The process of gene expression is affected by many extracellular stimulus signals, and the stochasticity of these signals reshapes gene expression. To adapt the fluctuation of the extracellular environment, genes have many strategies for augmenting their survival probability, frequency modulation, and amplitude modulation. However, it is unclear how genes utilize the stochasticity of signals to regulate gene expression and which strategy will be chosen to maximize cellular function. Here, we analyze a simple mechanistic model (...) to clarify the effect of extracellular random input on gene expression and burst kinetics at different timescales. We can see that in different contexts, extracellular noise has different effects on downstream gene expression, effects which include the following: extracellular noise will make the ON-OFF-state dwell time drift, which will influence the burst frequency and burst size of downstream gene expression under different modulation paradigms; comparing the burst parameter or gene expression products under different modulation paradigms, we can see that the amplitude signal is more sensitive in the case of extracellular noise input, whereas the signal in noiseless conditions is more sensitive when the random input is a fast process, which indicates that the amplitude signal is a superior and common signal in gene expression; and extracellular random input will change the bimodality for gene expression, but its influence is different for gene expression products under different modulation paradigms. These qualitative results reveal that extracellular random input can prompt the gene to achieve its function quickly under different modulation paradigms. (shrink)

Here I present and discuss a model that, among other things, appears able to describe the dynamics of cancer cell origin from the perspective of stable and unstable gene expression profiles. In identifying suchaberrantgene expression profiles as lying outside the normal stable states attracted through development and normal cell differentiation, the hypothesis explains why cancer cells accumulate mutations, to which they are not robust, and why these mutations create a new stable state far from the normal (...) class='Hi'>gene expression profile space. Such cells are in strong contrast with normal cell types that appeared as an attractor state in the gene expression dynamical system under cell‐cell interaction and achieved robustness to noise through evolution, which in turn also conferred robustness to mutation. In complex gene regulation networks, otheraberrantcellular states lacking such high robustness are expected to remain, which would correspond to cancer cells. (shrink)

Recent evidence indicates that transcriptional bursts are intrinsically amplified by messenger RNA cytoplasmic processing to generate large stochastic fluctuations in protein levels. These fluctuations can be exploited by cells to enable probabilistic bet‐hedging decisions. But large fluctuations in gene expression can also destabilize cell‐fate commitment. Thus, it is unclear if cells temporally switch from high to low noise, and what mechanisms enable this switch. Here, the discovery of a post‐transcriptional mechanism that attenuates noise in HIV is (...) reviewed. Early in its life cycle, HIV amplifies transcriptional fluctuations to probabilistically select alternate fates, whereas at late times, HIV utilizes a post‐transcriptional feedback mechanism to commit to a specific fate. Reanalyzing various reported post‐transcriptional negative feedback architectures reveals that they attenuate noise more efficiently than classic transcriptional autorepression, leading to the derivation of an assay to detect post‐transcriptional motifs. It is hypothesized that coupling transcriptional and post‐transcriptional autoregulation enables efficient temporal noise control to benefit developmental bet‐hedging decisions. (shrink)

Sex‐determining factors are usually assumed to be either genetic or environmental. The present paper aims at drawing attention to the potential contribution of developmental noise, an important but often‐neglected component of phenotypic variance. Mutual inhibitions between male and female pathways make sex a bistable equilibrium, such that random fluctuations in the expression of genes at the top of the cascade are sufficient to drive individual development toward one or the other stable state. Evolutionary modeling shows that stochastic sex (...) determinants should resist elimination by genetic or environmental sex determinants under ecologically meaningful settings. On the empirical side, many sex‐determination systems traditionally considered as environmental or polygenic actually provide evidence for large components of stochasticity. In reviewing the field, I argue that sex‐determination systems should be considered within a three‐ends continuum, rather than the classical two‐ends continuum. (shrink)

Extending a normal 24 hours day by four hours is unexpectedly highly disruptive to daily rhythms in gene expression in the blood. Using a paradigm in which human subjects were exposed to a 28 hours day, Archer and colleagues show how this sleep‐altering forced desynchrony protocol caused complex disruption to daily rhythms in distinct groups of genes. Such perturbations in the temporal organisation of the blood transcriptome arise quickly, and point to the fragile nature of coordinated genomic activity. (...) Chronic disruption of the daily and circadian rhythms in sleep compromise health and well‐being and this study reveals potential new molecular targets to combat the disruptive effects of shift work and jetlag. (shrink)

In this paper I address the question of whether the probabilities that appear in models of stochastic gene expression are objective or subjective. I argue that while our best models of the phenomena in question are stochastic models, this fact should not lead us to automatically assume that the processes are inherently stochastic. After distinguishing between models and reality, I give a brief introduction to the philosophical problem of the interpretation of probability statements. I argue that the objective (...) vs. subjective distinction is a false dichotomy and is an unhelpful distinction in this case. Instead, the probabilities in our models of gene expression exhibit standard features of both objectivity and subjectivity. (shrink)

