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Results for “transcription factor evolution”

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PubMed2002

OTEX, an androgen-regulated human member of the paired-like class of homeobox genes.

paired genes emerged early in evolution and code for homeobox transcription factors, having fundamental roles in various biological processes. We identified a novel human member of the paired-like class, which we named OTEX. A phylogenetic analysis revealed that OTEX belonged to the recently defined PEPP subfamily of paired-like homeobox genes. It was organized into three introns and, like the other PEPP genes, it was mapped to chromosome X. Its transcripts were detected mainly in the ovary, testis and epididymis, but also in the prostate and mammary gland. In the PC-3/ARwt prostate cell line, OTEX expression was stimulated dramatically following androgen treatment. Immunofluorescence studies revealed an exclusively nuclear localization of the OTEX protein. Mutation of the RARCRRHQRE amino acid sequence present at the C-terminus of the OTEX homeodomain resulted in a mainly cytoplasmic localization, indicating that this motif harboured the nuclear localization signal. No inherent transactivation function was seen for OTEX using the one-hybrid assay, and no homodimer formation was observed in the two-hybrid assay, suggesting that additional partners were needed for this activity. Taken together, the data show that OTEX represents a novel, androgen-regulated, paired-like homeobox protein, with possibly an important role in human reproduction.

Amino Acid Sequence↗

PubMed2003

A novel PEPP homeobox gene, TOX, is highly glutamic acid rich and specifically expressed in murine testis and ovary.

The homeobox gene superfamily has been highly conserved throughout evolution. These genes act as transcription factors during several important developmental processes. To explore the functional roles of homeobox genes in spermatogenesis, we performed a degenerate oligonucleotide polymerase chain reaction (PCR) screening of a testis cDNA library and isolated a novel mouse homeobox gene. This gene, which we named Tox, encodes a homeodomain protein distantly related to members of the Paired/Pax (Prd/Pax) family. A phylogenetic analysis revealed Tox to be a member of the recently defined PEPP subfamily of Paired-like homeobox genes. Tox was mapped to chromosome X, with its homeodomain organized into three exons. A special feature of Tox is that the encoded protein sequence contains two poly-glutamic acid (poly E) stretches, which make Tox highly acidic. Tox transcripts were detected predominately in the testis and ovary of mice. Tox expression in testes was initiated soon after birth, mainly in Sertoli cells and spermatogonia; however, in adult mice, Tox expression shifts to the spermatids and spermatozoa. Tox expression in ovaries was detected in somatic cells of follicles, early on in theca cells, and in both granulosa and theca cells at the later stages of follicular development. Based on these results, Tox may play an important role during gametogenesis.

Amino Acid Sequence↗

PubMed2004

Testing the conservation of the translational machinery over evolution in diverse environments: assaying Thermus thermophilus ribosomes and initiation factors in a coupled transcription-translation system from Escherichia coli.

Ribosomes from the extreme thermophile Thermus thermophilus are capable of translation in a coupled transcription-translation system derived from Escherichia coli. At 45 degrees C, T.thermophilus ribosomes translate at approximately 25-30% of the maximal rate of E.coli ribosomes, and synthesize full-length protein. T.thermophilus and E.coli subunits can be combined to effect translation, with the spectrum of proteins produced depending upon the source of the 30S subunit. In this system, T.thermophilus ribosomes function in concert with E.coli translational factors and tRNAs, with elongation and release factors being supplied from the E.coli extract, and purified initiation factors (IFs) being added exogenously. Cloned and purified T.thermophilus IF1, IF2 and IF3 supported the synthesis of the same products in vitro as the E.coli factors, although the relative levels of some polypeptides were factor dependent. We conclude that, at least between these two phylogenetically distant species, translational factor function and subunit-subunit interactions are conserved. This functional compatibility is remarkable given the extreme and highly divergent environments to which these species have adapted.

Escherichia coli↗

PubMed2026

Two Paralogues as They Like It: Conserved and Divergent Evolution of Vertebrate Gcm Genes.

