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PubMed2006

Neofunctionalization in vertebrates: the example of retinoic acid receptors.

Understanding the role of gene duplications in establishing vertebrate innovations is one of the main challenges of Evo-Devo (evolution of development) studies. Data on evolutionary changes in gene expression (i.e., evolution of transcription factor-cis-regulatory elements relationships) tell only part of the story; protein function, best studied by biochemical and functional assays, can also change. In this study, we have investigated how gene duplication has affected both the expression and the ligand-binding specificity of retinoic acid receptors (RARs), which play a major role in chordate embryonic development. Mammals have three paralogous RAR genes--RAR alpha, beta, and gamma--which resulted from genome duplications at the origin of vertebrates. By using pharmacological ligands selective for specific paralogues, we have studied the ligand-binding capacities of RARs from diverse chordates species. We have found that RAR beta-like binding selectivity is a synapomorphy of all chordate RARs, including a reconstructed synthetic RAR representing the receptor present in the ancestor of chordates. Moreover, comparison of expression patterns of the cephalochordate amphioxus and the vertebrates suggests that, of all the RARs, RAR beta expression has remained most similar to that of the ancestral RAR. On the basis of these results together, we suggest that while RAR beta kept the ancestral RAR role, RAR alpha and RAR gamma diverged both in ligand-binding capacity and in expression patterns. We thus suggest that neofunctionalization occurred at both the expression and the functional levels to shape RAR roles during development in vertebrates.

Amino Acid Sequence↗

PubMed2006

NFATc1 autoregulation: a crucial step for cell-fate determination.

Nuclear factor of activated T cell c (NFATc) transcription factors appeared in evolution with the emergence of lymphocytes in jawed fish. They have decisive roles in the development of the immune system and adaptive immune responses. Following immunoreceptor stimulation, NFAT factors control the expression of a large set of genes and thereby the fate of peripheral lymphocytes. NFATc1 and NFATc2 are the most prominent NFAT factors in peripheral T cells; they overlap in their function but differ remarkably in the mode of expression. NFATc2 is constitutively synthesized in T cells, whereas the expression of NFATc1/alphaA, the most prominent of six NFATc1 isoforms in peripheral T cells, is strongly induced following T-cell receptor and co-receptor stimulation and maintained by positive autoregulation. Findings concerning NFATc1 autoregulation in peripheral T lymphocytes and other cells suggest that positive autoregulation of NFATc1 is a crucial step in cell-fate determination.

Amino Acid Sequence↗

PubMed2004

A global view of the selection forces in the evolution of yeast cis-regulation.

The interaction between transcription factors and their DNA binding sites is key to understanding gene regulation. By performing a genome-wide study of the evolutionary dynamics in yeast promoters, we provide a first global view of the network of selection forces in the evolution of transcription factor binding sites. This analysis gives rise to new models for binding site activity, identifies families of related binding sites, and characterizes the functional similarities among them. We discovered rich and highly optimized selective pressures operating inside and around these families. In several cases, this organization reveals that a single transcription factor has multiple functional modes. We demonstrate how such functional heterogeneity is related to the binding site's affinity and how it is exploited in transcription programs.

Binding Sites↗

PubMed2006

The motor circuit.

Caenorhabditis elegans motor neurons control a range of activities including locomotion, foraging, defecation, and gender-specific functions. In this chapter,we focus primarily on motor neurons that regulate body movement, with particular emphasis on those in the ventral nerve cord (VNC). We describe the basic architecture and development of the motor circuit, genes that specify motor neuron fates, and models of how the motor circuit controls locomotion. We identify surprising similarities between the structure and development of the nematode and vertebrate axial nerve cords and speculate about the potential roles of conserved families of transcription factors in the evolution of these motor circuits.

Animals↗

PubMed1996

A network of specific minor-groove contacts is a common characteristic of paired-domain-DNA interactions.

Pax proteins are a family of transcription factors conserved during evolution and able to bind specific DNA sequences through a domain called a "paired domain'. The DNA-binding specificity of the Pax-8 paired domain was investigated. Site-selection experiments indicate that Pax-8 binds to a consensus sequence similar to those bound by Pax-2 and Pax-5. When consensus sequences of various paired domains are observed in light of recent structural studies describing paired-domain-DNA interaction [Xu, Rould, Jun, Desplan and Pabo (1995) Cell 80, 639-650], it appears that base-pairs contacted in the minor groove are conserved, while most of the base-pairs contacted in the major groove are not. Therefore a network of specific minor groove contacts is a common characteristic of paired-domain-DNA interactions. The functional importance of such a network was successfully tested by analysing the effect of consensus-based mutations on the Pax-8 binding site of the thyroglobulin promoter.