New genes have frequently formed and spread to fixation in a wide variety of organisms, constituting abundant sets of lineage‐specific genes. It was recently reported that an excess of primate‐specific and human‐specific genes were upregulated in the brains of fetuses and infants, and especially in the prefrontal cortex, which is involved in cognition. These findings reveal the prevalent addition of new genetic components to the transcriptome of the human brain. More generally, these findings suggest that genomes are continually evolving in (...) both sequence and content, eroding the conservation endowed by common ancestry. Despite increasing recognition of the importance of new genes, we highlight here that these genes are still seriously under‐characterized in functional studies and that new gene annotation is inconsistent in current practice. We propose an integrative approach to annotate new genes, taking advantage of functional and evolutionary genomic methods. We finally discuss how the refinement of new gene annotation will be important for the detection of evolutionary forces governing new gene origination. (shrink)

Nonsense‐mediated RNA decay (NMD) is an evolutionary conserved system of RNA surveillance that detects and degrades RNA transcripts containing nonsense mutations. Given that these mutations arise at a relatively low frequency, are there any as yet unknown substrates of NMD in a wild‐type cell? With this question in mind, Mendell et al.1 have used a microarray assay to identify those human genes under NMD regulation. Their results show that, in human cells, NMD regulates hundreds of physiologic transcripts and not just (...) those containing nonsense mutations. Among the NMD targets are a number of non‐functional RNAs expressed from vestigial sequences derived from retroviral and transposable elements. These findings support the notion that NMD is a high profile post‐transcriptional mechanism micromanaging the activity of multiple gene batteries and suppressing the expression of genetic remnants. BioEssays 27:463–466, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Gene expression activity is heterogeneous in a population of isogenic cells. Identifying the molecular basis of this variability will improve our understanding of phenomena like tumor resistance to drugs, virus infection, or cell fate choice. The complexity of the molecular steps and machines involved in transcription and translation could introduce sources of randomness at many levels, but a common constraint to most of these processes is its energy dependence. In eukaryotic cells, most of this energy is provided by (...) mitochondria. A clonal population of cells may show a large variability in the number and functionality of mitochondria. Here, we discuss how differences in the mitochondrial content of each cell contribute to heterogeneity in gene products. Changes in the amount of mitochondria can also entail drastic alterations of a cell's gene expression program, which ultimately leads to phenotypic diversity. (shrink)

The stunning possibility of “reprogramming” differentiated somatic cells to express a pluripotent stem cell phenotype (iPS, induced pluripotent stem cell) and the “ground state” character of pluripotency reveal fundamental features of cell fate regulation that lie beyond existing paradigms. The rarity of reprogramming events appears to contradict the robustness with which the unfathomably complex phenotype of stem cells can reliably be generated. This apparent paradox, however, is naturally explained by the rugged “epigenetic landscape” with valleys representing “preprogrammed” attractor states that (...) emerge from the dynamical constraints of the gene regulatory network. This article provides a pedagogical primer to the fundamental principles of gene regulatory networks as integrated dynamic systems and reviews recent insights in gene expression noise and fate determination, thereby offering a formal framework that may help us to understand why cell fate reprogramming events are inherently rare and yet so robust. (shrink)

Large protein assemblies are usually the effectors of major cellular processes. The intricate cell homeostasis network is divided into numerous interconnected pathways, each controlled by a set of protein machines. One of these master regulators is the CCR4‐NOT complex, which ultimately controls protein expression levels. This multisubunit complex assembles around a scaffold platform, which enables a wide variety of well‐studied functions from mRNA synthesis to transcript decay, as well as other tasks still being identified. Solving the structure of the (...) entire CCR4‐NOT complex will help to define the distribution of its functions. The recently published three‐dimensional reconstruction of the complex, in combination with the known crystal structures of some of the components, has begun to address this. Methodological improvements in structural biology, especially in cryoelectron microscopy, encourage further structural and protein‐protein interaction studies, which will advance our comprehension of the gene expression machinery. (shrink)

After a vertebrate dies, many of its organ systems, tissues, and cells remain functional while its body no longer works as a whole. We define this state as the “twilight of death” − the transition from a living body to a decomposed corpse. We claim that the study of the twilight of death is important to ethical, legal and medical science. We examined gene expression at the twilight of death in the zebrafish and mouse reaching the conclusion that (...) apparently thousands of transcripts significantly increase in abundance from life to several hours/days postmortem relative to live controls. Transcript dynamics of different genes provided “proof-of-principle” that models accurately predict an individual's elapsed-time-of-death. While many transcripts were associated with survival and stress compensation, others were associated with epigenetic factors, developmental control, and cancer. Future studies are needed to determine whether the high incidence of cancer in transplant recipients is due to the postmortem processes in donor organs. In organismal death, some organ systems, tissues and cells remain functional while the body no longer works as a whole. In the “twilight of death” − the transition from a living body to a decomposed corpse − thousands of gene transcripts increase in abundance relative to live controls. (shrink)

