox genes.


Global Developmental Gene Programing Involves a Nuclear Form of Fibroblast Growth Factor Receptor-1 (FGFR1).

Terranova C, Narla ST, Lee YW, Bard J, Parikh A, Stachowiak EK, Tzanakakis ES, Buck MJ, Birkaya B, Stachowiak MK - PLoS ONE (2015)

nFGFR1 regulates the expression of Homeobox genes in RA-treated NCs.(A) Heatmap illustrating the expression patterns of genes within the Hoxa-Hoxd clusters (left), and the associated binding of nFGFR1, RXR and Nur77 to the proximal promoter (right). (B) Expression of Hoxa genes in the presence of dominant-negative nuclear FGFR1(SP-/NLS)(TK-). mRNA expression was measured by RT-qPCR, in extracts from ESCs that had been transfected with either β-gal (control) or FGFR1(SP-/NLS)(TK-) and were then maintained in the presence of +LIF or +RA for 48 hours. In the presence of LIF, blocking nFGFR1 increased the levels of expression of the Hoxa1, 4 and 7 mRNAs. In RA-treated ESC, blocking nFGFR1 significantly reduced the RA-induced expression of all genes of the Hoxa cluster other than Hoxa5. * p-value <0.05; * relative to Bgal+LIF; + relative to β-gal+RA. (C) Expression of Hoxa genes in the presence of nFGFR1. nFGFR1 activates Hoxa gene expression to an extent similar to RA treatment. In the presence of LIF, FGFR1(SP-/NLS) induced significant upregulation of Hoxa1 and Hoxa2. * p value <0.05; * relative to Bgal+LIF; (D) RA-induced expression of Hoxa cluster genes in the presence of nuclear FGFR1(SP-/NLS). In the presence of RA, transfection of FGFR1(SP-/NLS) led to a marked increase in the expression of all Hoxa cluster genes. P-value <0.05; * relative to β-gal+LIF; + relative to β-gal +RA.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4414453&req=5

pone.0123380.g006: nFGFR1 regulates the expression of Homeobox genes in RA-treated NCs.(A) Heatmap illustrating the expression patterns of genes within the Hoxa-Hoxd clusters (left), and the associated binding of nFGFR1, RXR and Nur77 to the proximal promoter (right). (B) Expression of Hoxa genes in the presence of dominant-negative nuclear FGFR1(SP-/NLS)(TK-). mRNA expression was measured by RT-qPCR, in extracts from ESCs that had been transfected with either β-gal (control) or FGFR1(SP-/NLS)(TK-) and were then maintained in the presence of +LIF or +RA for 48 hours. In the presence of LIF, blocking nFGFR1 increased the levels of expression of the Hoxa1, 4 and 7 mRNAs. In RA-treated ESC, blocking nFGFR1 significantly reduced the RA-induced expression of all genes of the Hoxa cluster other than Hoxa5. * p-value <0.05; * relative to Bgal+LIF; + relative to β-gal+RA. (C) Expression of Hoxa genes in the presence of nFGFR1. nFGFR1 activates Hoxa gene expression to an extent similar to RA treatment. In the presence of LIF, FGFR1(SP-/NLS) induced significant upregulation of Hoxa1 and Hoxa2. * p value <0.05; * relative to Bgal+LIF; (D) RA-induced expression of Hoxa cluster genes in the presence of nuclear FGFR1(SP-/NLS). In the presence of RA, transfection of FGFR1(SP-/NLS) led to a marked increase in the expression of all Hoxa cluster genes. P-value <0.05; * relative to β-gal+LIF; + relative to β-gal +RA.
Mentions: Whereas in ESCs nFGFR1 binding was detected only at the Hoxd1 and Hoxd13 genes, in NCs it bound at Hoxa1, 2 and 4, as determined by both ChIP-seq experiments (Fig 6A and S8A Fig) and independent ChIP assays (S8B Fig). nFGFR1 also bound to genes in downstream Hox clusters: Hoxb9, Hoxc6, Hoxc8, Hoxd1, and Hoxd9 (Fig 6A and S8A Fig). RXR, in contrast, bound to the promoters in ESCs and vacated them in NCs, particularly within the Hoxa cluster (Fig 6A and S8A Fig), suggesting that RXR acts as a repressor and nFGFR1 as an activator of the same Hox genes.

Bottom Line: Nuclear FGFR1 targets genes in developmental pathways represented by Wnt/β-catenin, CREB, BMP, the cell cycle and cancer-related TP53 pathway, neuroectodermal and mesodermal programing networks, axonal growth and synaptic plasticity pathways.Nuclear FGFR1 targets the consensus sequences of transcription factors known to engage CREB-binding protein, a common coregulator of transcription and established binding partner of nuclear FGFR1.This investigation reveals the role of nuclear FGFR1 as a global genomic programmer of cell, neural and muscle development.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Anatomical Sciences, Western New York Stem Cell Culture and Analysis Center, State University of New York at Buffalo, Buffalo, New York, United States of America.

ABSTRACT
Genetic studies have placed the Fgfr1 gene at the top of major ontogenic pathways that enable gastrulation, tissue development and organogenesis. Using genome-wide sequencing and loss and gain of function experiments the present investigation reveals a mechanism that underlies global and direct gene regulation by the nuclear form of FGFR1, ensuring that pluripotent Embryonic Stem Cells differentiate into Neuronal Cells in response to Retinoic Acid. Nuclear FGFR1, both alone and with its partner nuclear receptors RXR and Nur77, targets thousands of active genes and controls the expression of pluripotency, homeobox, neuronal and mesodermal genes. Nuclear FGFR1 targets genes in developmental pathways represented by Wnt/β-catenin, CREB, BMP, the cell cycle and cancer-related TP53 pathway, neuroectodermal and mesodermal programing networks, axonal growth and synaptic plasticity pathways. Nuclear FGFR1 targets the consensus sequences of transcription factors known to engage CREB-binding protein, a common coregulator of transcription and established binding partner of nuclear FGFR1. This investigation reveals the role of nuclear FGFR1 as a global genomic programmer of cell, neural and muscle development.

No MeSH data available.


Related in: MedlinePlus