Gcm1 and Gcm2 are paralogous transcription factors in vertebrates that play key roles in the development of pharyngeal-derived epithelia, yet their deployment across vertebrate lineages remains incompletely understood. While Gcm2 shows deeply conserved pharyngeal expression across gnathostomes, Gcm1 has been mainly characterized in mammals, where it exhibits broader expression patterns. How Gcm1 is deployed in non-mammalian vertebrates has remained unexplored. Here, we performed a comparative analysis of Gcm1 expression in cartilaginous fishes, non-teleost actinopterygians, and amphibians. RNA in situ hybridization revealed conserved Gcm1 expression in gill epithelia across these taxa. Parallel analyses showed that Gcm2 is also expressed in gill epithelia, with overlapping but distinct spatial patterns. In addition, Gcm1 showed lineage-specific expression in bichir embryos, including strong expression in external gills and scattered epithelial cells in the yolk-sac membrane. In the external gills, Gcm1-positive cells possess vacuole-like cytoplasmic structures, suggesting a previously unrecognized epithelial cell population. Together, our findings indicate that Gcm1 and Gcm2 share ancestral expression in pharyngeal epithelia but have followed distinct evolutionary trajectories, with Gcm1 exhibiting greater lineage-specific diversification.

Animals↗

PubMed2001

Molecular evolution of the teosinte branched gene among maize and related grasses.

Several authors have proposed that changes in a small number of regulatory genes may be sufficient for the evolution of novel morphologies. Recent analyses have indicated that teosinte branched1 (tb1), a putative bHLH transcription factor, played such a role during the morphological evolution of maize from its wild ancestor, teosinte. To address whether or not tb1 played a similar role during the evolution of the Andropogoneae, the tribe to which maize belongs, and to examine the rate and pattern of tb1 evolution within this tribe, we analyzed tb1-like sequences from 23 members of the Andropogoneae and five other grasses. Our analysis revealed that the TB1 protein evolves slowly within three conserved domains but rapidly outside these domains. The nonconserved regions of the gene are characterized by both a high nonsynonymous substitution rate and frequent indels. The ratio of nonsynonymous substitutions per nonsynonymous site (d(N)) to synonymous substitutions per synonymous site (d(S)) was not significantly greater than 1.0, providing no evidence for positive selection. However, the d(N)/d(S) ratio varied significantly among lineages and was high compared with those of other plant nuclear genes. Variation in the d(N)/d(S) ratio among the Andropogoneae could be explained by unequal levels of purifying selection among lineages. Consistent with this interpretation, the rate of nonsynonymous substitution differed along several lineages, while the synonymous substitution rate did not differ significantly. Finally, using tb1, we examined phylogenetic relationships within the Andropogoneae. The phylogeny suggests that the tribe underwent a rapid radiation during its early history and that the monoecious Andropogoneae are polyphyletic.

Amino Acid Sequence↗

PubMed2025

Transposable Element-Mediated Cis-Regulation Drives the Evolution of dmrt1 as a Candidate Master Sex-Determining Gene in Black Carp.

Sex determination in vertebrates exhibits remarkable evolutionary plasticity, with diverse mechanisms and master sex-determining (MSD) genes arising independently across lineages. Among these, dmrt1, a dosage-sensitive gene, has repeatedly been recruited as an MSD gene through gene duplication or allelic diversification. However, the biochemical basis of such evolutionary transitions, particularly those driven by allelic diversification, remains largely unexplored. Here, we generated haplotype-resolved genome assemblies for both XX and XY black carp (Mylopharyngodon piceus) and identified a ∼40-kb region on chromosome 4, containing only dmrt1, as the candidate sex-determining locus. We discovered two Y-specific insertions in the dmrt1 promoter: a 13.4-kb highly repetitive element and an 11-bp motif. Functional assays revealed that these insertions act as enhancer and a promoter element, respectively, driving early, allele-specific upregulation of dmrt1 prior to gonadal differentiation. Notably, the 13.4-kb insertion contains transposable elements (TEs) functioning as cis-regulatory modules with transcription factor binding sites that mediate Y-specific activation. Our findings reveal a TE-mediated regulatory innovation that promoted dmrt1's evolution as a male-determining gene via allelic diversification, providing new insights into how mobile genetic elements drive the origin and diversification of sex-determining systems in vertebrates.

Animals↗

PubMed2001

A comparative genomics approach to prediction of new members of regulons.