The development of living organisms requires a precise coordination of all basic cellular processes, in space and time. Early embryogenesis of most species with externally deposited eggs starts with a series of extremely fast cleavage cycles. These divisions have a strong influence on gene expression as mitosis represses transcription and pre‐mRNA processing. In this review, we will describe the distinct adaptations for efficient gene expression and discuss the emerging role of the multifunctional NineTeen Complex (NTC) in (...) gene expression and genomic stability during fast proliferation. (shrink)

Gene clustering is a useful exploratory technique to group together genes with similar expression levels under distinct cell cycle phases or distinct conditions. It helps the biologist to identify potentially meaningful relationships between genes. In this study, we propose a clustering method based on multivariate normal mixture models, where the number of clusters is predicted via sequential hypothesis tests: at each step, the method considers a mixture model of m components (m = 2 in the first step) and (...) tests if in fact it should be m - 1. If the hypothesis is rejected, m is increased and a new test is carried out. The method continues (increasing m) until the hypothesis is accepted. The theoretical core of the method is the full Bayesian significance test, an intuitive Bayesian approach, which needs no model complexity penalization nor positive probabilities for sharp hypotheses. Numerical experiments were based on a cDNA microarray dataset consisting of expression levels of 205 genes belonging to four functional categories, for 10 distinct strains of Saccharomyces cerevisiae. To analyze the method’s sensitivity to data dimension, we performed principal components analysis on the original dataset and predicted the number of classes using 2 to 10 principal components. Compared to Mclust (model-based clustering), our method shows more consistent results. (shrink)

Non‐genetic forms of antimicrobial (drug) resistance can result from cell‐to‐cell variability that is not encoded in the genetic material. Data from recent studies also suggest that non‐genetic mechanisms can facilitate the development of genetic drug resistance. We speculate on how the interplay between non‐genetic and genetic mechanisms may affect microbial adaptation and evolution during drug treatment. We argue that cellular heterogeneity arising from fluctuations in gene expression, epigenetic modifications, as well as genetic changes contribute to drug resistance at (...) different timescales, and that the interplay between these mechanisms enhance pathogen resistance. Accordingly, developing a better understanding of the role of non‐genetic mechanisms in drug resistance and how they interact with genetic mechanisms will enhance our ability to combat antimicrobial resistance. Also see the video abstract here: https://youtu.be/aefGpdh-bgU. (shrink)

Gene expression network is also a type of complex network. It is challenging to analyze the gene expression network through relevant knowledge and algorithms of a complex network. In this paper, the existing characteristics of genes are analyzed from various indexes of the gene expression network to analyze key genes and TOP genes. Firstly, gene chip data are screened, gene data with obvious characteristics are selected, and relevant clustering characteristics are analyzed. Then, (...) the complex gene network structure is established, and gene networks with different threshold shapes and different sizes are selected. Finally, the relevant indexes and PR values after the PageRank algorithm are analyzed for complex networks under different thresholds, thus establishing the TOP gene and PR sequence. (shrink)

The larval arms of echinoid plutei are used for locomotion and feeding. They are composed of internal calcite skeletal rods covered by an ectoderm layer bearing a ciliary band. Skeletogenesis includes an autonomous molecular differentiation program in primary mesenchyme cells (PMCs), initiated when PMCs leave the vegetal plate for the blastocoel, and a patterning of the differentiated skeletal units that requires molecular cues from the overlaying ectoderm. The arms represent a larval feature that arose in the echinoid lineage during the (...) Paleozoic and offers a subject for the study of gene co-option in the evolution of novel larval features. We isolated new molecular markers in two closely related but differently developing species, Heliocidaris tuberculata and Heliocidaris erythrogramma. We report the expression of a larval arm-associated ectoderm gene tetraspanin, as well as two new PMC markers, advillin and carbonic anhydrase. Tetraspanin localizes to the animal half of blastula stage H. tuberculata and then undergoes a restriction into the putative oral ectoderm and future location of the postoral arms, where it continues to be expressed at the leading edge of both the postoral and anterolateral arms. In H. erythrogramma, its expression initiates in the animal half of blastulae and expands over the entire ectoderm from gastrulation onward. Advillin and carbonic anhydrase are upregulated in the PMCs postgastrulation and localized to the leading edge of the growing larval arms of H. tuberculata but do not exhibit coordinated expression in H. erythrogramma larvae. The tight spatiotemporal regulation of these genes in H. tuberculata along with other ontogenetic and phylogenetic evidence suggest that pluteus arms are novel larval organs, distinguishable from the processes of skeletogenesis per se. The dissociation of expression control in H. erythrogramma suggest that coordinate gene expression in H. tuberculata evolved as part of the evolution of pluteus arms, and is not required for larval or adult development. (shrink)

