Expression of the vertebrate Gli proteins in Drosophila reveals a distribution of activator and repressor activities

Development ◽  
2000 ◽  
Vol 127 (19) ◽  
pp. 4293-4301 ◽  
Author(s):  
P. Aza-Blanc ◽  
H.Y. Lin ◽  
A. Ruiz i Altaba ◽  
T.B. Kornberg
Keyword(s):  
Transcription Factors ◽  
Target Genes ◽  
Cubitus Interruptus ◽  
Drosophila Wing ◽  
Gli Proteins ◽  
Hedgehog Proteins ◽  
Overlapping Domains ◽  
Repressor Activity

The Cubitus interruptus (Ci) and Gli proteins are transcription factors that mediate responses to Hedgehog proteins (Hh) in flies and vertebrates, respectively. During development of the Drosophila wing, Ci transduces the Hh signal and regulates transcription of different target genes at different locations. In vertebrates, the three Gli proteins are expressed in overlapping domains and are partially redundant. To assess how the vertebrate Glis correlate with Drosophila Ci, we expressed each in Drosophila and monitored their behaviors and activities. We found that each Gli has distinct activities that are equivalent to portions of the regulatory arsenal of Ci. Gli2 and Gli1 have activator functions that depend on Hh. Gli2 and Gli3 are proteolyzed to produce a repressor form able to inhibit hh expression. However, while Gli3 repressor activity is regulated by Hh, Gli2 repressor activity is not. These observations suggest that the separate activator and repressor functions of Ci are unevenly partitioned among the three Glis, yielding proteins with related yet distinct properties.

scholarly journals Lipoproteins carry endocannabinoids that inhibit the Hedgehog pathway

2013 ◽  
Author(s):  
Helena Khaliullina ◽  
Mesut Bilgin ◽  
Julio L. Sampaio ◽  
Andrej Shevchenko ◽  
Suzanne Eaton
Keyword(s):  
Mass Spectrometry ◽  
Hedgehog Signaling ◽  
Hedgehog Signaling Pathway ◽  
Cubitus Interruptus ◽  
Drosophila Wing ◽  
Lipid Mass ◽  
Biochemical Fractionation ◽  
Wing Imaginal Discs ◽  
Hedgehog Proteins

Hedgehog proteins are lipid-modified secreted signaling molecules that regulate tissue development and homeostasis. Lipids contained in circulating lipoproteins repress the Hedgehog signaling pathway in the absence of Hedgehog ligand, but the identity of these lipids is unknown. Here, using biochemical fractionation and lipid mass spectrometry, we identify these inhibitory lipids as endocannabinoids. Endocannabinoids are present in lipoproteins of both flies and humans, and repress the pathway in both mammalian signaling assays and Drosophila wing imaginal discs. In Drosophila, endocannabinoids are required in vivo to keep the levels of Smoothened and full-length Cubitus interruptus (Ci155) low in the absence of Hedgehog. Furthermore, elevating their endogenous levels inhibits Hedgehog-dependent accumulation of Smoothened and Ci155. Interestingly, cannabis-derived phytocannabinoids are also potent pathway inhibitors in flies and mammals. These findings constitute a novel link between organismal metabolism and local Hedgehog signaling, and suggest previously unsuspected mechanisms for the broad physiological activities of cannabinoids.

scholarly journals Analysis of the transcriptional logic governing differential spatial expression in Hh target genes

2018 ◽  
Author(s):  
Manuel Cambón ◽  
Óscar Sánchez
Keyword(s):  
Transcription Factors ◽  
Cellular Response ◽  
Target Genes ◽  
Threshold Model ◽  
Theoretical Models ◽  
Transcriptional Responses ◽  
Cubitus Interruptus ◽  
Spatial Expression ◽  
Complex Process ◽  
Transcription Process