Identifying the complete transcriptional regulatory network for an organism is a major challenge. For each regulatory protein, we want to know all the genes it regulates, that is, its regulon. Examples of known binding sites can be used to estimate the binding specificity of the protein and to predict other binding sites. However, binding site predictions can be unreliable because determining the true specificity of the protein is difficult because of the considerable variability of binding sites. Because regulatory systems tend to be conserved through evolution, we can use comparisons between species to increase the reliability of binding site predictions. In this article, an approach is presented to evaluate the computational predictions of regulatory sites. We combine the prediction of transcription units having orthologous genes with the prediction of transcription factor binding sites based on probabilistic models. We augment the sets of genes in Escherichia coli that are expected to be regulated by two transcription factors, the cAMP receptor protein and the fumarate and nitrate reduction regulatory protein, through a comparison with the Haemophilus influenzae genome. At the same time, we learned more about the regulatory networks of H. influenzae, a species with much less experimental knowledge than E. coli. By studying orthologous genes subject to regulation by the same transcription factor, we also gained understanding of the evolution of the entire regulatory systems.

Amino Acid Sequence↗

PubMed1999

Developmental competence of the gut endoderm: genetic potentiation by GATA and HNF3/fork head proteins.

A long-standing problem in developmental biology has been to understand how the embryonic germ layers gain the competence to differentiate into distinct cell types. Genetic studies have shown that members of the GATA and HNF3/fork head transcription factor families are essential for the formation and differentiation of gut endoderm tissues in worms, flies, and mammals. Recent in vivo footprinting studies have shown that GATA and HNF3 binding sites in chromatin are occupied on a silent gene in endoderm that has the potential to be activated solely in that germ layer. These and other data indicate that these evolutionarily conserved factors help impart the competence of a gene to be activated in development, a phenomenon called genetic potentiation. The mechanistic implications of genetic potentiation and its general significance are discussed.

Animals↗

PubMed2005

Genetic interactions due to constitutive and inducible gene regulation mediated by the unfolded protein response in C. elegans.

The unfolded protein response (UPR) is an adaptive signaling pathway utilized to sense and alleviate the stress of protein folding in the endoplasmic reticulum (ER). In mammals, the UPR is mediated through three proximal sensors PERK/PEK, IRE1, and ATF6. PERK/PEK is a protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 to inhibit protein synthesis. Activation of IRE1 induces splicing of XBP1 mRNA to produce a potent transcription factor. ATF6 is a transmembrane transcription factor that is activated by cleavage upon ER stress. We show that in Caenorhabditis elegans, deletion of either ire-1 or xbp-1 is synthetically lethal with deletion of either atf-6 or pek-1, both producing a developmental arrest at larval stage 2. Therefore, in C. elegans, atf-6 acts synergistically with pek-1 to complement the developmental requirement for ire-1 and xbp-1. Microarray analysis identified inducible UPR (i-UPR) genes, as well as numerous constitutive UPR (c-UPR) genes that require the ER stress transducers during normal development. Although ire-1 and xbp-1 together regulate transcription of most i-UPR genes, they are each required for expression of nonoverlapping sets of c-UPR genes, suggesting that they have distinct functions. Intriguingly, C. elegans atf-6 regulates few i-UPR genes following ER stress, but is required for the expression of many c-UPR genes, indicating its importance during development and homeostasis. In contrast, pek-1 is required for induction of approximately 23% of i-UPR genes but is dispensable for the c-UPR. As pek-1 and atf-6 mainly act through sets of nonoverlapping targets that are different from ire-1 and xbp-1 targets, at least two coordinated responses are required to alleviate ER stress by distinct mechanisms. Finally, our array study identified the liver-specific transcription factor CREBh as a novel UPR gene conserved during metazoan evolution.

Activating Transcription Factor 6↗

PubMed2001

Proteasome inhibition induces nuclear translocation and transcriptional activation of the dioxin receptor in mouse embryo primary fibroblasts in the absence of xenobiotics.

The aryl hydrocarbon receptor (AHR) is a transcription factor that is highly conserved during evolution and shares important structural features with the Drosophila developmental regulators Sim and Per. Although much is known about the mechanism of AHR activation by xenobiotics, little information is available regarding its activation by endogenous stimuli in the absence of exogenous ligand. In this study, using embryonic primary fibroblasts, we have analyzed the role of proteasome inhibition on AHR transcriptional activation in the absence of xenobiotics. Proteasome inhibition markedly reduced cytosolic AHR without affecting its total cellular content. Cytosolic AHR depletion was the result of receptor translocation into the nuclear compartment, as shown by transient transfection of a green fluorescent protein-tagged AHR and by immunoblot analysis of nuclear extracts. Gel retardation experiments showed that proteasome inhibition induced transcriptionally active AHR-ARNT heterodimers able to bind to a consensus xenobiotic-responsive element. Furthermore, nuclear AHR was transcriptionally active in vivo, as shown by the induction of the endogenous target gene CYP1A2. Synchronized to AHR activation, proteasome inhibition also induced a transient increase in AHR nuclear translocator (ARNT) at the protein and mRNA levels. Since nuclear levels of AHR and ARNT are relevant for AHR transcriptional activation, our data suggest that proteasome inhibition, through a transient increase in ARNT expression, could promote AHR stabilization and accumulation into the nuclear compartment. An elevated content of nuclear AHR could favor AHR-ARNT heterodimers able to bind to xenobiotic-responsive elements and to induce gene transcription in the absence of xenobiotics. Thus, depending on the cellular context, physiologically regulated proteasome activity could participate in the control of endogenous AHR functions.