The use of Drosophila chromosomal rearrangements and transposon constructs involving the white gene reveals the existence of repressive chromatin domains that can spread over considerable genomic distances. One such type of domain is found in heterochromatin and is responsible for classical position‐effect variegation. Another type of repressive domain is established, beginning at specific sequences, by complexes of Polycomb Group proteins. Such complexes, which normally regulate the expression of many genes, including the homeotic loci, are responsible for silencing, white (...) gene variegation, pairing‐dependent effects and insertional targeting. (shrink)

The history of biological systematics documents a continuing tension between classifications in terms of nested hierarchies congruent with branching diagrams (the ‘Tree of Life’) versus reticulated relations. The recognition of conflicting character distribution led to the dissolution of the scala naturae into reticulated systems, which were then transformed into phylogenetic trees by the addition of a vertical axis. The cladistic revolution in systematics resulted in a representation of phylogeny as a strictly bifurcating pattern (cladogram). Due to the ubiquity of character (...) conflict—at the genetic or morphological level, or at any level in between—some characters will necessarily have to be discarded ( qua noise) in favor of others in support of a strictly bifurcating phylogenetic tree. Pattern analysts will seek maximal congruence in the distribution of characters (ultimately of any kind) relative to a branching tree-topology; process explainers will call such tree-topologies into question by reference to incompatible evolutionary processes. Pattern analysts will argue that process explanations must not be brought to bear on pattern reconstruction; process explainers will insist that the reconstructed pattern requires a process explanation to become scientifically relevant, i.e., relevant to evolutionary theory. The core question driving the current debate about the adequacy of the ‘Tree of Life’ metaphor seems to be whether the systematic dichotomization of the living world is an adequate representation of the complex evolutionary history of global biodiversity. In ‘Questioning the Tree of Life’, it seems beneficial to draw at least four conceptual distinctions: pattern reconstruction versus process explanation as different epistemological approaches to the study of phylogeny; open versus closed systems as expressions of different kinds of population (species) structures; phylogenetic trees versus cladograms as representations of evolutionary processes versus patterns of relationships; and genes versus species as expressions of different levels of causal integration and evolutionary transformation. (shrink)

Transcriptional enhancer sequences have been shown to play a pivotal role in the regulation of some highly expressed genes. First described in eukaryotic viruses, the discovery of enhancers has augmented the previously defined control‐sequence motifs to give a more complete understanding of eukaryotic transcriptional regulatory mechanisms. Some properties of enhancers that distinguish them from other regulatory sequences include their ability to function in a position‐ and orientation‐independent manner. Furthermore, the observation that some enhancers and transcriptional promoters exhibit tissue specificity in (...) their activity has generated considerable interest. Enhancer activation is thought to involve sequence‐specific DNA‐binding proteins but the process by which this leads to an increase in the initiation of transcription remains obscure. Although viral enhancers are more fully characterized, several cellular enhancers have recently been identified. One such enhancer sequence has been detected in a 3′ flanking region of a highly expressed human placental lactogen gene. This enhancer can increase the transcriptional rate of an adjacent gene by at least 50‐fold. (shrink)

Epigenetic and transcriptional variability contribute to the vast diversity of cellular and organismal phenotypes and are key in human health and disease. In this review, we describe different types, sources, and determinants of epigenetic and transcriptional variability, enabling cells and organisms to adapt and evolve to a changing environment. We highlight the latest research and hypotheses on how chromatin structure and the epigenome influence gene expression variability. Further, we provide an overview of challenges in the analysis of biological (...) variability. An improved understanding of the molecular mechanisms underlying epigenetic and transcriptional variability, at both the intra- and inter-individual level, provides great opportunity for disease prevention, better therapeutic approaches, and personalized medicine. Epigenetic and transcriptional variability mediate phenotypic plasticity, enabling adaptation to changing environments. In this review, we describe the sources of inter- and intra-individual variability and discuss epigenetic regulators of gene expression variability, including DNA methylation and chromatin structure. Understanding these molecular mechanisms will improve therapeutic approaches and personalized medicine. (shrink)

The circadian clock is a cell autonomous oscillator that controls many aspects of physiology through generating rhythmic gene expression in a time of day dependent manner. In addition, in endothermic mammals body temperature cycles contribute to rhythmic gene expression. These body temperature‐controlled rhythms are hard to distinguish from classic circadian rhythms if analyzed in vivo in endothermic organisms. However, they do not fulfill all criteria of being circadian if analyzed in cell culture or in conditions where (...) body temperature of an endothermic organism can be manipulated. Here we review and compare these characteristics, discuss the core clock independent mechanism of temperature‐controlled alternative splicing and highlight the requirement of double‐checking rhythms that appear circadian within an endothermic organism in a system that allows temperature manipulation. (shrink)

