Presented in six principal analytic chapters with supporting appendices, this book explores the role of Islam in precipitating Europe's twelfth century commercial renaissance. Employing the classic analytic techniques of economics, Gene Heck determines that medieval Europe's feudal interregnum was largely caused by indigenous governmental business regulation and not by shifts in international trade patterns. He then proceeds by demonstrating how Islamic economic precepts provided the ideological rationales that empowered medieval Europe to escape its three-centuries-long experiment in "Dark Age (...) economics" ― in the process, providing the West with its archetypic tools of capitalism. While treatises such as Maxime Rodinson's excellent book, Islam and Capitalism, document the capitalistic nature of the Islamic economic system, in applying modern economic method to medieval orientalist historiography, this work is unique in capturing both the evolution and the impact of the system's role in forging medieval history. (shrink)

Informed by a search of the literature about the usage of genetic testing information (GTI) by insurance companies, this paper presents a practical ethical analysis of several distinct public policy options that might be used to govern or constrain GTI usage by insurance providers. As medical research advances and the extension to the Human Genome Project (2016, https://en.wikipedia.org/wiki/human_genome_project_-_write) moves to its fullness over the next decade, such research efforts will allow the full synthesis of human DNA to be connected to (...) predictive health dispositions. As testing costs fall, there will be ever more pressure for citizens to disclose GTI. Genetic testing information is integral to future medical care because it can be used to better assess individually tailored medical therapies as well as to allow a more informed risk analysis by the insurance industry, which in some countries such as the USA underwrites a majority of citizen medical expenses. As discussed in this examination, the revelation of people’s uniquely personal GTI to insurers has enormous societal implications. The major contribution of the paper is to offer policy makers and concerned citizens a nuanced articulation of the basic options to regulate GTI, with a special consideration for ethical fairness and equity. As genetic-based medicine blossoms and pressures to reduce healthcare costs increase, there will be an ever greater impetus for countries to revisit their genetic testing policies. Organizations and policy makers striving to create GTI oversights perceived to be both “fair and effective” need to be aware of the ethical perspectives discussed in this paper. (shrink)

This paper provides a marketing ethics analysis that addresses the practice of selling genetic tests directly to the consumer. It details the complexity of this emergent sector by articulating the panoply of evolving ethical/social questions raised by this development. It advances the conversation about DTC genetic testing by reviewing the business and healthcare literature concerning this topic and by laying out the inherent ethical complications for consumers, marketers, and regulators. It also points to several possible public and company policy adjustments. (...) Because this area is relatively new and incredibly dynamic, its current discussion is necessarily an exercise in the “logic of discovery” rather than the “protocol of validation”. The paper serves as a primer for the types of GT being promoted. It also calls for a public discourse in the academic and general community to uncover and define the ethical guidelines and systemic adjustments necessary to create fairness in the various DTC transactions occurring between genetic test sellers and the buyers/clients of their services. (shrink)

The Streptococcus pyogenes CRISPR‐Cas system has gained widespread application as a genome editing and gene regulation tool as simultaneous cellular delivery of the Cas9 protein and guide RNAs enables recognition of specific DNA sequences. The recent discovery that Cas9 can also bind and cleave RNA in an RNA‐programmable manner indicates the potential utility of this system as a universal nucleic acid‐recognition technology. RNA‐targeted Cas9 (RCas9) could allow identification and manipulation of RNA substrates in live cells, empowering the study (...) of cellular gene expression, and could ultimately spawn patient‐ and disease‐specific diagnostic and therapeutic tools. Here we describe the development of RCas9 and compare it to previous methods for RNA targeting, including engineered RNA‐binding proteins and other types of CRISPR‐Cas systems. We discuss potential uses ranging from live imaging of transcriptional dynamics to patient‐specific therapies and applications in synthetic biology. (shrink)

Plasmodium falciparum is the most deadly human malarial parasite, responsible for an estimated 207 million cases of disease and 627,000 deaths in 2012. Recent studies reveal that the parasite actively regulates a large fraction of its genes throughout its replicative cycle inside human red blood cells and that epigenetics plays an important role in this precise gene regulation. Here, we discuss recent advances in our understanding of three aspects of epigenetic regulation in P. falciparum: changes in histone (...) modifications, nucleosome occupancy and the three‐dimensional genome structure. We compare these three aspects of the P. falciparum epigenome to those of other eukaryotes, and show that large‐scale compartmentalization is particularly important in determining histone decomposition and gene regulation in P. falciparum. We conclude by presenting a gene regulation model for P. falciparum that combines the described epigenetic factors, and by discussing the implications of this model for the future of malaria research. (shrink)

A discussion of plasticity genes and the genetic architecture of gene-environment interactions.