3T3 Cells↗

PubMed2004

Nuclear receptors: the evolution of diversity.

Nuclear receptors are an ancient family of transcription factors. Some receptors are regulated by small lipophilic ligands, whereas others are constitutive transcriptional activators or repressors. The evolution of this diversity is poorly understood, and it remains an open question as to whether or not the ancestral receptor was ligand-regulated. The recent cloning, from a snail, of an estrogen receptor that does not bind estrogen not only suggests that the steroid receptors are much more ancient than previous thought, but also points toward a mechanism through which nuclear receptors can lose the ability to be ligand regulated.

Amino Acid Sequence↗

PubMed2006

A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span.

Oxidative stress influences cell survival and homeostasis, but the mechanisms underlying the biological effects of oxidative stress remain to be elucidated. Here, we demonstrate that the protein kinase MST1 mediates oxidative-stress-induced cell death in primary mammalian neurons by directly activating the FOXO transcription factors. MST1 phosphorylates FOXO proteins at a conserved site within the forkhead domain that disrupts their interaction with 14-3-3 proteins, promotes FOXO nuclear translocation, and thereby induces cell death in neurons. We also extend the MST-FOXO signaling link to nematodes. Knockdown of the C. elegans MST1 ortholog CST-1 shortens life span and accelerates tissue aging, while overexpression of cst-1 promotes life span and delays aging. The cst-1-induced life-span extension occurs in a daf-16-dependent manner. The identification of the FOXO transcription factors as major and evolutionarily conserved targets of MST1 suggests that MST kinases play important roles in diverse biological processes including cellular responses to oxidative stress and longevity.

14-3-3 Proteins↗

PubMed2004

Evolution of human IgH3'EC duplicated structures: both enhancers HS1,2 are polymorphic with variation of transcription factor's consensus sites.

The enhancer complex regulatory region at the 3' of the immunoglobulin heavy cluster (IgH3'EC) is duplicated in apes along with four constant genes and the region is highly conserved throughout humans. Both human IgH3'ECs consist of three loci high sensitive (HS) to DNAse I with enhancer activity. It is thus possible that the presence of structural divergences between the two IgH3'ECs and of relative polymorphisms correspond to functional regulatory changes. To analyse the polymorphisms of these almost identical regions, it resulted mandatory to identify the presence of divergent sequences, in order to select distinctive primers for specific PCR genomic amplifications. To this aim, we first compared the two entire IgH3'ECs in silicio, utilising the updated GenBank (GB) contigs, then we analysed the two IgH3'ECs by cloning and sequencing amplicons from independent genomes. In silicio analysis showed that several inversions, deletions and short insertions had occurred after the duplication. We analysed in detail, by sequencing specific regions, the polymorphisms occurring in enhancer HS1,2-A (which lies in IgH3'EC-1, 3' to the Calpha-1 gene) and in enhancer HS1,2-B (which lies in IgH3'EC-2, 3' to Calpha-2). Polymorphisms are due to the repetition (occurring one to four times) of a 38-bp sequence present at the 3' of the core of enhancers HS1,2. The structure of both human HS1,2 enhancers has revealed not yet described polymorphic features due to the presence of variable spacer elements separating the 38-bp repetitions and to variable external elements bordering the repetition cluster. We found that one of the external elements gave rise to a divergent allele 3 in the two clusters. The frequency of the different alleles of the two loci varies in the Italian population and allele 3 of both loci are very rare. The analysis of the Callicebus moloch, Gorilla gorilla and Pan troglodytes HS1,2 enhancers showed the transformation from the ancestral structure with the 31- to the 17-bp external element in hominids. The relevance of the polymorphisms in the HS1,2 enhancers is due to the variable number of binding sites for the transcription factors: NF-kappaB, CMYB, BSAP1/2, AP1/4, E47, MyoD and muE5 and thus to the possible influence of these variations on switch, production of Ig and on maturation of B cells.