Monoallelic gene expression has played a significant role in the evolution of mammals enabling the expansion of a vast repertoire of olfactory receptor types and providing increased sensitivity and diversity. Monoallelic expression of immune receptor genes has also increased diversity for antigen recognition, while the same mechanism that marks a single allele for preferential rearrangement also provides a distinguishing feature for directing hypermutations. Random monoallelic expression of the X chromosome is necessary to balance gene dosage (...) across sexes. In marsupials only the maternal X chromosome is expressed, while in eutherian mammals the paternal X genes are silenced in the developing placenta and early blastocyst. These examples of epigenetic gene regulation commonly employ asynchrony of replication, the binding of polycomb proteins and antisense RNA, and histone modifications to chromatin structure. The same is true for genomic imprinting which among vertebrates is unique to mammals and represents a special kind of epigenetic modification that is heritable according to parent of origin. Genomic imprinting pervades many aspects of mammalian growth and evolution but in particular has played a significant role in the co‐adaptive evolution of the mother and foetus. (shrink)

Despite the extensive literature describing the somatic genetic alterations in cancer cells, the precise origins of cancer cells remain controversial. In this article, I suggest that the etiology of cancer and the generation of genetic instability in cancer cells should be considered in the light of recent findings on both the stochastic nature of gene expression and its regulation at tissue level. By postulating that gene expression is intrinsically probabilistic and that stabilization of gene (...) class='Hi'>expression arises by cellular interactions in “morphogenetic fields”, development and cellular differentiation can be rethought in an evolutionary perspective. In particular, this article proposes that disruptions of cellular interactions are the initial source of abnormal gene expression in cancer cells. Consequently, cancer phenotypes such as genetic and epigenetic instabilities, and also the presence of cells with stem cell‐like properties, may result from inaccurate and aberrant patterns of gene expression generated by microenvironmental alterations. Finally, the therapeutic implications of this view are discussed. BioEssays 27:1277–1285, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Alterations in the expression of certain genes or in their products can render benign tumor cells metastatic. Experimentally this has been quickly performed by transferring dominantly acting oncogenes such as c‐H‐rasEJ into susceptible cells, but in vivo such a rapid qualitative change in a dominantly acting oncogene occurs only rarely, and progression to highly metastatic phenotypes is thought to occur through a slow stepwise process. Such slow changes can be reversible and need not involve known dominantly acting oncogenes, consistent (...) with clinical observations. An important element of the natural progression of tumors to malignancy may be their ability to circumvent microenvironmental controls that regulate growth and cellular diversity and to evolve into heterogeneous phenotypes, a process that appears to involve mainly quantitative changes in gene expression but which can be rapidly stimulated in cell culture by the introduction of a dominantly acting oncogene. It is proposed that the highly malignant cells that have slowly evolved in vivo with only a few qualitative gene changes have undergone extensive cycles of diversification and accumulation of quantitative changes in the expression of genes that encode products that are related to malignancy and metastasis. Thus, highly malignant cellular phenotypes can arise quickly through specific qualitative changes in critical controlling genes or more slowly by less critical qualitative genetic changes, coupled with cellular diversification and accumulation of quantitative changes in gene expression. (shrink)

Polyphenic differences between individuals arise not through differences at the genome level but as a result of specific cues received during development. Polyphenisms often involve entire suites of characters, as shown dramatically by the polyphenic castes found in many social insect colonies. An understanding of the genetic architecture behind polyphenisms provides a novel means of studying the interplay between genomes, gene expression and phenotypes. Here we discuss polyphenisms and molecular genetic tools now available to unravel their developmental bases (...) in insects. We focus on several recent studies that have tracked gene-expression patterns during social insect caste determination. BioEssays 23:62–68, 2001. Published 2001 John Wiley & Sons, Inc. (shrink)

The signal for sex determination in the nematode Caenorhabditis elegans is the ratio between the number of × chromosomes and the number of sets of autosomes (the X/A ratio). Animals with an X/A ratio of 0.67 (a triploid with two × chromosomes) or less are males. Animals with an X/A ratio of 0.75 or more are hermaphrodites. Thus, diploid males have one × chromosome and diploid hermaphrodites have two × chromosomes. However, the difference in X‐chromosome number between the sexes is (...) not reflected in general levels of X‐linked gene expression because of the phenomenon of dosage compensation. In dosage compensation, X‐linked gene expression appears to be ‘turned down’ in 2X animals to the 1X level of expression. An intriguing and unexplained finding is that mutations and X‐chromosome duplications that elevate X‐linked gene expression also feminize triploid males. One way that this relationship between sex determination and X‐linked gene expression may be operating is discussed. (shrink)

