scholarly journals Genomic Selection Identifies Vertebrate Transcription Factor Fezf2 Binding Sites and Target Genes

2011 ◽  
Vol 286 (21) ◽  
pp. 18641-18649 ◽  
Author(s):  
Lishan Chen ◽  
Jiashun Zheng ◽  
Nan Yang ◽  
Hao Li ◽  
Su Guo
Keyword(s):  
Transcription Factor ◽  
Genomic Selection ◽  
Binding Sites ◽  
Target Genes

scholarly journals Low-affinity transcription factor binding sites shape morphogen responses and enhancer evolution

2013 ◽  
Vol 368 (1632) ◽  
pp. 20130018 ◽  
Author(s):  
Andrea I. Ramos ◽  
Scott Barolo
Keyword(s):  
Transcription Factor ◽  
Binding Affinity ◽  
Binding Sites ◽  
Target Genes ◽  
Gene Activation ◽  
Transcriptional Response ◽  
Morphogen Gradients ◽  
Weak Binding ◽  
Initial Hypothesis

In the era of functional genomics, the role of transcription factor (TF)–DNA binding affinity is of increasing interest: for example, it has recently been proposed that low-affinity genomic binding events, though frequent, are functionally irrelevant. Here, we investigate the role of binding site affinity in the transcriptional interpretation of Hedgehog (Hh) morphogen gradients . We noted that enhancers of several Hh-responsive Drosophila genes have low predicted affinity for Ci, the Gli family TF that transduces Hh signalling in the fly. Contrary to our initial hypothesis, improving the affinity of Ci/Gli sites in enhancers of dpp , wingless and stripe , by transplanting optimal sites from the patched gene, did not result in ectopic responses to Hh signalling. Instead, we found that these enhancers require low-affinity binding sites for normal activation in regions of relatively low signalling. When Ci/Gli sites in these enhancers were altered to improve their binding affinity, we observed patterning defects in the transcriptional response that are consistent with a switch from Ci-mediated activation to Ci-mediated repression. Synthetic transgenic reporters containing isolated Ci/Gli sites confirmed this finding in imaginal discs. We propose that the requirement for gene activation by Ci in the regions of low-to-moderate Hh signalling results in evolutionary pressure favouring weak binding sites in enhancers of certain Hh target genes.

scholarly journals The TEA Transcription Factor Tec1 Confers Promoter-Specific Gene Regulation by Ste12-Dependent and -Independent Mechanisms

2010 ◽  
Vol 9 (4) ◽  
pp. 514-531 ◽  
Author(s):  
Barbara Heise ◽  
Julia van der Felden ◽  
Sandra Kern ◽  
Mario Malcher ◽  
Stefan Brückner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcriptional Activation ◽  
Binding Sites ◽  
Target Genes ◽  
Specific Gene ◽  
Dependent Manner ◽  
A Genome ◽  
Regulated Gene Expression

ABSTRACT In Saccharomyces cerevisiae, the TEA transcription factor Tec1 is known to regulate target genes together with a second transcription factor, Ste12. Tec1-Ste12 complexes can activate transcription through Tec1 binding sites (TCSs), which can be further combined with Ste12 binding sites (PREs) for cooperative DNA binding. However, previous studies have hinted that Tec1 might regulate transcription also without Ste12. Here, we show that in vivo, physiological amounts of Tec1 are sufficient to stimulate TCS-mediated gene expression and transcription of the FLO11 gene in the absence of Ste12. In vitro, Tec1 is able to bind TCS elements with high affinity and specificity without Ste12. Furthermore, Tec1 contains a C-terminal transcriptional activation domain that confers Ste12-independent activation of TCS-regulated gene expression. On a genome-wide scale, we identified 302 Tec1 target genes that constitute two distinct classes. A first class of 254 genes is regulated by Tec1 in a Ste12-dependent manner and is enriched for genes that are bound by Tec1 and Ste12 in vivo. In contrast, a second class of 48 genes can be regulated by Tec1 independently of Ste12 and is enriched for genes that are bound by the stress transcription factors Yap6, Nrg1, Cin5, Skn7, Hsf1, and Msn4. Finally, we find that combinatorial control by Tec1-Ste12 complexes stabilizes Tec1 against degradation. Our study suggests that Tec1 is able to regulate TCS-mediated gene expression by Ste12-dependent and Ste12-independent mechanisms that enable promoter-specific transcriptional control.

