Browse
Submit Data
Databases
API
Help

Dataset Information

16 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The Unicellular Ancestry of Groucho-Mediated Repression and the Origins of Metazoan Transcription Factors.

ABSTRACT: Groucho is a co-repressor that interacts with many transcription factors playing a crucial role in animal development. The evolutionary origins of Groucho are not clear. It is generally regarded as being a distinct animal-specific protein, although with similarities to the yeast Tup-like proteins. Here, it is shown that Groucho has true orthologs in unicellular relatives of animals. Based on their phylogenetic distribution, and an analysis of ligand-binding residues, these genes are unlikely to be orthologs of the fungal Tup-like genes. By identifying conserved candidate Groucho interaction motifs (GIMs) in nonmetazoan transcription factors, it is demonstrated that the details of molecular interactions between Groucho and transcription factors are likely to have been established prior to the origin of animals, but that the association of GIMs with many transcription factor types can be regarded as a metazoan innovation.

SUBMITTER: Copley RR

PROVIDER: S-EPMC4943189 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

The Unicellular Ancestry of Groucho-Mediated Repression and the Origins of Metazoan Transcription Factors.

Copley Richard R RR

Genome biology and evolution 20160627 6

Groucho is a co-repressor that interacts with many transcription factors playing a crucial role in animal development. The evolutionary origins of Groucho are not clear. It is generally regarded as being a distinct animal-specific protein, although with similarities to the yeast Tup-like proteins. Here, it is shown that Groucho has true orthologs in unicellular relatives of animals. Based on their phylogenetic distribution, and an analysis of ligand-binding residues, these genes are unlikely to ...[more]

PMID: 27189982

Similar Datasets

Unexpected repertoire of metazoan transcription factors in the unicellular holozoan Capsaspora owczarzaki.

Project description:How animals (metazoans) originated from their single-celled ancestors remains a major question in biology. As transcriptional regulation is crucial to animal development, deciphering the early evolution of associated transcription factors (TFs) is critical to understanding metazoan origins. In this study, we uncovered the repertoire of 17 metazoan TFs in the amoeboid holozoan Capsaspora owczarzaki, a representative of a unicellular lineage that is closely related to choanoflagellates and metazoans. Phylogenetic and comparative genomic analyses with the broadest possible taxonomic sampling allowed us to formulate new hypotheses regarding the origin and evolution of developmental metazoan TFs. We show that the complexity of the TF repertoire in C. owczarzaki is strikingly high, pushing back further the origin of some TFs formerly thought to be metazoan specific, such as T-box or Runx. Nonetheless, TF families whose beginnings antedate the origin of the animal kingdom, such as homeodomain or basic helix-loop-helix, underwent significant expansion and diversification along metazoan and eumetazoan stems.

| S-EPMC4342549 | biostudies-literature

Analysis of Groucho-histone interactions suggests mechanistic similarities between Groucho- and Tup1-mediated repression.

Project description:The Drosophila Groucho (Gro) protein is the defining member of a family of metazoan corepressors that have roles in many aspects of development, including segmentation, dorsal/ventral pattern formation, Notch signaling, and Wnt/Wg signaling. Previous speculation has suggested that Gro may be orthologous to the yeast corepressor Tup1. In support of this idea, a detailed alignment between the C-terminal WD-repeat domains of these two proteins shows that each Gro WD repeat is most similar to the Tup1 WD repeat occupying the corresponding position in that protein. Our analysis of Gro-histone interactions provides further support for a close evolutionary relationship between Gro and Tup1. In particular, we show that, as with the N-terminal region of Tup1, the N-terminal region of Gro is necessary and sufficient for direct binding to histones. The highest affinity interaction is with histone H3 and binding is primarily observed with hypoacetylated histones. Using transient transfection assays, we show that a Gal4-Gro fusion protein containing the histone-binding domain is able to repress transcription. Deletions that weaken histone binding also weaken repression. These findings, along with our recent report that Gro interacts with the histone deacetylase Rpd3, suggest a mechanism for Gro-mediated repression.

| S-EPMC113153 | biostudies-literature

Differential in vivo requirements for oligomerization during Groucho-mediated repression.

Project description:The Groucho (Gro)/transducin-like enhancer of split family of transcriptional corepressors are implicated in many signalling pathways that are important in development and disease, including those mediated by Notch, Wnt and Hedgehog. Here, we describe a genetic screen in Drosophila that yielded 50 new gro alleles, including the first protein-null allele, and has two mutations in the conserved Q oligomerization domain that have been proposed to have an essential role in corepressor activity. One of these latter mutations, encoding an amino-terminal protein truncation that lacks part of the Q domain, abolishes oligomerization in vitro and renders the protein unstable in vivo. Nevertheless, the mutation is not a null: maternal mutant embryos have intermediate segmentation phenotypes and relatively normal terminal patterning suggesting that the mutant protein retains partial corepressor activity. Our results show that homo-oligomerization of Gro is not obligatory for its action in vivo, and that Gro represses transcription through more than one molecular mechanism.

| S-EPMC2246631 | biostudies-literature

Degringolade, a SUMO-targeted ubiquitin ligase, inhibits Hairy/Groucho-mediated repression.