Animals↗

PubMed2003

Mouse Snail family transcription repressors regulate chondrocyte, extracellular matrix, type II collagen, and aggrecan.

Snail family genes are conserved among species during evolution and encode transcription factors expressed at different stages of development in different tissues. These genes are involved in a broad spectrum of biological functions: cell differentiation, cell motility, cell cycle regulation, and apoptosis. However, little is known about the target genes involved in these functions. Here we show that mouse Snail family members, Snail (Sna) and Slug (Slugh), are involved in chondrocyte differentiation by controlling the expression of type II collagen (Col2a1) and aggrecan. In situ hybridization analysis of developing mouse limb demonstrated that Snail and Slug mRNAs were highly expressed in hypertrophic chondrocytes. Inversely, the expression of collagen type II mRNA disappeared during hypertrophic differentiation. Snail and Slug mRNA expression was down-regulated during differentiation of the mouse chondrogenic cell line ATDC5 and overexpression of exogenous Snail or Slug in ATDC5 cells inhibited expression of collagen type II and aggrecan mRNA. Reporter analysis revealed Snail and Slug suppressed the promoter activity of Col2a1, and the E-boxes in the promoter region were the responsible element. Gel shift assay demonstrated the binding of Snail to the E-box. Because type II collagen and aggrecan are major functional components of extracellular matrix in cartilage, these results suggest an important role for Snail-related transcription repressors during chondrocyte differentiation.

Aggrecans↗

PubMed2001

Evolution of hematopoiesis: Three members of the PU.1 transcription factor family in a cartilaginous fish, Raja eglanteria.

T lymphocytes and B lymphocytes are present in jawed vertebrates, including cartilaginous fishes, but not in jawless vertebrates or invertebrates. The origins of these lineages may be understood in terms of evolutionary changes in the structure and regulation of transcription factors that control lymphocyte development, such as PU.1. The identification and characterization of three members of the PU.1 family of transcription factors in a cartilaginous fish, Raja eglanteria, are described here. Two of these genes are orthologs of mammalian PU.1 and Spi-C, respectively, whereas the third gene, Spi-D, is a different family member. In addition, a PU.1-like gene has been identified in a jawless vertebrate, Petromyzon marinus (sea lamprey). Both DNA-binding and transactivation domains are highly conserved between mammalian and skate PU.1, in marked contrast to lamprey Spi, in which similarity is evident only in the DNA-binding domain. Phylogenetic analysis of sequence data suggests that the appearance of Spi-C may predate the divergence of the jawed and jawless vertebrates and that Spi-D arose before the divergence of the cartilaginous fish from the lineage leading to the mammals. The tissue-specific expression patterns of skate PU.1 and Spi-C suggest that these genes share regulatory as well as structural properties with their mammalian orthologs.

Amino Acid Sequence↗

PubMed1994

Evolution of distinct DNA-binding specificities within the nuclear receptor family of transcription factors.

Nuclear receptors are ligand-activated transcription factors that interact with response elements within regulated genes. Most receptors, typified by the estrogen receptor, have three amino acids within the DNA-binding domain that specify recognition of the sequence TGACCT within the response element. However, in the glucocorticoid group of receptors, these residues have evolved to recognize the sequence TGTTCT. Saturation mutagenesis was used to investigate the role played by two of these residues (Gly-439 and Ser-440 of the human glucocorticoid receptor) in receptor specificity. We conclude that these residues, and their equivalents in the estrogen receptor, play roles unique to the respective amino acids. In the glucocorticoid receptor the side chain hydroxyl group is the important component of Ser-440 that contributes to specificity by inhibiting interaction with estrogen response elements. Several substitution mutants at position 439 interact well with estrogen response elements; therefore, the unique specificity feature of Glu-439, which mimics the estrogen receptor, is its inhibition of interaction with noncognate sites. In contrast to position 440, where most substitutions prevent interaction with DNA, replacements of residue 439 have the potential to contribute to the evolution of DNA-binding specificities within the nuclear receptor family. The liver-enriched HNF-4 and Drosophila Tailless transcription factors are known examples of receptors that have diverged at this position.