Although the interdisciplinary nature of contemporary biological sciences has been addressed by philosophers, historians, and sociologists of science, the different ways in which engineering concepts and methods have been applied in biology have been somewhat neglected. We examine - using the mechanistic philosophy of science as an analytic springboard - the transfer of network methods from engineering to biology through the cases of two biology laboratories operating at the California Institute of Technology. The two laboratories study gene regulatory networks, (...) but in remarkably different ways. The research strategy of the Davidson lab fits squarely into the traditional mechanist philosophy in its aim to decompose and reconstruct, in detail, gene regulatory networks of a chosen model organism. In contrast, the Elowitz lab constructs minimal models that do not attempt to represent any particular naturally evolved genetic circuits. Instead, it studies the principles of gene regulation through a template-based approach that is applicable to any kinds of networks, whether biological or not. We call for the mechanists to consider whether the latter approach can be accommodated by the mechanistic approach, and what kinds of modifications it would imply for the mechanistic paradigm of explanation, if it were to address modelling more generally. (shrink)

A network of gene regulation organized in a hierarchical and combinatorial manner is crucially involved in the development of the neural network, and has to be considered one of the main substrates of genetic change in its evolution. Though qualitative features may emerge by way of the accumulation of rather unspecific quantitative changes, it is reasonable to assume that at least in some cases specific combinations of regulatory parts of the genome initiated new directions of evolution, leading to (...) novel capabilities of the brain. These notions are applied, in this paper, to the evolution of the capability of cognition-based human empa­thy. It is suggested that it has evolved as a secondary effect of the evolution of strategic thought. Development of strategies depends on abstract representations of one’s own pos­sible future states in one’s own brain to allow assessment of their emotional desirability, but also on the representation and emotional evaluation of possible states of others, allowing anticipation of their behaviour. This is best achieved if representations of others are con­nected to one’s own emotional centres in a manner similar to self-representations. For this reason, the evolution of the human brain is assumed to have established representations with such linkages. No group selection is involved, because the quality of strategic thought affects the fitness of the individual. A secondary effect of this linkage is that both the actual states and the future perspectives of others elicit vicarious emotions, which may contribute to the motivations of altruistic behaviour. (shrink)

I show that gene regulation networks are qualitatively consistent and therefore sufficiently similar to linearly seperable connectionist networks to warrant that the connectionist framework be applied to gene regulation. On this view, natural selection designs gene regulation networks to overcome the difficulty of development. I offer some general lessons about their evolvability that can be learned by examining the generic features of connectionist networks.

Because a large number of molecular mechanisms involved in gene regulation have been described during the last decades, it is now becoming possible to address questions about the global structure of gene regulatory networks, at least in the case of some of the best-characterized organisms.This paper presents a global characterization of the transcriptional regulation in Escherichiacoli on the basis of the current data. The connectivity of the corresponding network was evaluated by analyzing the distribution of the (...) number of genes regulated by a given regulatory protein, and the distribution of the number of regulatory genes regulating a given regulated gene. The mean connectivity found (between 2 and 3) shows a rather loosely interconnected structure. Special emphasis is given to circular sequences of interactions (“circuits”) because of their critical dynamical properties. Only one-element circuits were found, in which negative autoregulation is the dominant architecture. These global properties are discussed in light of several pertinent theoretical approaches, as well as in terms of physiological and evolutionary considerations. BioEssays 20:433–440, 1998. © 1998 John Wiley & Sons Inc. (shrink)

Because a large number of molecular mechanisms involved in gene regulation have been described during the last decades, it is now becoming possible to address questions about the global structure of gene regulatory networks, at least in the case of some of the best-characterized organisms.This paper presents a global characterization of the transcriptional regulation in Escherichiacoli on the basis of the current data. The connectivity of the corresponding network was evaluated by analyzing the distribution of the (...) number of genes regulated by a given regulatory protein, and the distribution of the number of regulatory genes regulating a given regulated gene. The mean connectivity found (between 2 and 3) shows a rather loosely interconnected structure. Special emphasis is given to circular sequences of interactions (“circuits”) because of their critical dynamical properties. Only one-element circuits were found, in which negative autoregulation is the dominant architecture. These global properties are discussed in light of several pertinent theoretical approaches, as well as in terms of physiological and evolutionary considerations. BioEssays 20:433–440, 1998. © 1998 John Wiley & Sons Inc. (shrink)