Skin is one of the most thoroughly studied epithelia and can be used as a model for transcriptional control of epithelial differentiation. In particular, the stages of epidermal development and differentiation from a simple epithelium are well characterized. Temporal gene expression during development can be used to assign roles for transcription factors in epidermal differentiation. Approaches to understanding transcriptional regulation in epidermis include extensive promoter analysis and expression studies, in some cases coupled to functional studies. This work (...) has not produced any consensus about the importance of any particular factor or class of factors in epidermal specification. There is, as yet, nothing similar to the myo D family of tissue‐specific and cell‐type determining factors in epidermis. These studies, however, have revealed much about control of the differentiation process in epidermis. Most recently, there has been a suggestion that epithelial transcription can be influenced directly by the status of the adhesion complexes at the cell surface, providing a direct link between one of the distinguishing features of the epithelial state and gene transcription. (shrink)

Polyphenic differences between individuals arise not through differences at the genome level but as a result of specific cues received during development. Polyphenisms often involve entire suites of characters, as shown dramatically by the polyphenic castes found in many social insect colonies. An understanding of the genetic architecture behind polyphenisms provides a novel means of studying the interplay between genomes, gene expression and phenotypes. Here we discuss polyphenisms and molecular genetic tools now available to unravel their developmental bases (...) in insects. We focus on several recent studies that have tracked gene‐expression patterns during social insect caste determination. BioEssays 23:62–68, 2001. Published 2001 John Wiley & Sons, Inc. (shrink)

Trypanosoma brucei mitochondria contain unusual small circular DNAs of unknown function. These are catenated with a long informational DNA sequence containing genes homologous to those found in other mitochondria. Although these genes are transcribed throughout the life cycle, differential production of the mitochondrial respiratory system during the life cycle is accompanied by differential abundance of specific transcripts and differential polyadenylation of mitochondrial gene transcripts. Multiple transcripts occur for most of the mitochondrial genes. Transcripts of the apocytochrome b gene (...) possessing nucleotide sequences at their 5′ ends which are not present in mitochondrial DNA are found at stages of the life cycle when the respiratory system is expressed. These results suggest the presence of post‐transcriptional mechanisms that regulate the expression of mitochondrial genes during the life cycle of T. brucei. (shrink)

While the definition of the ‘genotype’ has undergone dramatic changes in the transition from classical to molecular genetics, the definition of the ‘phenotype’ has remained for a long time within the classical framework. In addition, while the notion of the genotype has received significant attention from philosophers of biology, the notion of the phenotype has not. Recent developments in the technology of measuring gene-expression levels have made it possible to conceive of phenotypic traits in terms of levels of (...) gene expression. We demonstrate that not only has this become possible but it has also become an actual practice. This suggests a significant change in our conception of the phenotype: as in the case of the ‘genotype’, phenotypes can now be conceived in quantitative and measurable terms on a comprehensive molecular level. We discuss in what sense gene expression profiles can be regarded as phenotypic traits and whether these traits are better described as a novel concept of phenotype or as an extension of the classical concept. We argue for an extension of the classical concept and call for an examination of the type of extension involved. (shrink)

The Neo‐Darwinian concept of natural selection is plausible when one assumes a straightforward causation of phenotype by genotype. However, such simple 1:1 mapping must now give place to the modern concepts of gene regulatory networks and gene expression noise. Both can, in the absence of genetic mutations, jointly generate a diversity of inheritable randomly occupied phenotypic states that could also serve as a substrate for natural selection. This form of epigenetic dynamics challenges Neo‐Darwinism. It needs to (...) incorporate the non‐linear, stochastic dynamics of gene networks. A first step is to consider the mathematical correspondence between gene regulatory networks and Waddington's metaphoric ‘epigenetic landscape’, which actually represents the quasi‐potential function of global network dynamics. It explains the coexistence of multiple stable phenotypes within one genotype. The landscape's topography with its attractors is shaped by evolution through mutational re‐wiring of regulatory interactions – offering a link between genetic mutation and sudden, broad evolutionary changes. (shrink)

Emerging evidence suggests that DNA topology plays an instructive role in cell fate control through regulation of gene expression. Transcription produces torsional stress, and the resultant supercoiling of the DNA molecule generates an array of secondary structures. In turn, local DNA architecture is harnessed by the cell, acting within sensory feedback mechanisms to mediate transcriptional output. MYC is a potent oncogene, which is upregulated in the majority of cancers; thus numerous studies have focused on detailed understanding of its (...) regulation. Dissection of regulatory regions within the MYC promoter provided the first hint that intimate feedback between DNA topology and associated DNA remodeling proteins is critical for moderating transcription. As evidence of such regulation is also found in the context of many other genes, here we expand on the prototypical example of the MYC promoter, and also explore DNA architecture in a genome-wide context as a global mechanism of transcriptional control. Torsional stress, and supercoiling generated by transcription, shape the topology of DNA. Furthermore, the resultant secondary DNA structures and their interacting partners provide feedback to regulate gene expression. Emerging evidence suggests these mechanisms, identified through analysis of the MYC promoter, are applicable genome-wide. (shrink)

