Competition between histone and transcription factor binding regulates the onset of transcription in zebrafish embryos.
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ABSTRACT:
SUBMITTER: Joseph SR
PROVIDER: S-EPMC5451213 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The very small fraction of putative binding sites (BSs) that are occupied by transcription factors (TFs) in vivo can be highly variable across different cell types. This observation has been partly attributed to changes in chromatin accessibility and histone modification (HM) patterns surrounding BSs. Previous studies focusing on BSs within DNA regulatory regions found correlations between HM patterns and TF binding specificities. However, a mechanistic understanding of TF-DNA binding specificity determinants is still not available. The ability to predict in vivo TF binding on a genome-wide scale requires the identification of features that determine TF binding based on evolutionary relationships of DNA binding proteins. To reveal protein family-dependent mechanisms of TF binding, we conducted comprehensive comparisons of HM patterns surrounding BSs and non-BSs with exactly matched core motifs for TFs in three cell lines: 33 TFs in GM12878, 37 TFs in K562, and 18 TFs in H1-hESC. These TFs displayed protein family-specific preferences for HM patterns surrounding BSs, with high agreement among cell lines. Moreover, compared to models based on DNA sequence and shape at flanking regions of BSs, HM-augmented quantitative machine-learning methods resulted in increased performance in a TF family-specific manner. Analysis of the relative importance of features in these models indicated that TFs, displaying larger HM pattern differences between BSs and non-BSs, bound DNA in an HM-specific manner on a protein family-specific basis. We propose that TF family-specific HM preferences reveal distinct mechanisms that assist in guiding TFs to their cognate BSs by altering chromatin structure and accessibility.
| S-EPMC5848611 | biostudies-literature
Project description:Histone deacetylases (HDACs) catalyze the removal of acetyl molecules from histone and non-histone substrates playing important roles in chromatin remodeling and control of gene expression. Class I HDAC1 is a critical regulator of cell cycle progression, cellular proliferation and differentiation during development; it is also regulated by many post-translational modifications (PTMs). Herein we characterize a new mitosis-specific phosphorylation of HDAC1 driven by Aurora kinases A and B. We show that this phosphorylation affects HDAC1 enzymatic activity and it is critical for the maintenance of a proper proliferative and developmental plan in a complex organism. Notably, we find that Aurora-dependent phosphorylation of HDAC1 regulates histone acetylation by modulating the expression of genes directly involved in the developing zebrafish central nervous system. Our data represent a step towards the comprehension of HDAC1 regulation by its PTM code, with important implications in unravelling its roles both in physiology and pathology.
| S-EPMC4960611 | biostudies-literature
Project description:BackgroundThe epigenetic regulator Histone Deacetylase 1 (Hdac1) is required for specification and patterning of neurones and myelinating glia during development of the vertebrate central nervous system (CNS). This co-ordinating function for Hdac1 is evolutionarily conserved in zebrafish and mouse, but the mechanism of action of Hdac1 in the developing CNS is not well-understood.ResultsA genome-wide comparative analysis of the transcriptomes of Hdac1-deficient and wild-type zebrafish embryos was performed, which identified an extensive programme of gene expression that is regulated by Hdac1 in the developing embryo. Using time-resolved expression profiling of embryos, we then identified a small subset of 54 genes within the Hdac1-regulated transcriptome that specifically exhibit robust and sustained Hdac1-dependent expression from early neurogenesis onwards. 18 of these 54 stringently Hdac1-regulated genes encode DNA-binding transcription factors that are implicated in promoting neuronal specification and CNS patterning, including the proneural bHLH proteins Ascl1a and Ascl1b, as well as Neurod4 and Neurod. Relatively few genes are strongly repressed by Hdac1 but expression of the Notch target gene her6 is attenuated by Hdac1 in specific sub-regions of the developing CNS, from early stages of neurogenesis onwards. Selected members of the stringently Hdac1-regulated group of genes were tested for Hdac1 binding to their promoter-proximal cis-regulatory elements. Surprisingly, we found that Hdac1 is specifically and stably associated with DNA sequences within the promoter region of ascl1b during neurogenesis, and that this Hdac1-ascl1b interaction is abolished in hdac1 mutant embryos.ConclusionsWe conclude that Hdac1 regulates histone acetylation and methylation in the developing zebrafish embryo and promotes the sustained, co-ordinate transcription of a small set of transcription factor genes that control expansion and diversification of cell fates within the developing CNS. Our in vivo chromatin immunoprecipitation results also suggest a specific function for Hdac1 in directly regulating transcription of a key member of this group of genes, ascl1b, from the beginning of neurogenesis onwards. Taken together, our observations indicate a novel role for Hdac1 as a positive regulator of gene transcription during development of the vertebrate CNS, in addition to its more well-established function in transcriptional repression.