Animals↗

PubMed1997

A transcriptional modification motif encoded by homeobox and fork head genes.

Homeodomain and fork head domain proteins are thought to act as transcription factors by binding to specific DNA target sequences and interacting with other proteins. Here I describe a motif which is present in members of both groups of transcription factor and which has been shown to modulate their ability to activate transcription. The presence of this motif in both homeodomain and fork head proteins indicates they may control transcription by a similar molecular mechanism, perhaps by interacting with the same cofactors.

Amino Acid Sequence↗

PubMed2005

Neutral evolution of the nonbinding region of the anthocyanin regulatory gene Ipmyb1 in Ipomoea.

Plant transcription factors often contain domains that evolve very rapidly. Although it has been suggested that this rapid evolution may contribute substantially to phenotypic differentiation among species, this suggestion has seldom been tested explicitly. We tested the validity of this hypothesis by examining the rapidly evolving non-DNA-binding region of an R2R3-myb transcription factor that regulates anthocyanin expression in flowers of the genus Ipomoea. We first provide evidence that the W locus in Ipomoea purpurea, which determines whether flowers will be pigmented or white, corresponds to a myb gene segregating in southeastern U.S. populations for one functional allele and one nonfunctional allele. While the binding domain exhibits substantial selective constraint, the nonbinding region evolves at an average K(a)/K(s) ratio of 0.74. This elevated rate of evolution is due to relaxed constraint rather than to increased levels of positive selection. Despite this relaxed constraint, however, approximately 20-25% of the codons, randomly distributed throughout the nonbinding region, are highly constrained, with the remainder evolving neutrally, indicating that the entire region performs important function(s). Our results provide little indication that rapid evolution in this regulatory gene is driven by natural selection or that it is responsible for floral-color differences among Ipomoea species.

Alleles↗

PubMed1998

Evolution of the dystrophin muscular promoter and 5' flanking region in primates.

About 1.6 kb of the noncoding region upstream of the muscular dystrophin gene was sequenced in human and other primates. The alignment showed the existence of many stretches of conserved sequences among the compared species distributed all along the investigated fragment, including the 5' end. In correspondence to these conserved boxes, we identified several new putative cis-acting elements that have similarity to known control regions of other muscle-specific genes. In some cases, however, the conserved sequences did not correspond to any known transcription factor binding sites. The rate of evolution estimated site by site all along the investigated region revealed a nonhomogeneous distribution of the substitution rate, several sequences exhibited a very slow rate of evolution suggesting that evolutionary forces of different nature may be at work. On the basis of the sequence alignment, we reconstructed the phylogenetic relationships within the hominoid lineage. In addition, we estimated the relative rate of evolution between hominoid and Old World monkeys, confirming the existence of an evolutionary slowdown in the hominoid lineage.

Animals↗

PubMed1998

[Differentiating the activity of anticancer drugs: the role of transcription factors].

The understanding of the mechanisms responsible for the emergence and evolution of cancers has been in constant progress due to advances in molecular biology. Today it allows to conceive therapeutic alternatives to conventional cytotoxic chemotherapy. Among these, differentiation strategy, which aims at reinducing tumour cells towards a normal phenotype, has known a first clinical application with the use of retinoic acid in acute promyelocytic leukemias. Anthracyclines, traditionally employed in cytotoxic chemotherapy, present also a high potential of differentiation. Their mode of action takes place via the activation of transcription factors, which are proteins that are able to modulate the expression of genes by fixing to regulatory sequences of DNA. These observations therefore allow us to foresee a new pharmacology based on transcription factors for the treatment of cancers.

Animals↗

PubMed1992

Conservation of binding site specificity of three yeast DNA binding proteins.

Sequence specific binding of protein extracts from 13 different yeast species to three oligonucleotide probes and two points mutants derived from Saccharomyces cerevisiae DNA binding proteins were tested using mobility shift assays. The probes were high affinity binding sites for GRF1/RAP1/ABF1 and CP1/CPF1. Most yeasts in the genus Saccharomyces showed specific binding to all three probes and also displayed similar sequence requirements when challenged by molar excesses of mutant probes. The affinities for the probes varied amongst the other yeasts tested, but in general, CPF1 binding activity was the most widespread, while the other two were more limited.

Basic Helix-Loop-Helix Leucine Zipper Transcriptio↗