The precocious induction in vivo and in culture of insect and amphibian metamorphosis by exogenous ecdysteroids and thyroid hormones, and its retardation or inhibition by juvenile hormone and prolactin, respectively, has allowed the analysis of such diverse processes of post‐embryonic development as morphogenesis, tissue remodelling, functional reorganization, and programmed cell death. Metamorphosis in vertebrates also shares many similarities with mammalian development in the late foetal and perinatal period. This review describes the regulation of expression of some of the ‘adult’ (...) gene products during metamorphosis in invertebrates and vertebrates. Recent studies on metamorphosis have revealed the important role played by auto‐induction of hormone receptor genes, based on which a model will be presented to explain the activation of ‘downstream’ genes which give rise to the adult phenotype. It will also be argued that metamorphosis is an ideal model for analyzing some of the major mechanisms governing post‐embryonic development. (shrink)

Physiological concentrations of retinoic acid can induce acute alterations in the expression of the enzyme tissue transglutaminase in cultured macrophages. The induction of this enzyme offers a probe to study the mechanism of retinoid action in both normal and leukemic cells.

RNA polymerase II (RNAP II) non‐coding transcription is now known to cover almost the entire eukaryotic genome, a phenomenon referred to as pervasive transcription. As a consequence, regions previously thought to be non‐transcribed are subject to the passage of RNAP II and its associated proteins for histone modification. This is the case for the nucleosome‐depleted regions (NDRs), which provide key sites of entry into the chromatin for proteins required for the initiation of coding gene transcription and DNA replication. In (...) this review, recent data on the effects of pervasive transcription through NDRs are summarized and a model is proposed to explain how RNAP II‐driven transcription is able to modify the nucleosomes flanking the NDRs, leading to nucleosome repositioning and NDR closure. Even though much of the mechanistic detail underlying these events remains to be elucidated, such a model provides a basis to explain how non‐coding transcription through NDRs can regulate the initiation of coding gene expression and DNA replication. (shrink)

Phytochrome is known to regulate the expression of several major nuclearencoded polypeptides at the level of transcription. Both in vivo in vitro methods are currently being used to determine the step(s) between the light activation of phytochrome and changes in gene expression.

Measuring gene expression on a global scale has been one of the vexing problems of cell biology. Velculescu et al.(1) recently proposed a system for identifying gene expression levels based on very short sequence tags – about nine base pairs – located at a specific site within a gene transcript. By coupling the strategy to current automated sequencing machines and the large expressed sequence tag databases, it should be possible to follow changes in gene (...) expression for large numbers of genes economically and accurately. (shrink)

Serial analysis of gene expression (SAGE) is a powerful technique that can be used for global analysis of gene expression. Its chief advantage over other methods is that it does not require prior knowledge of the genes of interest and provides qualitative and quantitative data of potentially every transcribed sequence in a particular cell or tissue type. This is a technique of expression profiling, which permits simultaneous, comparative and quantitative analysis of gene‐specific, 9‐ to (...) 13‐basepair sequences. These short sequences, called SAGE tags, are linked together for efficient sequencing. The sequencing data are then analyzed to identify each gene expressed in the cell and the levels at which each gene is expressed. The main benefit of SAGE includes the digital output and the identification of novel genes. In this review, we present an outline of the method, various bioinformatics methods for data analysis and general applications of this important technology. BioEssays 26:916–922, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Honey bees are eusocial insects and the workers inform their nestmates of information regarding the location of food source using symbolic communication, called ‘dance communication’, that are based on their highly advanced learning abilities. Mushroom bodies (MBs), a higher-order center in the honey bee brain, comprise some subtypes/populations of interneurons termed Kenyon cells (KCs) that are distinguished by their cell body size and location in the MBs, as well as their gene expression profiles. Although the role of MBs (...) in learning ability has been studied extensively in the honey bee, the roles of each KC subtype and their evolution in hymenopteran insects remain mostly unknown. This mini-review describes recent progress in the analysis of gene/protein expression profiles and possible functions of KC subtypes/populations in the honey bee. Especially, the discovery of novel KC subtype/population, ‘middle-type KCs’ and ‘KC population expressing FoxP’, necessitated a redefinition of the KC subtype/population. Analysis of the effects of inhibiting gene function in a KC subtype-preferential manner revealed the function of the gene product as well as of the subtype where it is expressed. Genes expressed in a KC subtype/population-preferential manner can be used to trace the differentiation of KC subtypes during the honey bee ontogeny and the possible evolution of KC subtypes in hymenopteran insects. Current findings suggest that the three KC subtypes are unique characteristics to the aculeate hymenopteran insects. Finally, recent application of genome editing for the study of KC subtype functions in the honey bee is described. Genes expressed in a KC subtype-preferential manner can be good candidate target genes for genome editing, because they are likely related to highly advanced brain functions and some of them are dispensable for normal development and sexual maturation in honey bees. (shrink)