C/ebpα and Pu.1 Are Members of a Critical Regulatory Network Required for Hoxa9-Mediated Immortalization

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 650-650
Author(s):  
Cailin Collins ◽  
Jingya Wang ◽  
Joel Bronstein ◽  
Jay L. Hess
Keyword(s):  
Transcription Factor ◽  
Binding Sites ◽  
Target Genes ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Epigenetic Modifications ◽  
Conditional Knockout ◽  
Motif Analysis ◽  
Myeloid Leukemias

Abstract Abstract 650 HOXA9 is a homeodomain-containing transcription factor that plays important roles in both development and hematopoiesis. Deregulation of HOXA9 occurs in a variety of acute lymphoid and myeloid leukemias and plays a key role in their pathogenesis. More than 50% of acute myeloid leukemia (AML) cases show up-regulation of HOXA9, which correlates strongly with poor prognosis. Nearly all cases of AML with mixed lineage leukemia (MLL) translocations have increased HOXA9 expression, as well as cases with mutation of the nucleophosmin gene NPM1, overexpression of CDX2, and fusions of NUP98. Despite the crucial role that HOXA9 plays in development, hematopoiesis and leukemia, its transcriptional targets and mechanisms of action are poorly understood. Previously we identified Hoxa9 and Meis1 binding sites in myeloblastic cells, profiled their epigenetic modifications, and identified the target genes regulated by Hoxa9. Hoxa9 and Meis1 co-bind at hundreds of promoter distal, highly evolutionarily conserved sites showing high levels of histone H3K4 monomethylation and CBP/p300 binding characteristic of enhancers. Hoxa9 association at these sites correlates strongly with increases in histone H3K27 acetylation and activation of downstream target genes, including many proleukemic gene loci. De novo motif analysis of Hoxa9 binding sites shows a marked enrichment of motifs for the transcription factors in the C/EBP and ETS families, and C/ebpα and the ETS transcription factor Pu.1 were found to cobind at Hoxa9-regulated enhancers. Both C/ebpα and Pu.1 are known to play critical roles in the establishment of functional enhancers during normal myeloid development and are mutated or otherwise deregulated in various myeloid leukemias. To determine the importance of co-association of Hoxa9, C/ebpα and Pu.1 at myeloid enhancers, we generated cell lines from C/ebpα and Pu.1 conditional knockout mice (kindly provided by Dr. Daniel Tenen, Harvard University) by immortalization with Hoxa9 and Meis1. In addition we transformed bone marrow with a tamoxifen-regulated form of Hoxa9. Strikingly, loss of C/ebpα or Pu.1, or inactivation of Hoxa9, blocks proliferation and leads to myeloid differentiation. ChIP experiments show that both C/ebpα and Pu.1 remain bound to Hoxa9 binding sites in the absence of Hoxa9. After the loss of Pu.1, both Hoxa9 and C/ebpα dissociate from Hoxa9 binding sites with a corresponding decrease in target gene expression. In contrast, loss of C/ebpα does not lead to an immediate decrease in either Hoxa9 or Pu.1 binding, suggesting that C/ebpα may be playing a regulatory as opposed to a scaffolding role at enhancers. Current work focuses on performing ChIP-seq analysis to assess how C/ebpα and Pu.1 affect Hoxa9 and Meis1 binding and epigenetic modifications genome-wide, and in vivo leukemogenesis assays to confirm the requirement of both Pu.1 and C/ebpα in the establishment and maintenance of leukemias with high levels of Hoxa9. Collectively, our findings implicate C/ebpα and Pu.1 as members of a critical transcription factor network required for Hoxa9-mediated transcriptional regulation in leukemia. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Identification of key tissue-specific, biological processes by integrating enhancer information in maize gene regulatory networks

2020 ◽  
Author(s):  
Maud Fagny ◽  
Marieke Lydia Kuijjer ◽  
Maike Stam ◽  
Johann Joets ◽  
Olivier Turc ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Binding Sites ◽  
Regulatory Network ◽  
Tissue Specificity ◽  
Target Genes ◽  
Specific Gene ◽  
Tissue Specific ◽  
Genome Wide ◽  
Gene Regulatory