AbstractThis work provides theoretical tools to analyse the transcriptional effects of certain biochemical mechanisms (i.e. affinity and cooperativity) that have been proposed in previous literature to explain the differential spatial expression of Hedgehog target genes involved in Drosophila development. Specifically we have focused on the expression of decapentaplegic and patched. The transcription of these genes is believed to be controlled by opposing gradients of the activator and repressor forms of the transcription factor Cubitus interruptus (Ci). This study is based on a thermodynamic approach, which provides expression rates for these genes. These expression rates are controlled by transcription factors which are competing and cooperating for common binding sites. We have made mathematical representations of the different expression rates which depend on multiple factors and variables. The expressions obtained with the model have been refined to produce simpler equivalent formulae which allow for their mathematical analysis. Thanks to this, we can evaluate the correlation between the different interactions involved in transcription and the biological features observed at tissular level. These mathematical models can be applied to other morphogenes to help understand the complex transcriptional logic of opposing activator and repressor gradients.Author summaryMorphogenic differentiation is a complex process that involves emission, reception and cellular response to different signals. It is well known that the same morphogenic signal can give rise to different cellular transcriptional responses that usually depend, among other factors, on transcription factors. In concordance with the activator threshold model, classically it has been distinguished between high and low threshold target genes in order to explain how cells receiving the same signal can activate different genes. However, in particular cases where the transcription is controlled by two opposing transcription factors, it has been tested that this logic is not valid. This motivates the necessity for describing new theoretical models in order to understand better these cellular responses. By a theoretical analysis we have deduced different versions of transcriptional logic that are significantly determined by how the opposing transcription factors cooperate between them in the transcription process. We have also tested these different scenarios focussing on the Drosophila Hh target genes, and we have reproduced similar conclusions to the ones obtained by other methodologies.

scholarly journals The repressor and activator forms of Cubitus interruptus control Hedgehog target genes through common generic gli-binding sites

Development ◽  
2000 ◽  
Vol 127 (14) ◽  
pp. 2999-3007 ◽  
Author(s):  
B. Muller ◽  
K. Basler
Keyword(s):  
Dna Sequences ◽  
Binding Sites ◽  
Target Genes ◽  
Regulatory Elements ◽  
Cubitus Interruptus ◽  
Transcriptional Effect ◽  
Necessary And Sufficient ◽  
Enhancer Sequences ◽  
Repressor Activity

The Drosophila Gli homolog Cubitus interruptus (Ci) controls the transcription of Hedgehog (Hh) target genes. A repressor form of Ci arises in the absence of Hh signalling by proteolytic cleavage of intact Ci, whereas an activator form of Ci is generated in response to the Hh signal. These different activities of Ci regulate overlapping but distinct subsets of Hh target genes. To investigate the mechanisms by which the two activities of Ci exert their opposite transcriptional effect, we dissect here the imaginal disc enhancer of the dpp gene, which responds to both activities of Ci. Within a minimal disc enhancer, we identify the DNA sequences that are necessary and sufficient for the control by Ci, show that the same sequences respond to the activator and repressor forms of Ci, and demonstrate that their activities can be replaced by a single synthetic Gli-binding site. We further show that the enhancer sequences of patched, a gene responding only to the activator form of Ci, effectively integrate also the repressor activity of Ci if placed into a dpp context. These results provide in vivo evidence against the employment of distinct binding sites for the different forms of Ci and suggest that target genes responding to only one form must have acquired distant cis-regulatory elements for their selective behavior.

scholarly journals Regulatory Network Analysis in Estradiol-Treated Human Endothelial Cells

2021 ◽  
Vol 22 (15) ◽  
pp. 8193
Author(s):  
Daniel Pérez-Cremades ◽  
Ana B. Paes ◽  
Xavier Vidal-Gómez ◽  
Ana Mompeón ◽  
Carlos Hermenegildo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Regulatory Network ◽  
Mirna Target ◽  
Target Genes ◽  
Functional Characterization ◽  
Human Endothelial Cells ◽  
Mrna Targets ◽  
Canonical Pathways