The multistep pathway of eukaryotic gene expression involves a series of highly regulated events in the nucleus and cytoplasm. In the nucleus, genes are transcribed into pre‐messenger RNAs which undergo a series of nuclear processing steps. Mature mRNAs are then transported to the cytoplasm, where they are translated into protein and degraded at a rate dictated by transcript‐ and cell‐type‐specific cues. Until recently, these individual nuclear and cytoplasmic events were thought to be primarily regulated by different RNA‐ and (...) DNA‐binding proteins that are localized either only in the nucleus or only the cytoplasm. Here, we describe multifunctional proteins that control both nuclear and cytoplasmic steps of gene expression. One such class of multifunctional proteins (e.g., Bicoid and Y‐box proteins) regulates both transcription and translation whereas another class (e.g., Sex‐lethal) regulates both nuclear RNA processing and translation. Other events controlled by multifunctional proteins include assembly of spliceosome components, spliceosome recycling, RNA editing, cytoplasmic mRNA localization, and cytoplasmic RNA stability. The existence of multifunctional proteins may explain the paradoxical involvement of the nucleus in an RNA surveillance pathway (nonsense‐mediated decay) that detects cytoplasmic signals (premature termination codons). We speculate that shuttling multifunctional proteins serve to efficiently link RNA metabolism in the cytoplasmic and nuclear compartments. BioEssays 23:775–787, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

The term functional domain is often used to describe the region containing the cis acting sequences that regulate a gene locus. “Strong” domain models propose that the domain is a spatially isolated entity consisting of a region of extended accessible chromatin bordered by insulators that have evolved to act as functional boundaries. However, the observation that independently regulated loci can overlap partially or completely raises questions about functional requirements for physically isolated domain structures. An alternative model, the “weak” domain (...) model, proposes that domain structure is determined by the distribution of binding sites for positively acting factors, without a requirement for functional boundaries. The domain would effectively be the region that contains these factor-binding sites. Specificity of promoter-enhancer interactions would play a major role in maintaining the functional autonomy of adjacent genes. Sequences that interfere with these interactions (frequently characterised as insulators) would be selected against if they occurred within the domain but not at the edges, or in the interdomain regions. As a result, insulators would often be found near the borders of domains without necessarily being selected to act as boundaries. BioEssays 22:657–665, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Control of DNA supercoiling by the free-energy of hydrolysis of ATP that involves gene expression is analyzed in terms of three levels of unconnected metabolic pathways. These are synthesis and breakdown of topoisomerase mRNAs, synthesis and breakdown of topoisomerase proteins and supercoiling and relaxation of DNA. The so-called square-matrix method previously developed for the control of metabolic pathways, is extended to deal with this hierarchical control system. It turns out that also in this case, the matrix of control (...) coefficients is equal to the inverse of the so-called elasticity matrix, which contains all relevant elasticity coefficients as well as information about the structure and connectedness of the pathways involved. For a simpler case of a hierarchy of two systems, we demonstrate that the explicit matrix inversion method may be replaced by an implicit method in which the regulatory effects that run through the other level are described by an additional elasticy coefficient which may then be treated as if local. (shrink)

Advances in biochemistry, chemistry and engineering have enabled the development of a new gene expression assay. This ‘chip‐based’ approach utilizes microscopic arrays of cDNAs printed on glass as high‐density hybridization targets. Fluorescent probe mixtures derived from total cellular messenger RNA (mRNA) hybridize to cognate elements on the array, allowing accurate measurement of the expression of the corresponding genes. Array densities of >1,000 cDNAs per cm2 enable quantitative expression monitoring of a large number of genes in a (...) single hybridization. A two‐color fluorescence detection scheme allows rapid and simultaneous differential expression analysis of independent biological samples. Mass‐produced microarrays provide a new tool for genome expression analysis that may revolutionize genetic dissection, drug discovery and human disease diagnostics. (shrink)

Light effects on the activity of several genes have recently been exploited in studies of plant gene expression. We discuss here some examples involving nuclear genes of higher plants, with emphasis on responses mediated by the phytochrome system. Recent work has revealed considerable diversity in the responses of different genes, indicating that several different regulatory programs are probably involved. A start has been made in studies of nuclear events associated with the changes in expression. Transcriptional regulation almost (...) certainly occurs, although many details remain to be studied and effects on mRNA processing and turnover have not been ruled out. Recent in vitro mutagenesis and gene transfer experiments with the gene for the small subunit of RuBP carboxylase indicate that sequences involved in regulating the level of expression in the light are located 5′ to the gene within about 1 kb of the start of transcription. (shrink)