Amino Acid Sequence↗

PubMed2006

Oogamy: inventing the sexes.

The male-female dichotomy has evolved independently in nearly all lineages of multicellular organisms. Why this should be the case is still uncertain, but recent studies of mating-type genes in green algae open a promising new way to explore molecular-genetic aspects of the evolution of dichotomous sexes.

Algal Proteins↗

PubMed1993

Isolation of the CCAAT transcription factor subunit EFIA cDNA and a potentially functional EFIA processed pseudogene from Bos taurus: insights into the evolution of the EFIA/dbpB/YB-1 gene family.

The genomic copy multiplicity of the CCAAT transcription complex component enhancer factor I subunit A (EFIA) has been examined. When a mammalian genomic Southern blot was hybridized to a rat EFIA cDNA, a complex pattern consisting of numerous related sequences was found in all the species examined, with Bos taurus being the least complex. An EFIA#1 cDNA from Bos taurus was isolated from a primary lung endothelial cell cDNA library by screening with the 1489-bp rat EFIA cDNA. The deduced bovine EFIA#1 amino acid (aa) sequence is 98% identical to rat EFIA and 100% identical to human EFIA/DbpB/YB-1 family member DNA-binding protein B (DbpB). In addition, a processed EFIA pseudogene from Bos taurus, designated bovine psi EFIA#1, was obtained from a genomic library by screening with a rat EFIA cDNA probe. The bovine psi EFIA#1 gene has an ORF which, if expressed, would encode a 140-aa sequence, with aa 31-140 having 84% identity to bovine EFIA#1. The genomic cloning data indicate that processed pseudogenes are partially responsible for the complexity of the EFIA genomic Southern blots. The phenomenon of 'repeat induced point mutation' (ripping) at bovine psi EFIA#1 gene CpG dinucleotides occurs at a 6.5-fold higher frequency than expected from random mutagenesis. Therefore, ripping is likely to be the mechanism by which the bovine EFIA#1 pseudogene's ectopic recombination potential was inactivated.

Amino Acid Sequence↗

PubMed2004

Structure and evolution of transcriptional regulatory networks.

The regulatory interactions between transcription factors and their target genes can be conceptualised as a directed graph. At a global level, these regulatory networks display a scale-free topology, indicating the presence of regulatory hubs. At a local level, substructures such as motifs and modules can be discerned in these networks. Despite the general organisational similarity of networks across the phylogenetic spectrum, there are interesting qualitative differences among the network components, such as the transcription factors. Although the DNA-binding domains of the transcription factors encoded by a given organism are drawn from a small set of ancient conserved superfamilies, their relative abundance often shows dramatic variation among different phylogenetic groups. Large portions of these networks appear to have evolved through extensive duplication of transcription factors and targets, often with inheritance of regulatory interactions from the ancestral gene. Interactions are conserved to varying degrees among genomes. Insights from the structure and evolution of these networks can be translated into predictions and used for engineering of the regulatory networks of different organisms.

Amino Acid Motifs↗

PubMed1994

Evolutionary relationships and functional conservation among vertebrate Max-associated proteins: the zebra fish homolog of Mxi1.

In mammals, current evidence supports the view that Myc-responsive activities are regulated in part through an intracellular balance between levels of transcriptionally-active Myc/Max heterodimers and those of transcriptionally-inert Max/Max, Mad/Max and Mxi1/Max complexes. To gain insight into the roles of Mad and Mxi1 in cellular growth and differentiation and to fortify key structure-function relationships from an evolutionary standpoint, low stringency hybridization screens were used to identify potential homologs of these Max-associated proteins in the zebra fish genome. A single class of cDNA clones that cross-hybridized both to human mad and mxi1 probes was shown to encode a putative protein with significantly greater homology to mammalian Mxi1 than to Mad, particularly in the basic and helix-loop-helix (bHLH) regions. The high degree of structural relatedness between vertebrate Mxi1 proteins apparent in molecular modelling studies was consistent with the findings that the HLH/leucine zipper (LZ) region of zMxi1 exhibited the same profile of dimerization specificities as its mammalian counterpart in the two-hybrid system and that zmxi1 could, like human mxi1 (Lahoz et al., 1994), suppress the oncogenic potential of mouse c-myc in a mammalian cell. Finally, a comparison of steady-state zc-myc and zmxi1 mRNA levels during zebra fish embryogenesis demonstrated (i) high levels of zc-myc relative to zmxi1 mRNA during initiation of organogenesis, a period characterized by intense growth and active differentiation and (ii) rising levels of zmxi1 mRNA during progression towards the terminally differentiated state. These contrasting patterns of developmental expression together with the capacity of zmxi1 to repress myc-induced transformation support a model for the regulation, by Max-associated proteins, of Myc functions in the control of normal cell development and neoplastic growth.