Because a large number of molecular mechanisms involved in gene regulation have been described during the last decades, it is now becoming possible to address questions about the global structure of gene regulatory networks, at least in the case of some of the best-characterized organisms.This paper presents a global characterization of the transcriptional regulation in Escherichiacoli on the basis of the current data. The connectivity of the corresponding network was evaluated by analyzing the distribution of the (...) number of genes regulated by a given regulatory protein, and the distribution of the number of regulatory genes regulating a given regulated gene. The mean connectivity found (between 2 and 3) shows a rather loosely interconnected structure. Special emphasis is given to circular sequences of interactions (“circuits”) because of their critical dynamical properties. Only one-element circuits were found, in which negative autoregulation is the dominant architecture. These global properties are discussed in light of several pertinent theoretical approaches, as well as in terms of physiological and evolutionary considerations. BioEssays 20:433–440, 1998. © 1998 John Wiley & Sons Inc. (shrink)

Over the last decades, it has become evident that highly complex networks of regulators govern post‐transcriptional regulation of gene expression. A novel class of Argonaute (Ago)‐associated RNA molecules, the agotrons, was recently shown to function in a Drosha‐ and Dicer‐independent manner, hence bypassing the maturation steps required for canonical microRNA (miRNA) biogenesis. Agotrons are found in most mammals and associate with Ago as ∼100 nucleotide (nt) long RNA species. Here, we speculate on the functional and biological relevance of (...) agotrons: (i) agotrons could serve as non‐promiscuous miRNA‐like regulators with reduced off‐targeting or (ii) agotrons could encompass other putative functions, such as protecting Ago proteins from taking up aberrant short RNAs or by rescuing and stabilizing otherwise unloaded Ago‐proteins from degradation. Collectively, agotrons have emerged as a novel class of interesting non‐coding RNA molecules, but their full functional potential and biological impact still remain to be disclosed. (shrink)

Micro RNAs (miRNAs) have been shown to control many cellular processes including developmental timing in different organisms. The prediction that miRNAs are involved in regulating hox genes of flies and mouse is quite a recent idea and is supported by the finding that mir‐196 represses Hoxb8 gene expression. The non‐coding regions that encode these miRNAs are also conserved across species in the same way as other mechanisms that regulate expression of hox genes. On the contrary, until now no homeotic (...) phenotype, a hallmark of any hox gene mutation, had been associated with any hox miRNA. Recent work on bithorax complex miRNA (miR–iab‐4–5p) shows, for the first time, that miRNAs can lead to homeotic transformation. This miRNA regulates Ultrabithorax (Ubx) and results in the transformation of haltere to wing.1 This study unveils a new complexity and finesse to the regulation of hox gene expression pattern that is needed for determining the anteroposterior body axis in all bilaterians. BioEssays 28: 445–448, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

In the mouse, at least 16 genes regulate vesicle trafficking to specialized lysosome‐related organelles, including platelet dense granules and melanosomes. Fourteen of these genes have been identified by positional cloning. All 16 mouse mutants are models for the genetically heterogeneous human disease, Hermansky–Pudlak Syndrome (HPS). Five HPS genes encode known vesicle trafficking proteins. Nine genes are novel, are found only in higher eukaryotes and encode members of three protein complexes termed BLOCs (Biogenesis of Lysosome‐related Organelles Complexes). Mutations in murine HPS (...) genes, which encode protein co‐members of BLOCs, produce essentially identical phenotypes. In addition to their well‐known effects on pigmentation, platelet function and lysosome secretion, HPS genes control a wide range of physiological processes including immune recognition, neuronal functions and lung surfactant trafficking. Studies of the molecular functions of HPS proteins will reveal important details of vesicle trafficking and may lead to therapies for HPS. BioEssays 26:616–628, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Recent work on kinetoplast DNA and on CAP‐DNA and Eco RI‐DNA complexes shows that certain sequences cause DNA to be highly bent, and that other sequences bend in response to the sequence‐specific binding of proteins. These results demonstrate that alterations of DNA structure may facilitate gene regulation and DNA packaging.