AbstractEnhancers are important regulators of gene expression during numerous crucial processes including tissue differentiation across development. In plants, their recent molecular characterization revealed their capacity to activate the expression of several target genes through the binding of transcription factors. Nevertheless, identifying these target genes at a genome-wide level remains a challenge, in particular in species with large genomes, where enhancers and target genes can be hundreds of kilobases away. Therefore, the contribution of enhancers to regulatory network is still poorly understood in plants. In this study, we investigate the enhancer-driven regulatory network of two maize tissues at different stages: leaves at seedling stage and husks (bracts) at flowering. Using a systems biology approach, we integrate genomic, epigenomic and transcriptomic data to model the regulatory relationship between transcription factors and their potential target genes. We identify regulatory modules specific to husk and V2-IST, and show that they are involved in distinct functions related to the biology of each tissue. We evidence enhancers exhibiting binding sites for two distinct transcription factor families (DOF and AP2/ERF) that drive the tissue-specificity of gene expression in seedling immature leaf and husk. Analysis of the corresponding enhancer sequences reveals that two different transposable element families (TIR transposon Mutator and MITE Pif/Harbinger) have shaped the regulatory network in each tissue, and that MITEs have provided new transcription factor binding sites that are involved in husk tissue-specificity.SignificanceEnhancers play a major role in regulating tissue-specific gene expression in higher eukaryotes, including angiosperms. While molecular characterization of enhancers has improved over the past years, identifying their target genes at the genome-wide scale remains challenging. Here, we integrate genomic, epigenomic and transcriptomic data to decipher the tissue-specific gene regulatory network controlled by enhancers at two different stages of maize leaf development. Using a systems biology approach, we identify transcription factor families regulating gene tissue-specific expression in husk and seedling leaves, and characterize the enhancers likely to be involved. We show that a large part of maize enhancers is derived from transposable elements, which can provide novel transcription factor binding sites crucial to the regulation of tissue-specific biological functions.

scholarly journals T-Gene: Improved target gene prediction

2019 ◽  
Author(s):  
Timothy O’Connor ◽  
Charles E. Grant ◽  
Mikael Bodén ◽  
Timothy L. Bailey
Keyword(s):  
Transcription Factor ◽  
Binding Sites ◽  
Target Gene ◽  
Target Genes ◽  
Gene Prediction ◽  
Regulatory Element ◽  
Statistical Significance ◽  
Web Server ◽  
Expression Data ◽  
Command Line Tool

AbstractMotivationIdentifying the genes regulated by a given transcription factor (its “target genes”) is a key step in developing a comprehensive understanding of gene regulation. Previously we developed a method for predicting the target genes of a transcription factor (TF) based solely on the correlation between a histone modification at the TF’s binding site and the expression of the gene across a set of tissues. That approach is limited to organisms for which extensive histone and expression data is available, and does not explicitly incorporate the genomic distance between the TF and the gene.ResultsWe present the T-Gene algorithm, which overcomes these limitations. T-Gene can be used to predict which genes are most likely to be regulated by a TF, and which of the TF’s binding sites are most likely involved in regulating particular genes. T-Gene calculates a novel score that combines distance and histone/expression correlation, and we show that this score accurately predicts when a regulatory element bound by a TF is in contact with a gene’s promoter, achieving median positive predictive value (PPV) above 50%. T-Gene is easy to use via its web server or as a command-line tool, and can also make accurate predictions (median PPV above 40%) based on distance alone when extensive histone/expression data is not available for the organism. T-Gene provides an estimate of the statistical significance of each of its predictions.AvailabilityThe T-Gene web server, source code, histone/expression data and genome annotation files are provided at http://[email protected]

beta3-tubulin is directly repressed by the engrailed protein in Drosophila

Development ◽  
1997 ◽  
Vol 124 (13) ◽  
pp. 2527-2536 ◽  
Author(s):  
N. Serrano ◽  
H.W. Brock ◽  
F. Maschat
Keyword(s):  
Transcription Factor ◽  
Binding Sites ◽  
Transgenic Line ◽  
Target Genes ◽  
Regulatory Protein ◽  
Polytene Chromosomes ◽  
First Intron ◽  
Direct Target

In Drosophila, Engrailed is a nuclear regulatory protein with essential roles during embryonic development. Although Engrailed is a transcription factor, little progress has been achieved in identifying its target genes. We report here the identification of an effector gene, the beta3-tubulin gene, as a direct target of Engrailed. The cytological location of beta3-tubulin, 60C, is a strong site of Engrailed binding on polytene chromosomes. Immunostaining analysis of a transgenic line containing a P[beta3-tubulin-lacZ] construct shows an additional site of Engrailed binding at the location of the transgene. Molecular analysis allowed identification of several Engrailed binding sites, both in vitro and in vivo, within the first intron of the beta3-tubulin locus. Engrailed binding sites identified in vitro are active in larvae. Furthermore, expression of beta3-tubulin is derepressed in the ectoderm of engrailed mutant embryos. Repression of beta3-tubulin by Engrailed is also obtained when Engrailed is ectopically expressed in embryonic mesoderm. Finally, two different sets of Engrailed binding sites are shown to be involved in the early and late regulation of beta3-tubulin by Engrailed during embryogenesis.

