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PubMed2001

Molecular evolution of the homeodomain family of transcription factors.

The homeodomain family of transcription factors plays a fundamental role in a diverse set of functions that include body plan specification, pattern formation and cell fate determination during metazoan development. Members of this family are characterized by a helix-turn-helix DNA-binding motif known as the homeodomain. Homeodomain proteins regulate various cellular processes by specifically binding to the transcriptional control region of a target gene. These proteins have been conserved across a diverse range of species, from yeast to human. A number of inherited human disorders are caused by mutations in homeodomain-containing proteins. In this study, we present an evolutionary classification of 129 human homeodomain proteins. Phylogenetic analysis of these proteins, whose sequences were aligned based on the three-dimensional structure of the homeodomain, was performed using a distance matrix approach. The homeodomain proteins segregate into six distinct classes, and this classification is consistent with the known functional and structural characteristics of these proteins. An ancestral sequence signature that accurately describes the unique sequence characteristics of each of these classes has been derived. The phylogenetic analysis, coupled with the chromosomal localization of these genes, provides powerful clues as to how each of these classes arose from the ancestral homeodomain.

Amino Acid Sequence↗
PubMed1994

Molecular evolution of the MyoD family of transcription factors.

Myogenesis in skeletal muscle is a cascade of developmental events whose initiation involves the MyoD family of transcription factors. Evolutionary analyses of amino acid sequences of this family of transcriptional activators suggest that the vertebrate genes MyoD1, myf-5, Myog (myogenin), and myf-6 were derived by gene duplications from a single ancestral gene. A common genetic origin predicts some functional redundancy between MyoD1 and myf-5 and between Myog and myf-6. Experimental studies have suggested that these pairs of genes can substitute for each other during myogenesis. Separate analyses of the conserved basic helix-loop-helix and nonconserved flanking elements yield similar branching sequences but show evolutionary change in the basic helix-loop-helix region has occurred at a much slower rate.

Animals↗
PubMed2000

Formation of regulator/target gene relationships during evolution.

The Foxn1-like forkhead/winged-helix transcription factor genes have been maintained in single copy throughout chordate evolution. Among other functions, Foxn1 (formerly known as Whn) regulates the expression of hair keratin genes in the hair follicle, which represents an evolutionarily novel organ characteristic of mammals. We show here that fish and mouse Foxn1-like genes are functionally equivalent in hair keratin gene activation, suggesting the absence of functionally relevant changes over the course of several hundred million years of vertebrate evolution. In contrast, the Foxn1-like gene from the cephalochordate Branchiostoma lanceolatum is inactive in this assay because of changes in the region located N-terminal to DNA binding and transcriptional activation domains of the protein. Our results indicate that functionally relevant changes in cis-regulatory regions are not necessarily accompanied by corresponding changes in transcription factor proteins in the formation of evolutionarily novel regulator/target gene relationships.

Amino Acid Sequence↗
PubMed2006

Directed evolution of plant basic helix-loop-helix transcription factors for the improvement of transactivational properties.

Myc-RP from Perilla frutescens and Delila from Antirrhinum majus, two plant basic helix-loop-helix transcription factors (bHLH TFs) involved in the flavonoid biosynthetic pathway, have been used for the improvement of transactivational properties by directed evolution. Through two rounds of DNA shuffling, Myc-RP variants with up to 70-fold increase in transcriptional activities have been identified using a yeast transactivation system. In a tobacco protoplast transient expression assay, one of the most improved variants, M2-1, also shows significant increase of transactivation. The majority of resulting mutations (approximately 53%) are localized in the acidic (activation) domains of the improved Myc-RP variants. In variant M2-1, three of the four mutations (L301P/N354D/S401F) are in the acidic domain. The fourth mutation (K157M) is localized to a helix within the N-terminal interaction domain. Combinatorial site-directed mutagenesis reveals that, while the acidic domain mutations contribute modestly to the increase in activity, the K157M substitution is responsible for 80% of the improvement observed in variant M2-1. The transactivation activity of the K157M/N354D double mutant is equal to that of M2-1. These results suggest that the interaction domain plays a critical role in transactivation of these bHLH TFs. Delila variants have also been screened for increased activities toward the Arabidopsis chalcone synthase (CHS) promoter, a pathway promoter that responds weakly to the bHLH TFs. Variants with increased activity on the CHS promoter, while maintaining wildtype-level activities on the naturally responsive dihydroflavonol reductase promoter, have been obtained. This study demonstrates that functional properties of TFs can be modified by directed evolution.

Acyltransferases↗
PubMed2005

Discovery of the principal specific transcription factors of Apicomplexa and their implication for the evolution of the AP2-integrase DNA binding domains.