Amino Acid Sequence↗

PubMed2003

Hypomutable regions of yeast TFIIB in a unigenic evolution test represent structural domains.

As genome sequences of many organisms - including humans - are being decoded, there is a great need for genetic tools to analyze newly discovered genes/proteins. A 'unigenic evolution' approach has been previously proposed for dissecting protein domains, which is based on the assumption that functionally important regions of a protein may tolerate missense mutations less well than other regions. We describe a unigenic evolution analysis of general transcription factor IIB (TFIIB) - a protein that is well characterized both structurally and functionally - to better understand the molecular basis of this genetic approach. The overall distribution profile of hypomutable regions within yeast TFIIB correlates extremely well with the known compact structural domains, suggesting that the unigenic evolution approach can help reveal structural properties of a protein. We further show that a small region located immediately carboxyl-terminal to the zinc ribbon motif is functionally important despite its strong hypermutability. Our study further demonstrates the usefulness of the unigenic evolution approach in dissecting protein domains, but suggests that the mutability of different regions of a protein in such a test is determined primarily by their structural properties.

Amino Acid Sequence↗

PubMed2004

Using humans to study the physiological evolution of energy metabolism: a tribute to Peter Hochachka.

Comparative physiology traditionally relies on unusual animals to explore the mechanistic basis or evolution of physiological processes. Despite his credentials as a comparative physiologist, much of the recent work by Peter Hochachka relied upon humans as "comparative" models. Technological advances in clinical analyses and expanding databases of genomic diversity have made humans a very "convenient" model to study the evolution of metabolism. For example, a growing number of metabolic diseases have been shown to have a genetic basis. Obesity, type II diabetes, metabolic syndrome X may each have linkages to polymorphisms in genes encoding transcriptional regulators of bioenergetic genes. Genetic polymorphisms and gene families for these important transcription factors inspire questions about the evolution of energy metabolism in other animals. Thus, these biomedical studies provide important direction for researchers interested in exploring the regulatory basis of interspecies variations in bioenergetics.

Biological Evolution↗

PubMed2002

The evolution of DNA regulatory regions for proteo-gamma bacteria by interspecies comparisons.

The comparison of homologous noncoding DNA for organisms a suitable evolutionary distance apart is a powerful tool for the identification of cis regulatory elements for transcription and translation and for the study of how they assemble into functional modules. We have fit the three parameters of an affine global probabilistic alignment algorithm to establish the background mutation rate of noncoding sequence between E. coli and a series of gamma proteobacteria ranging from Salmonella to Vibrio. The lower bound we find to the neutral mutation rate is sufficiently high, even for Salmonella, that most of the conservation of noncoding sequence is indicative of selective pressures rather than of insufficient time to evolve. We then use a local version of the alignment algorithm combined with our inferred background mutation rate to assign a significance to the degree of local sequence conservation between orthologous genes, and thereby deduce a probability profile for the upstream regulatory region of all E. coli protein-coding genes. We recover 75%-85% (depending on significance level) of all regulatory sites from a standard compilation for E. coli, and 66%-85% of sigma sites. We also trace the evolution of known regulatory sites and the groups associated with a given transcription factor. Furthermore, we find that approximately one-third of paralogous gene pairs in E. coli have a significant degree of correlation in their regulatory sequence. Finally, we demonstrate an inverse correlation between the rate of evolution of transcription factors and the number of genes they regulate. Our predictions are available at http://www.physics.rockefeller.edu/([tilde-see text])siggia.

Algorithms↗

PubMed2000

Overlapping expression of amphioxus homologs of the thyroid transcription factor-1 gene and thyroid peroxidase gene in the endostyle: insight into evolution of the thyroid gland.