Background/Aims: Estrogen has been reported to have beneficial effects on vascular biology through direct actions on endothelium. Together with transcription factors, miRNAs are the major drivers of gene expression and signaling networks. The objective of this study was to identify a comprehensive regulatory network (miRNA-transcription factor-downstream genes) that controls the transcriptomic changes observed in endothelial cells exposed to estradiol. Methods: miRNA/mRNA interactions were assembled using our previous microarray data of human umbilical vein endothelial cells (HUVEC) treated with 17β-estradiol (E2) (1 nmol/L, 24 h). miRNA–mRNA pairings and their associated canonical pathways were determined using Ingenuity Pathway Analysis software. Transcription factors were identified among the miRNA-regulated genes. Transcription factor downstream target genes were predicted by consensus transcription factor binding sites in the promoter region of E2-regulated genes by using JASPAR and TRANSFAC tools in Enrichr software. Results: miRNA–target pairings were filtered by using differentially expressed miRNAs and mRNAs characterized by a regulatory relationship according to miRNA target prediction databases. The analysis identified 588 miRNA–target interactions between 102 miRNAs and 588 targets. Specifically, 63 upregulated miRNAs interacted with 295 downregulated targets, while 39 downregulated miRNAs were paired with 293 upregulated mRNA targets. Functional characterization of miRNA/mRNA association analysis highlighted hypoxia signaling, integrin, ephrin receptor signaling and regulation of actin-based motility by Rho among the canonical pathways regulated by E2 in HUVEC. Transcription factors and downstream genes analysis revealed eight networks, including those mediated by JUN and REPIN1, which are associated with cadherin binding and cell adhesion molecule binding pathways. Conclusion: This study identifies regulatory networks obtained by integrative microarray analysis and provides additional insights into the way estradiol could regulate endothelial function in human endothelial cells.

scholarly journals Role of Satb1 and Satb2 Transcription Factors in the Glutamate Receptors Expression and Ca2+ Signaling in the Cortical Neurons In Vitro

2021 ◽  
Vol 22 (11) ◽  
pp. 5968
Author(s):  
Egor A. Turovsky ◽  
Maria V. Turovskaya ◽  
Evgeniya I. Fedotova ◽  
Alexey A. Babaev ◽  
Viktor S. Tarabykin ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Nmda Receptor ◽  
Cortical Neurons ◽  
Target Genes ◽  
Cortical Cell ◽  
Inhibitory System ◽  
Selective Agonist ◽  
Genes Encoding ◽  
Deficient Mice

Transcription factors Satb1 and Satb2 are involved in the processes of cortex development and maturation of neurons. Alterations in the expression of their target genes can lead to neurodegenerative processes. Molecular and cellular mechanisms of regulation of neurotransmission by these transcription factors remain poorly understood. In this study, we have shown that transcription factors Satb1 and Satb2 participate in the regulation of genes encoding the NMDA-, AMPA-, and KA- receptor subunits and the inhibitory GABA(A) receptor. Deletion of gene for either Satb1 or Satb2 homologous factors induces the expression of genes encoding the NMDA receptor subunits, thereby leading to higher amplitudes of Ca2+-signals in neurons derived from the Satb1-deficient (Satb1fl/+ * NexCre/+) and Satb1-null mice (Satb1fl/fl * NexCre/+) in response to the selective agonist reducing the EC50 for the NMDA receptor. Simultaneously, there is an increase in the expression of the Gria2 gene, encoding the AMPA receptor subunit, thus decreasing the Ca2+-signals of neurons in response to the treatment with a selective agonist (5-Fluorowillardiine (FW)). The Satb1 deletion increases the sensitivity of the KA receptor to the agonist (domoic acid), in the cortical neurons of the Satb1-deficient mice but decreases it in the Satb1-null mice. At the same time, the Satb2 deletion decreases Ca2+-signals and the sensitivity of the KA receptor to the agonist in neurons from the Satb1-null and the Satb1-deficient mice. The Satb1 deletion affects the development of the inhibitory system of neurotransmission resulting in the suppression of the neuron maturation process and switching the GABAergic responses from excitatory to inhibitory, while the Satb2 deletion has a similar effect only in the Satb1-null mice. We show that the Satb1 and Satb2 transcription factors are involved in the regulation of the transmission of excitatory signals and inhibition of the neuronal network in the cortical cell culture.

scholarly journals High Energy Intake Induced Overexpression of Transcription Factors and Its Regulatory Genes Involved in Acceleration of Hepatic Lipogenesis: A Rat Model for Type 2 Diabetes