The comparative genomics of apicomplexans, such as the malarial parasite Plasmodium, the cattle parasite Theileria and the emerging human parasite Cryptosporidium, have suggested an unexpected paucity of specific transcription factors (TFs) with DNA binding domains that are closely related to those found in the major families of TFs from other eukaryotes. This apparent lack of specific TFs is paradoxical, given that the apicomplexans show a complex developmental cycle in one or more hosts and a reproducible pattern of differential gene expression in course of this cycle. Using sensitive sequence profile searches, we show that the apicomplexans possess a lineage-specific expansion of a novel family of proteins with a version of the AP2 (Apetala2)-integrase DNA binding domain, which is present in numerous plant TFs. About 20-27 members of this apicomplexan AP2 (ApiAP2) family are encoded in different apicomplexan genomes, with each protein containing one to four copies of the AP2 DNA binding domain. Using gene expression data from Plasmodium falciparum, we show that guilds of ApiAP2 genes are expressed in different stages of intraerythrocytic development. By analogy to the plant AP2 proteins and based on the expression patterns, we predict that the ApiAP2 proteins are likely to function as previously unknown specific TFs in the apicomplexans and regulate the progression of their developmental cycle. In addition to the ApiAP2 family, we also identified two other novel families of AP2 DNA binding domains in bacteria and transposons. Using structure similarity searches, we also identified divergent versions of the AP2-integrase DNA binding domain fold in the DNA binding region of the PI-SceI homing endonuclease and the C-terminal domain of the pleckstrin homology (PH) domain-like modules of eukaryotes. Integrating these findings, we present a reconstruction of the evolutionary scenario of the AP2-integrase DNA binding domain fold, which suggests that it underwent multiple independent combinations with different types of mobile endonucleases or recombinases. It appears that the eukaryotic versions have emerged from versions of the domain associated with mobile elements, followed by independent lineage-specific expansions, which accompanied their recruitment to transcription regulation functions.

Amino Acid Sequence↗
PubMed2001

Rapid evolution of cis-regulatory sequences via local point mutations.

Although the evolution of protein-coding sequences within genomes is well understood, the same cannot be said of the cis-regulatory regions that control transcription. Yet, changes in gene expression are likely to constitute an important component of phenotypic evolution. We simulated the evolution of new transcription factor binding sites via local point mutations. The results indicate that new binding sites appear and become fixed within populations on microevolutionary timescales under an assumption of neutral evolution. Even combinations of two new binding sites evolve very quickly. We predict that local point mutations continually generate considerable genetic variation that is capable of altering gene expression.

Animals↗
PubMed1990

Characterization of chicken octamer-binding proteins demonstrates that POU domain-containing homeobox transcription factors have been highly conserved during vertebrate evolution.

The DNA sequence motif ATTTGCAT (octamer) or its inverse complement has been identified as an evolutionarily conserved element in the promoter region of immunoglobulin genes. Two major DNA-binding proteins that bind in a sequence-specific manner to the octamer DNA sequence have been identified in mammalian species--a ubiquitously expressed protein (Oct-1) and a lymphoid-specific protein (Oct-2). During characterization of the promoter region of the chicken immunoglobulin light chain gene, we identified two homologous octamer-binding proteins in chicken B cells. When the cloning of the human gene for Oct-2 revealed it to be a member of a distinct family of homeobox genes, we sought to determine if the human Oct-2 cDNA could be used to identify homologous chicken homeobox genes. Using a human Oct-2 homeobox-specific DNA probe, we were able to identify 6-10 homeobox-containing genes in the chicken genome, demonstrating that the Oct-2-related subfamily of homeobox genes exists in avian species. Low-stringency screening of a chicken embryonic cDNA library allowed us to clone one of these genes. DNA sequence analysis revealed it to be the chicken homologue of the human Oct-1 gene. The predicted protein sequence of the chicken Oct-1 gene demonstrated that the gene for Oct-1 has been highly conserved during vertebrate evolution with an overall 96% amino acid sequence identity between the chicken and human proteins. The previously described POU domain (termed POU for its presence in the Pit-1, Oct-1/Oct-2, and Unc-86 genes) and homeobox domain are 100% conserved between the two protein products. Together, our data show that the POU-containing subfamily of homeobox genes have been highly conserved during vertebrate evolution, apparently as a result of selection for their DNA-binding and transcriptional regulatory properties.

Amino Acid Sequence↗
PubMed2006

Across-tissue expression and evolution of genes controlled by the Aire transcription factor.