The endostyle is a pharyngeal organ of uro- chordates, cephalochordates, and primitive vertebrates. This organ has iodine-concentrating and iodine-metabolism activities, and therefore the endostyle is considered to be homologous to the follicle of the thyroid gland. In higher vertebrates the genes for both thyroid transcription factor-1 (TTF-1) and thyroid peroxidase (TPO) are expressed in the thyroid gland follicle. TTF-1 regulates the expression of TPO, which encodes an iodinating enzyme associated with thyroid hormone synthesis. A recent study showed that the ascidian TTF-1 and TPO genes are specifically expressed in the endostyle, but that the expression domains of these genes are not overlapping, suggesting that ascidian TPO is not regulated by TTF-1. To investigate the molecular mechanisms involved in the formation and function of the endostyle, with special reference to the evolution of the follicle of the thyroid gland, I isolated and characterized cDNA clones for the amphioxus homologs of the TTF-1 gene (BbTTF-1) and TPO gene (BbTPO) from Branchiostoma belcheri. Reverse transcriptase-polymerase chain reaction/Southern blotting revealed that both amphioxus TTF-1 and TPO genes are expressed mainly in the adult endostyle. Spatial and temporal expression patterns assessed by in situ hybridization revealed that BbTTF-1 is expressed in the endodermal cells during early embryogenesis and is maintained in all zones of the adult endostyle. On the other hand, expression of BbTPO is chiefly in zones 5 and 6 of the adult endostyle where it overlaps with that of BbTTF-1, and to a lesser extent in zones 1 and 3. This restriction of the expression of BbTTF-1 and BbTPO to the endostyle strongly suggests that the endostyle is homologous to the follicle of the thyroid gland. Moreover, the spatial and temporal expression patterns of these genes suggest that TTF-1 regulates TPO expression. The coexpression of these genes in amphioxus suggests that regulation of TPO by TTF-1 was present in the common ancestor of cephalochordates (acraniates) and craniates.

Amino Acid Sequence↗

PubMed2004

ETS transcription factors: possible targets for cancer therapy.

Ets family (ETS) transcription factors, characterized by an evolutionally conserved Ets domain, play important roles in cell development, cell differentiation, cell proliferation, apoptosis and tissue remodeling. Most of them are downstream nuclear targets of Ras-MAP kinase signaling, and the deregulation of ETS genes results in the malignant transformation of cells. Several ETS genes are rearranged in human leukemia and Ewing tumors to produce chimeric oncoproteins. Furthermore, the aberrant expression of several ETS genes is often observed in various types of human malignant tumors. Considering that some ETS transcription factors are involved in malignant transformation and tumor progression, including invasion, metastasis and neo-angiogenesis through the activation of cancer-related genes, they could be potential molecular targets for selective cancer therapy.

Cell Transformation, Neoplastic↗

PubMed2004

An enigmatic fourth runt domain gene in the fugu genome: ancestral gene loss versus accelerated evolution.

BACKGROUND: The runt domain transcription factors are key regulators of developmental processes in bilaterians, involved both in cell proliferation and differentiation, and their disruption usually leads to disease. Three runt domain genes have been described in each vertebrate genome (the RUNX gene family), but only one in other chordates. Therefore, the common ancestor of vertebrates has been thought to have had a single runt domain gene. RESULTS: Analysis of the genome draft of the fugu pufferfish (Takifugu rubripes) reveals the existence of a fourth runt domain gene, FrRUNT, in addition to the orthologs of human RUNX1, RUNX2 and RUNX3. The tiny FrRUNT packs six exons and two putative promoters in just 3 kb of genomic sequence. The first exon is located within an intron of FrSUPT3H, the ortholog of human SUPT3H, and the first exon of FrSUPT3H resides within the first intron of FrRUNT. The two gene structures are therefore "interlocked". In the human genome, SUPT3H is instead interlocked with RUNX2. FrRUNT has no detectable ortholog in the genomes of mammals, birds or amphibians. We consider alternative explanations for an apparent contradiction between the phylogenetic data and the comparison of the genomic neighborhoods of human and fugu runt domain genes. We hypothesize that an ancient RUNT locus was lost in the tetrapod lineage, together with FrFSTL6, a member of a novel family of follistatin-like genes. CONCLUSIONS: Our results suggest that the runt domain family may have started expanding in chordates much earlier than previously thought, and exemplify the importance of detailed analysis of whole-genome draft sequence to provide new insights into gene evolution.

Amino Acid Sequence↗