Project description:Transcriptional cofactors are essential for proper embryonic development. One such cofactor in Drosophila, Degringolade (Dgrn), encodes a RING finger/E3 ubiquitin ligase. Dgrn and its mammalian ortholog RNF4 are SUMO-targeted ubiquitin ligases (STUbLs). STUbLs bind to SUMOylated proteins via their SUMO interaction motif (SIM) domains and facilitate substrate ubiquitylation. In this study, we show that Dgrn is a negative regulator of the repressor Hairy and its corepressor Groucho (Gro/transducin-like enhancer (TLE)) during embryonic segmentation and neurogenesis, as dgrn heterozygosity suppresses Hairy mutant phenotypes and embryonic lethality. Mechanistically Dgrn functions as a molecular selector: it targets Hairy for SUMO-independent ubiquitylation that inhibits the recruitment of its corepressor Gro, without affecting the recruitment of its other cofactors or the stability of Hairy. Concomitantly, Dgrn specifically targets SUMOylated Gro for sequestration and antagonizes Gro functions in vivo. Our findings suggest that by targeting SUMOylated Gro, Dgrn serves as a molecular switch that regulates cofactor recruitment and function during development. As Gro/TLE proteins are conserved universal corepressors, this may be a general paradigm used to regulate the Gro/TLE corepressors in other developmental processes.

| S-EPMC3094120 | biostudies-literature

Transcription factors FOXG1 and Groucho/TLE promote glioblastoma growth.

Project description:Glioblastoma (GBM) is the most common and deadly malignant brain cancer, with a median survival of <2 years. GBM displays a cellular complexity that includes brain tumour-initiating cells (BTICs), which are considered as potential key targets for GBM therapies. Here we show that the transcription factors FOXG1 and Groucho/TLE are expressed in poorly differentiated astroglial cells in human GBM specimens and in primary cultures of GBM-derived BTICs, where they form a complex. FOXG1 knockdown in BTICs causes downregulation of neural stem/progenitor and proliferation markers, increased replicative senescence, upregulation of astroglial differentiation genes and decreased BTIC-initiated tumour growth after intracranial transplantation into host mice. These effects are phenocopied by Groucho/TLE knockdown or dominant inhibition of the FOXG1:Groucho/TLE complex. These results provide evidence that transcriptional programmes regulated by FOXG1 and Groucho/TLE are important for BTIC-initiated brain tumour growth, implicating FOXG1 and Groucho/TLE in GBM tumourigenesis.

| S-EPMC3984242 | biostudies-literature

The EH1 motif in metazoan transcription factors.

Project description:BackgroundThe Engrailed Homology 1 (EH1) motif is a small region, believed to have evolved convergently in homeobox and forkhead containing proteins, that interacts with the Drosophila protein groucho (C. elegans unc-37, Human Transducin-like Enhancers of Split). The small size of the motif makes its reliable identification by computational means difficult. I have systematically searched the predicted proteomes of Drosophila, C. elegans and human for further instances of the motif.ResultsUsing motif identification methods and database searching techniques, I delimit which homeobox and forkhead domain containing proteins also have likely EH1 motifs. I show that despite low database search scores, there is a significant association of the motif with transcription factor function. I further show that likely EH1 motifs are found in combination with T-Box, Zinc Finger and Doublesex domains as well as discussing other plausible candidate associations. I identify strong candidate EH1 motifs in basal metazoan phyla.ConclusionCandidate EH1 motifs exist in combination with a variety of transcription factor domains, suggesting that these proteins have repressor functions. The distribution of the EH1 motif is suggestive of convergent evolution, although in many cases, the motif has been conserved throughout bilaterian orthologs. Groucho mediated repression was established prior to the evolution of bilateria.

| S-EPMC1310626 | biostudies-literature

Groucho-mediated repression may result from a histone deacetylase-dependent increase in nucleosome density.