| S-EPMC3032698 | biostudies-literature
Project description:Gene expression in higher organisms is thought to be regulated by a complex network of transcription factor binding and chromatin modifications, yet the relative importance of these two factors remains a matter of debate. Here, we show that a computational approach allows surprisingly accurate prediction of histone modifications solely from knowledge of transcription factor binding both at promoters and at potential distal regulatory elements. This accuracy significantly and substantially exceeds what could be achieved by using DNA sequence as an input feature. Remarkably, we show that transcription factor binding enables strikingly accurate predictions across different cell lines. Analysis of the relative importance of specific transcription factors as predictors of specific histone marks recapitulated known interactions between transcription factors and histone modifiers. Our results demonstrate that reported associations between histone marks and gene expression may be indirect effects caused by interactions between transcription factors and histone-modifying complexes.
| S-EPMC4169916 | biostudies-literature
Project description:Precise spatiotemporal regulation of the SIX1 homeoprotein is required to coordinate vital tissue development, including myogenesis. Whereas SIX1 is downregulated in most tissues following embryogenesis, it is re-expressed in numerous cancers, including tumors derived from muscle progenitors. Despite crucial roles in development and disease, the upstream regulation of SIX1 expression has remained elusive. Here, we identify the first direct mechanism for Six1 regulation in embryogenesis, through microRNA30a (miR30a)-mediated repression. In zebrafish somites, we show that miR30a and six1a and six1b (hereafter six1a/b) are expressed in an inverse temporal pattern. Overexpression of miR30a leads to a reduction in six1a/b levels, and results in increased apoptosis and altered somite morphology, which phenocopies six1a/b knockdown. Conversely, miR30a inhibition leads to increased Six1 expression and abnormal somite morphology, revealing a role for endogenous miR30a as a muscle-specific miRNA (myomiR). Importantly, restoration of six1a in miR30a-overexpressing embryos restores proper myogenesis. These data demonstrate a new role for miR30a at a key node in the myogenic regulatory gene network through controlling Six1 expression.
| S-EPMC4021474 | biostudies-literature
Project description:Binding of transcription factors to DNA is a key regulatory step in the control of gene expression. DNA sequences with high affinity for transcription factors occur more frequently in the genome than instances of genes bound or regulated by these factors. How specific gene regulation is achieved by transcription factors remains unclear. We used genome-wide approaches to study how trans factors shape the binding and regulatory landscape of Pho4, a budding yeast transcription factor that activates gene expression in response to phosphate limitation. In no phosphate (0mM phosphate) medium, Pho4 is transported into the nucleus and activates transcription of a set of genes (PHO) that are necessary for cell survival in phosphate limited environment. In high phosphate (10mM phosphate) medium, Pho4 is transported outside of the nucleus and the transcription program of PHO genes are turned off. Here we examined the transcription profiling of S. cerevisiae (W303) in various strains treated in media with 10mM or 0mM inorganic phosphate, to study the the transcription activation by Pho4 its cooperative binding factor Pho2, and its competitive binding factor Cbf1.