Bioinformatic Analysis of Transcriptional Regulation by Nur77 in Central Nervous System and Immune System

2021 ◽  
Author(s):  
Montserrat Olivares Costa ◽  
Fernando Faunes ◽  
María Estela Andrés
Keyword(s):  
Stem Cells ◽  
Central Nervous System ◽  
Nervous System ◽  
Transcription Factor ◽  
Immune Cells ◽  
Binding Sites ◽  
Target Genes ◽  
Bioinformatic Analysis ◽  
Neuronal Stem Cells

Abstract ObjectiveThe objectives of this work were to find genes regulated by Nur77 in neurons and to evaluate the possible common role of this transcription factor in neurons and lymphatic cells using published experimentally generated databases of ChIP-Seq and a microarray. We also characterized Nur77 binding throughout the genome. ResultsWe identified 113 Nur77 target genes in neuronal stem cells and 116 in neuronal cells. Cell adhesion and anchoring processes emerged as regulated by Nur77 in neurons and lymphatic cells. We found 9 common genes regulated by Nur77. Finally, we described a significant distribution of Nur77 binding sites in strong enhancers and active promoters. This work is a first step to understand the role of Nur77 and its common targets in neurons and immune cells.

scholarly journals Beyond Trees: Regulons and Regulatory Motif Characterization

Genes ◽  
2020 ◽  
Vol 11 (9) ◽  
pp. 995
Author(s):  
Xuhua Xia
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Binding Sites ◽  
Target Genes ◽  
Biological Function ◽  
Regulatory Motifs ◽  
Candidate Target ◽  
Tree Genetics ◽  
Growth And Reproduction

Trees and their seeds regulate their germination, growth, and reproduction in response to environmental stimuli. These stimuli, through signal transduction, trigger transcription factors that alter the expression of various genes leading to the unfolding of the genetic program. A regulon is conceptually defined as a set of target genes regulated by a transcription factor by physically binding to regulatory motifs to accomplish a specific biological function, such as the CO-FT regulon for flowering timing and fall growth cessation in trees. Only with a clear characterization of regulatory motifs, can candidate target genes be experimentally validated, but motif characterization represents the weakest feature of regulon research, especially in tree genetics. I review here relevant experimental and bioinformatics approaches in characterizing transcription factors and their binding sites, outline problems in tree regulon research, and demonstrate how transcription factor databases can be effectively used to aid the characterization of tree regulons.

scholarly journals A direct and widespread role for the nuclear receptor EcR in mediating the response to ecdysone in Drosophila

2019 ◽  
Author(s):  
Christopher M. Uyehara ◽  
Daniel J. McKay
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Dna Binding ◽  
Nuclear Receptor ◽  
Binding Sites ◽  
Target Genes ◽  
Transcriptional Responses ◽  
Developmental Transitions ◽  
The Impact

ABSTRACTThe ecdysone pathway was amongst the first experimental systems employed to study the impact of steroid hormones on the genome. In Drosophila and other insects, ecdysone coordinates developmental transitions, including wholesale transformation of the larva into the adult during metamorphosis. Like other hormones, ecdysone controls gene expression through a nuclear receptor, which functions as a ligand-dependent transcription factor. Although it is clear that ecdysone elicits distinct transcriptional responses within its different target tissues, the role of its receptor, EcR, in regulating target gene expression is incompletely understood. In particular, EcR initiates a cascade of transcription factor expression in response to ecdysone, making it unclear which ecdysone-responsive genes are direct EcR targets. Here, we use the larval-to-prepupal transition of developing wings to examine the role of EcR in gene regulation. Genome-wide DNA binding profiles reveal that EcR exhibits widespread binding across the genome, including at many canonical ecdysone-response genes. However, the majority of its binding sites reside at genes with wing-specific functions. We also find that EcR binding is temporally dynamic, with thousands of binding sites changing over time. RNA-seq reveals that EcR acts as both a temporal gate to block precocious entry to the next developmental stage as well as a temporal trigger to promote the subsequent program. Finally, transgenic reporter analysis indicates that EcR regulates not only temporal changes in target enhancer activity but also spatial patterns. Together, these studies define EcR as a multipurpose, direct regulator of gene expression, greatly expanding its role in coordinating developmental transitions.SIGNIFICANCENuclear receptors (NRs) are sequence-specific DNA binding proteins that act as intracellular receptors for small molecules such as hormones. Prior work has shown that NRs function as ligand-dependent switches that initiate a cascade of gene expression changes. The extent to which NRs function as direct regulators of downstream genes in these hierarchies remains incompletely understood. Here, we study the role of the NR EcR in metamorphosis of the Drosophila wing. We find that EcR directly regulates many genes at the top of the hierarchy as well as at downstream genes. Further, we find that EcR binds distinct sets of target genes at different developmental times. This work helps inform how hormones elicit tissue- and temporal-specific responses in target tissues.

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