Project description:Groucho (Gro) is a Drosophila melanogaster transcriptional corepressor that directly interacts with the histone deacetylase Rpd3. Although previous studies suggest that this interaction is required for repression of Gro-responsive reporters in cultured cells, the in vivo significance of this interaction and the mechanism by which it leads to repression remain largely unexplored. In this study, we show that Gro is partially dependent on Rpd3 for repression, supporting the idea that Rpd3-mediated repression is one mode of Gro-mediated repression. We demonstrate that Gro colocalizes with Rpd3 to the chromatin of a target gene and that this is accompanied by the deacetylation of specific lysines within the N-terminal tails of histones H3 and H4. Gro overexpression leads to wing patterning defects and ectopic repression in the wing disc of transcription directed by the vestigial quadrant enhancer. These effects are reversed by the histone deacetylase inhibitors TSA and HC-Toxin and by the reduction of Rpd3 gene dosage. Furthermore, repression of the vestigial quadrant enhancer is accompanied by a Gro-mediated increase in nucleosome density, an effect that is reversed by histone deacetylase inhibitors. We propose a model in which Gro-mediated histone deacetylation results in increased nucleosome density leading to transcriptional repression.

| S-EPMC2854148 | biostudies-literature

PRDI-BF1/Blimp-1 repression is mediated by corepressors of the Groucho family of proteins.

Project description:The PRDI-BF1/Blimp-1 protein is a transcriptional repressor required for normal B-cell differentiation, and it has been implicated in the repression of beta-interferon (IFN-beta) and c-myc gene expression. Here, we show that PRDI-BF1 represses transcription of the IFN-beta promoter and of an artificial promoter through an active repression mechanism. We also identified a minimal repression domain in PRDI-BF1 that is sufficient for transcriptional repression when tethered to DNA as a Gal4 fusion protein. Remarkably, this repression domain interacts specifically with hGrg, TLE1, and TLE2 proteins, all of which are members of the Groucho family of transcriptional corepressors. In addition, the hGrg protein itself can function as a potent repressor when tethered to DNA through the Gal4 DNA-binding domain. We also find that the amino-terminal glutamine-rich domains of hGrg and TLE1 are sufficient to mediate dimerization of the two Groucho family proteins. Proteins containing only this domain can function as a dominant-negative inhibitor of PRDI-BF1 repression, and can significantly increase the IFN-beta promoter activity after virus induction. We conclude that PRDI-BF1/Blimp-1 represses transcription by recruiting a complex of Groucho family proteins to DNA, and suggest that such corepressor complexes are required for the postinduction repression of the IFN-beta promoter.

| S-EPMC316372 | biostudies-literature

Metazoan-like signaling in a unicellular receptor tyrosine kinase.

Project description:BackgroundReceptor tyrosine kinases (RTKs) are crucial components of signal transduction systems in multicellular animals. Surprisingly, numerous RTKs have been identified in the genomes of unicellular choanoflagellates and other protists. Here, we report the first biochemical study of a unicellular RTK, namely RTKB2 from Monosiga brevicollis.ResultsWe cloned, expressed, and purified the RTKB2 kinase, and showed that it is enzymatically active. The activity of RTKB2 is controlled by autophosphorylation, as in metazoan RTKs. RTKB2 possesses six copies of a unique domain (designated RM2) in its C-terminal tail. An isolated RM2 domain (or a synthetic peptide derived from the RM2 sequence) served as a substrate for RTKB2 kinase. When phosphorylated, the RM2 domain bound to the Src homology 2 domain of MbSrc1 from M. brevicollis. NMR structural studies of the RM2 domain indicated that it is disordered in solution.ConclusionsOur results are consistent with a model in which RTKB2 activation stimulates receptor autophosphorylation within the RM2 domains. This leads to recruitment of Src-like kinases (and potentially other M. brevicollis proteins) and further phosphorylation, which may serve to increase or dampen downstream signals. Thus, crucial features of signal transduction circuitry were established prior to the evolution of metazoans from their unicellular ancestors.

| S-EPMC3584944 | biostudies-literature

REGULATOR: a database of metazoan transcription factors and maternal factors for developmental studies.

Project description:Genes encoding transcription factors that constitute gene-regulatory networks and maternal factors accumulating in egg cytoplasm are two classes of essential genes that play crucial roles in developmental processes. Transcription factors control the expression of their downstream target genes by interacting with cis-regulatory elements. Maternal factors initiate embryonic developmental programs by regulating the expression of zygotic genes and various other events during early embryogenesis.This article documents the transcription factors of 77 metazoan species as well as human and mouse maternal factors. We improved the previous method using a statistical approach adding Gene Ontology information to Pfam based identification of transcription factors. This method detects previously un-discovered transcription factors. The novel features of this database are: (1) It includes both transcription factors and maternal factors, although the number of species, in which maternal factors are listed, is limited at the moment. (2) Ontological representation at the cell, tissue, organ, and system levels has been specially designed to facilitate development studies. This is the unique feature in our database and is not available in other transcription factor databases.A user-friendly web interface, REGULATOR ( http://www.bioinformatics.org/regulator/ ), which can help researchers to efficiently identify, validate, and visualize the data analyzed in this study, are provided. Using this web interface, users can browse, search, and download detailed information on species of interest, genes, transcription factor families, or developmental ontology terms.

| S-EPMC4411712 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data