Aire (autoimmune regulatory protein) enhances expression of certain genes in thymic medullary epithelial cells (MECs). Using publicly available data, we examined expression patterns, across 82 distinct tissue types, of genes previously identified as Aire-activated, Aire-repressed, and Aire-independent. Consistent with the hypothesis that the effect of Aire in MECs is to increase expression of tissue-specific genes, Aire-activated genes had a low overall level of expression but a large range between the lowest and the highest levels of expression in different tissues. By contrast, Aire-repressed genes tended to have a high overall level of expression and less marked differences between the highest and the lowest levels of expression. Nonetheless, the expression scores of Aire-repressed genes showed broader ranges of values than those of Aire-independent genes. Phylogenetic analyses of members of two gene families that included two Aire-activated genes illustrated two contrasting patterns of the relationship of Aire-activated genes within the same family. The two Aire-activated members of the major urinary protein family arose through a recent gene duplication (after the rat-mouse divergence), whereas the most recent common ancestor of the two Aire-activated members of cytochrome p450 family 2 duplicated prior to the radiation of the eutherian orders. In the latter family, the Aire-activated Cyp2a4 gene and the Aire-independent Cyp2a5 gene arose through a recent duplication, after the rat-mouse divergence. Thus the set of Aire-activated genes is subject to change over evolutionary time and includes genes of recent origin.

Animals↗
PubMed2005

Cardiac transcription factor Csx/Nkx2-5: Its role in cardiac development and diseases.

During the past decade, an emerging body of evidence has accumulated that cardiac transcription factors control a cardiac gene program and play a critical role in transcriptional regulation during cardiogenesis and during the adaptive process in adult hearts. Especially, an evolutionally conserved homeobox transcription factor Csx/Nkx2-5 has been in the forefront in the field of cardiac biology, providing molecular insights into the mechanisms of cardiac development and diseases. Csx/Nkx2-5 is indispensable for normal cardiac development, and mutations of the gene are associated with human congenital heart diseases (CHD). In the present review, the regulation of a cardiac gene program by Csx/Nkx2-5 is summarized, with an emphasis on its role in the cardiac development and diseases.

Animals↗
PubMed1998

Multifunctional lens crystallins and corneal enzymes. More than meets the eye.

The abundant water-soluble proteins, called crystallins, of the transparent, refractive eye lens have been recruited from metabolic enzymes and stress-protective proteins by a process called "gene sharing." Many crystallins are also present at lower concentration in nonocular tissues where they have nonrefractive roles. The complex expression pattern of the mouse alpha B-crystallin/small heat shock protein gene is developmentally controlled at the transcriptional level by a combinatorial use of shared and lens-specific regulatory elements. A number of crystallin genes, including that for alpha B-crystallin, are activated by Pax-6, a conserved transcription factor for eye evolution. Aldehyde dehydrogenase class 3 and transketolase are metabolic enzymes comprising extremely high proportions of the water-soluble proteins of the cornea and may have structural as well as enzymatic roles, reminiscent of lens enzyme-crystallins. Inductive processes appear to be important for the corneal-preferred expression of these enzymes. The use of the same protein for entirely different functions by a gene-sharing mechanism may be a general strategy based on evolutionary tinkering at the level of gene regulation.

Animals↗
PubMed2025

Evolution of promoter-proximal pausing enabled a new layer of transcription control.

Promoter-proximal pausing of RNA polymerase (Pol) II is a key regulatory step during transcription. Despite the central role of pausing in gene regulation, we do not understand the evolutionary processes that led to the emergence of Pol II pausing or its transition to a rate-limiting step actively controlled by transcription factors. Here, we analyzed transcription in species across the tree of life. Unicellular eukaryotes display an accumulation of Pol II near transcription start sites, which we propose transitioned to the longer-lived, focused pause observed in metazoans. This transition coincided with the evolution of new subunits in the negative elongation factor (NELF) and 7SK complexes. Depletion of NELF in mammals shifted the promoter-proximal buildup of Pol II from the pause site into the early gene body and compromised transcriptional activation for a set of heat-shock genes. Our work details the evolutionary history of Pol II pausing and sheds light on how new transcriptional regulatory mechanisms evolve.

RNA Polymerase II↗
PubMed2001

Eye specification in Drosophila: perspectives and implications.

The discovery that Drosophila eyeless is homologous to vertebrate Pax6 produced enormous interest in eye specification and a reappraisal of eye evolution. While the transcription factor Eyeless/Pax6 is necessary and in some circumstances sufficient to induce eye development the simple story of eye specification has become more epic than haiku. At least seven other nuclear proteins act with Eyeless/Pax6 to induce the eye and, furthermore, extrinsic developmental signals are required. Some striking similarities between later events of retinal patterning in vertebrates and insects have led to a deeper debate on the evolutionary path to these apparently quite different organs.

Animals↗
PubMed2003

Turnover of binding sites for transcription factors involved in early Drosophila development.