Biomedicines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 76 ◽  
Author(s):  
Suresh P. Khadke ◽  
Aniket A. Kuvalekar ◽  
Abhay M. Harsulkar ◽  
Nitin Mantri
Keyword(s):  
Type 2 Diabetes ◽  
Transcription Factors ◽  
Glucose Tolerance ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
High Energy ◽  
Tolerance Test ◽  
Diabetic Control ◽  
Ppar Γ

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by impaired insulin action and its secretion. The objectives of the present study were to establish an economical and efficient animal model, mimicking pathophysiology of human T2DM to understand probable molecular mechanisms in context with lipid metabolism. In the present study, male Wistar rats were randomly divided into three groups. Animals were fed with high fat diet (HFD) except healthy control (HC) for 12 weeks. After eight weeks, intra peritoneal glucose tolerance test was performed. After confirmation of glucose intolerance, diabetic control (DC) group was injected with streptozotocin (STZ) (35 mg/kg b.w., i.p.). HFD fed rats showed increase (p ≤ 0.001) in glucose tolerance and HOMA-IR as compared to HC. Diabetes rats showed abnormal (p ≤ 0.001) lipid profile as compared to HC. The hepatocyte expression of transcription factors SREBP-1c and NFκβ, and their target genes were found to be upregulated, while PPAR-γ, CPT1A and FABP expressions were downregulated as compared to the HC. A number of animal models have been raised for studying T2DM, but the study has been restricted to only the biochemical level. The model is validated at biochemical, molecular and histopathological levels, which can be used for screening new therapeutics for the effective management of T2DM.

scholarly journals Screening Driving Transcription Factors in the Processing of Gastric Cancer

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Guangzhong Xu ◽  
Kai Li ◽  
Nengwei Zhang ◽  
Bin Zhu ◽  
Guosheng Feng
Keyword(s):  
Gastric Cancer ◽  
Transcription Factors ◽  
Regulatory Network ◽  
Target Genes ◽  
Transcriptional Regulatory Network ◽  
Expression Profiles ◽  
Functional Enrichment ◽  
Regulatory Mechanisms ◽  
Integrated Analysis ◽  
Transcriptional Regulatory

Background. Construction of the transcriptional regulatory network can provide additional clues on the regulatory mechanisms and therapeutic applications in gastric cancer.Methods. Gene expression profiles of gastric cancer were downloaded from GEO database for integrated analysis. All of DEGs were analyzed by GO enrichment and KEGG pathway enrichment. Transcription factors were further identified and then a global transcriptional regulatory network was constructed.Results. By integrated analysis of the six eligible datasets (340 cases and 43 controls), a bunch of 2327 DEGs were identified, including 2100 upregulated and 227 downregulated DEGs. Functional enrichment analysis of DEGs showed that digestion was a significantly enriched GO term for biological process. Moreover, there were two important enriched KEGG pathways: cell cycle and homologous recombination. Furthermore, a total of 70 differentially expressed TFs were identified and the transcriptional regulatory network was constructed, which consisted of 566 TF-target interactions. The top ten TFs regulating most downstream target genes were BRCA1, ARID3A, EHF, SOX10, ZNF263, FOXL1, FEV, GATA3, FOXC1, and FOXD1. Most of them were involved in the carcinogenesis of gastric cancer.Conclusion. The transcriptional regulatory network can help researchers to further clarify the underlying regulatory mechanisms of gastric cancer tumorigenesis.