2011-06-29 | GSE23580 | GEO
Project description:Tribless family proteins are pseudokinases that lack DFG (Asp-Phe-Gly) motif in the functional kinase domain, regulating Akt and BMP pathways, insulin metabolism, hypoxia, and ubiquitination. This report concerns expression patterns and functional roles of trb3 in zebrafish embryonic development. trb3 is evolutionarily well-conserved and located on zebrafish chromosome 11. Spatiotemporal expression studies show that trb3 transcripts are abundant throughout embryogenesis, but confined to mesendodermal cells during the late blastula phase. Over-expression of trb3 ventralizes the embryos while a knockdown of trb3 using morpholino alters positioning of the heart, liver, and pancreatic buds as well as gut looping. Furthermore, constitutive activation of TGF-signaling with TARAM-A* (TGF-related type I receptor) significantly increases the level of trb3 transcripts during the late blastula phase. Over-expression of trb3 reduces the level of smurf1 transcripts, a member of TGF-signaling. We thus propose that Trb3 governs left-right (LR) axis patterning as a component of TGF-signaling in vertebrate embryonic development.
| S-EPMC3887966 | biostudies-literature
Project description:Chromatin proteins have expanded the mammalian synthetic biology toolbox by enabling control of active and silenced states at endogenous genes. Others have reported synthetic proteins that bind DNA and regulate genes by altering chromatin marks, such as histone modifications. Previously, we reported the first synthetic transcriptional activator, the "Polycomb-based transcription factor" (PcTF) that reads histone modifications through a protein-protein interaction between the polycomb chromodomain motif and trimethylated lysine 27 of histone H3 (H3K27me3). Here, we describe the genome-wide behavior of the polycomb-based transcription factor fusion protein. Transcriptome and chromatin profiling revealed several polycomb-based transcription factor-sensitive promoter regions marked by distal H3K27me3 and proximal fusion protein binding. These results illuminate a mechanism in which polycomb-based transcription factor interactions bridge epigenomic marks with the transcription initiation complex at target genes. In three cancer-derived human cell lines tested here, some target genes encode developmental regulators and tumor suppressors. Thus, the polycomb-based transcription factor represents a powerful new fusion protein-based method for cancer research and treatment where silencing marks are translated into direct gene activation.
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Project description:Ras-responsive element-binding protein 1 (Rreb1) is a zinc-finger transcription factor acting downstream of RAS signaling. Rreb1 has been implicated in cancer and Noonan-like RASopathies. However, little is known about its role in mammalian non-disease states. Here, we show that Rreb1 is essential for mouse embryonic development. Loss of Rreb1 led to a reduction in the expression of vasculogenic factors, cardiovascular defects, and embryonic lethality. During gastrulation, the absence of Rreb1 also resulted in the upregulation of cytoskeleton-associated genes, a change in the organization of F-ACTIN and adherens junctions within the pluripotent epiblast, and perturbed epithelial architecture. Moreover, Rreb1 mutant cells ectopically exited the epiblast epithelium through the underlying basement membrane, paralleling cell behaviors observed during metastasis. Thus, disentangling the function of Rreb1 in development should shed light on its role in cancer and other diseases involving loss of epithelial integrity.
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Project description:Transcription factors (TFs) are proteins that bind to specific sites on the DNA and regulate gene activity. Identifying where TF molecules bind and how much time they spend on their target sites is key to understanding transcriptional regulation. It is usually assumed that the free energy of binding of a TF to the DNA (the affinity of the site) is highly correlated to the amount of time the TF remains bound (the occupancy of the site). However, knowing the binding energy is not sufficient to infer actual binding site occupancy. This mismatch between the occupancy predicted by the affinity and the observed occupancy may be caused by various factors, such as TF abundance, competition between TFs or the arrangement of the sites on the DNA. We investigated the relationship between the affinity of a TF for a set of binding sites and their occupancy. In particular, we considered the case of the transcription factor lac repressor (lacI) in E.coli, and performed stochastic simulations of the TF dynamics on the DNA for various combinations of lacI abundance and competing TFs that contribute to macromolecular crowding. We also investigated the relationship of site occupancy and the information content of position weight matrices (PWMs) used to represent binding sites. Our results showed that for medium and high affinity sites, TF competition does not play a significant role for genomic occupancy except in cases when the abundance of the TF is significantly increased, or when the PWM displays relatively low information content. Nevertheless, for medium and low affinity sites, an increase in TF abundance (for both cognate and non-cognate molecules) leads to an increase in occupancy at several sites.
| S-EPMC3785477 | biostudies-literature