Despite the importance of cis-regulatory regions in evolution, little is know about their evolutionary dynamics. In this report, we analyze the process of evolution of binding sites for transcription factors using as a model a well characterized system, the Drosophila early developmental enhancers. We compare the sequences of eight enhancer regions for early developmental genes between Drosophila melanogaster and other two species, Drosophila virilis and Drosophila pseudoobscura, searching for the presence/absence of 104 biochemically verified binding sites from D. melanogaster. We also modeled the binding specificity of each binding site by the use of well-defined positional weight matrices (PWMs). The comparisons showed that turnover of binding sites seems to fit a molecular clock, at an approximate rate of 0.94% of gain/loss of binding sites per million years. This intense turnover affects both high and low affinity binding sites at the same extent. Furthermore, the subset of overlapping binding sites is also subjected to this high turnover. Conserved binding sites seem to be constrained to maintain not only location but also the exact sequence at each particular position. Finally, we detected a significant decrease in mean PWM scores for the D. virilis binding sites in the case of Hunchback. Possible explanations for this fact are discussed.

Animals↗
PubMed2005

Evolutionary population genetics of promoters: predicting binding sites and functional phylogenies.

We study the evolution of transcription factor-binding sites in prokaryotes, using an empirically grounded model with point mutations and genetic drift. Selection acts on the site sequence via its binding affinity to the corresponding transcription factor. Calibrating the model with populations of functional binding sites, we verify this form of selection and show that typical sites are under substantial selection pressure for functionality: for cAMP response protein sites in Escherichia coli, the product of fitness difference and effective population size takes values 2NDeltaF of order 10. We apply this model to cross-species comparisons of binding sites in bacteria and obtain a prediction method for binding sites that uses evolutionary information in a quantitative way. At the same time, this method predicts the functional histories of orthologous sites in a phylogeny, evaluating the likelihood for conservation or loss or gain of function during evolution. We have performed, as an example, a cross-species analysis of E. coli, Salmonella typhimurium, and Yersinia pseudotuberculosis. Detailed lists of predicted sites and their functional phylogenies are available.

Bacteria↗
PubMed2000

Regulatory evolution and the origin of the bilaterians.

The adult body plan of bilaterians is achieved by imposing regional specifications on pluripotential cells. The establishment of spatial domains is governed in part by regulating expression of transcription factors. The key to understanding bilaterian evolution is contingent on our understanding of how the regulation of these transcription factors influenced bilaterian stem-group evolution.

Animals↗
PubMed1992

Embryonal long terminal repeat-binding protein is a murine homolog of FTZ-F1, a member of the steroid receptor superfamily.

The embryonal long terminal repeat-binding protein, ELP, is present in undifferentiated mouse embryonal carcinoma cells. It binds to and suppresses transcription of the Moloney leukemia virus long terminal repeat in undifferentiated murine embryonal carcinoma cells. We report here that ELP is a mouse homolog of Drosophila FTZ-F1, which positively regulates transcription of the fushi tarazu gene in blastoderm-stage embryos of the fly. As members of the steroid receptor superfamily, ELP and FTZ-F1 have both DNA binding and putative ligand binding domains which are well conserved between the two. ELP and FTZ-F1 function in cells in the extremely early stage of development. A high degree of conservation between the two transcription factors during the evolution of these species indicates the importance of their functions in early-stage embryogenesis. In addition, the sequence elements they recognize do not contain repeat units, in contrast to other steroid receptors, which usually bind to either palindromic or direct repeat sequences.

Amino Acid Sequence↗
PubMed2000

dlarp, a new candidate Hox target in Drosophila whose orthologue in mouse is expressed at sites of epithelium/mesenchymal interactions.

Hox complex genes are key developmental regulators highly conserved throughout evolution. They encode transcription factors that initiate genetic programs of diversified morphogenesis along the anteroposterior embryonic axis. We report the characterization of the novel Drosophila Hox target gene dlarp, isolated from a further screen of a previously described library of genomic DNA fragments associated in vivo with Ultrabithorax proteins. The dlarp spatio-temporal pattern of transcription in wild-type and homeotic mutant embryos is consistent with a positive regulation by Sex combs reduced and Ultrabithorax in the parasegment 2 ectoderm and the abdominal mesoderm, respectively. The teashirt gene product, thought to act in concert with Hox proteins, is also required for the transcriptional control of this target. Search in databases revealed that dlarp has been highly conserved during evolution. The embryonic expression pattern of the mouse orthologue does not support a function downstream of Hox proteins. It is mainly transcribed in neural structures and in developing organs characterized by epithelial-mesenchymal interactions.

Amino Acid Sequence↗