Interacting functions of snail, twist and huckebein during the early development of germ layers in Drosophila

Development ◽  
1994 ◽  
Vol 120 (5) ◽  
pp. 1137-1150 ◽  
Author(s):  
R. Reuter ◽  
M. Leptin
Keyword(s):  
Transcription Factors ◽  
Digestive Tract ◽  
Early Development ◽  
Target Genes ◽  
Anterior Part ◽  
Posterior Part ◽  
Germ Layers ◽  
Mesoderm Development ◽  
Ventral Furrow

Two zygotic genes, snail (sna) and twist (twi), are required for mesoderm development, which begins with the formation of the ventral furrow. Both twi and sna are expressed ventrally in the blastoderm, encode transcription factors and promote the invagination of the ventral furrow by activating or repressing appropriate target genes. However, sna and twi alone do not define the position of the ventral furrow, since they are also expressed in ventral cells that do not invaginate. We show that huckebein (hkb) sets the anterior and the posterior borders of the ventral furrow, but acts by different modes of regulation. In the posterior part of the blastoderm, hkb represses the expression of sna in the endodermal primordium (which we suggest to be adjacent to the mesodermal primordium). In the anterior part, hkb antagonizes the activation of target genes by twi and sna. Here, bicoid permits the co-expression of hkb, sna and twi, which are all required for the development of the anterior digestive tract. We suggest that mesodermal fate is determined where sna and twi but not hkb are expressed. Anteriorly hkb together with sna determines endodermal fate, and hkb together with sna and twi are required for foregut development.

EGF receptor signaling induces pointed P1 transcription and inactivates Yan protein in the Drosophila embryonic ventral ectoderm

Development ◽  
1996 ◽  
Vol 122 (11) ◽  
pp. 3355-3362 ◽  
Author(s):  
L. Gabay ◽  
H. Scholz ◽  
M. Golembo ◽  
A. Klaes ◽  
B.Z. Shilo ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Target Genes ◽  
Egf Receptor ◽  
Protein A ◽  
Drosophila Embryo ◽  
Cell Fates ◽  
Secondary Target ◽  
Graded Activity ◽  
Definition Of

The induction of different cell fates along the dorsoventral axis of the Drosophila embryo requires a graded activity of the EGF receptor tyrosine kinase (DER). Here we have identified primary and secondary target genes of DER, which mediate the determination of discrete ventral cell fates. High levels of DER activation in the ventralmost cells trigger expression of the transcription factors encoded by ventral nervous system defective (vnd) and pointed P1 (pntPl). Concomitant with the induction of pntP1, high levels of DER activity lead to inactivation of the Yan protein, a transcriptional repressor of Pointed-target genes. These two antagonizing transcription factors subsequently control the expression of secondary target genes such as otd, argos and tartan. The simultaneous effects of the DER pathway on pntP1 induction and Yan inactivation may contribute to the definition of the border of the ventralmost cell fates.

scholarly journals Novel Transcriptional Mechanisms for Regulating Metabolism by Thyroid Hormone

2018 ◽  
Vol 19 (10) ◽  
pp. 3284 ◽  
Author(s):  
Brijesh Kumar Singh ◽  
Rohit Anthony Sinha ◽  
Paul Michael Yen
Keyword(s):  
Transcription Factors ◽  
Thyroid Hormone ◽  
Target Genes ◽  
Regulation Of Transcription ◽  
Post Translational Modification ◽  
Hormone Response Elements ◽  
Conventional View ◽  
Metabolic Genes ◽  
Activation Of Transcription ◽  
Rna Transcript

The thyroid hormone plays a key role in energy and nutrient metabolisms in many tissues and regulates the transcription of key genes in metabolic pathways. It has long been believed that thyroid hormones (THs) exerted their effects primarily by binding to nuclear TH receptors (THRs) that are associated with conserved thyroid hormone response elements (TREs) located on the promoters of target genes. However, recent transcriptome and ChIP-Seq studies have challenged this conventional view as discordance was observed between TH-responsive genes and THR binding to DNA. While THR association with other transcription factors bound to DNA, TH activation of THRs to mediate effects that do not involve DNA-binding, or TH binding to proteins other than THRs have been invoked as potential mechanisms to explain this discrepancy, it appears that additional novel mechanisms may enable TH to regulate the mRNA expression. These include activation of transcription factors by SIRT1 via metabolic actions by TH, the post-translational modification of THR, the THR co-regulation of transcription with other nuclear receptors and transcription factors, and the microRNA (miR) control of RNA transcript expression to encode proteins involved in the cellular metabolism. Together, these novel mechanisms enlarge and diversify the panoply of metabolic genes that can be regulated by TH.

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