Numerous genes contain regulatory elements located many tens of kilobases away from the promoter they control. Specific mechanisms must be required to ensure that such distant elements can find and interact with their proper targets but not with extraneous genes. This review explores the connections between transvection phenomena, the activation of domains of homeotic gene expression, position effect variegation and silencers. These various examples of long‐distance effects suggest that, in all cases, related forms of chromatin packaging may be involved.

The interrelationships among recent theories on the regulation of gene activity and differentiation in higher organisms are reviewed. Interpretations within these theories of the various components of chromosomes are re-evaluated and a unified conceptual framework of hierarchical genetic control mechanisms in eukaryotes is presented.

Sixteen years ago, Michael Ashburner and his colleagues proposed a hierarchical model for the genetic control of polytene chromosome puffing by the steroid hormone ecdysone. The recent molecular isolation and characterization of three early ecdysone‐inducible genes has confirmed many aspects of this model — these genes are directly induced by ecdysone, repressed by ecdysone‐induced proteins, and appear to encode DNA binding regulatory proteins. The three early genes are also remarkably similar in structure. They are all unusually long and complex, with (...) multiple transcripts that direct the synthesis of several related proteins from each locus. Proteins encoded by two of the early genes bind to both early and late ecdysone‐induced puffs, implying that they are key regulators in the hierarchy. (shrink)

In the yeast Saccharomyces cerevisiae, the regulation of expression of many of the enzymes for amino acid biosynthesis involves an interlinked general control system. Molecular and genetic analyses of this system reveal an underlying set of hierarchical transcriptional controls and a novel translational regulatory mechanism for governing expression of a key activator gene.

Gene regulatory networks are intensively studied in biology. One of the main aims of these studies is to gain an understanding of how the structure of genetic networks relates to specific functions such as chemotaxis and the circadian clock. Scientists have examined this question by using model organisms such as Drosophila and mathematical models. In the last years, synthetic models—engineered genetic networks—have become more and more important in the exploration of gene regulation. What is the potential of (...) this new approach in the investigation of gene network structures? How do synthetic models relate to model organisms and mathematical models? (shrink)

The gene regulation function (GRF) provides an operational description of a promoter behavior as a function of the concentration of one of its transcriptional regulators. Behind this apparently trivial definition lies a central concept in biological control: the GRF provides the input/output relationship of each edge in a transcriptional network, independently from the molecular interactions involved. Here we discuss how existing methods allow direct measurement of the GRF, and how several trade‐offs between scalability and accuracy have hindered its (...) application to relatively large networks. We discuss the theoretical and technical requirements for obtaining the GRF. Based on these requirements, we introduce a simplified and easily scalable method that is able to capture the significant parameters of the GRF. The GRF is able to predict the behavior of a simple genetic circuit, illustrating how addressing the quantitative nature of gene regulation substantially increases our comprehension on the mechanisms of gene control. (shrink)

In human languages, a palindrome reads the same forward as backward (e.g., ‘madam’). In regulatory DNA, a palindrome is an inverted sequence repeat that allows a transcription factor to bind as a homodimer or as a heterodimer with another type of transcription factor. Regulatory palindromes are typically imperfect, that is, the repeated sequences differ in at least one base pair, but the functional significance of this asymmetry remains poorly understood. Here, we review the use of imperfect palindromes in Drosophila photoreceptor (...) differentiation and mammalian steroid receptor signaling. Moreover, we discuss mechanistic explanations for the predominance of imperfect palindromes over perfect palindromes in these two gene regulatory contexts. Lastly, we propose to elucidate whether specific imperfectly palindromic variants have specific regulatory functions in steroid receptor signaling and whether such variants can help predict transcriptional outcomes as well as the response of individual patients to drug treatments. (shrink)

It is well established that microRNAs (miRNAs) induce mRNA degradation by binding to 3′ untranslated regions (UTRs). The functionality of sites in the coding domain sequence (CDS), on the other hand, remains under discussion. Such sites have limited impact on target mRNA abundance and recent work suggests that miRNAs bind in the CDS to inhibit translation. What then could be the regulatory benefits of translation inhibition through CDS targeting compared to mRNA degradation following 3′ UTR binding? We propose that these (...) domain‐dependent effects serve to diversify the functional repertoire of post‐transcriptional gene expression control. Possible regulatory benefits may include tuning the time‐scale and magnitude of post‐transcriptional regulation, regulating protein abundance depending on or independently of the cellular state, and regulation of the protein abundance of alternative splice variants. Finally, we review emerging evidence that these ideas may generalize to RNA‐binding proteins beyond miRNAs and Argonaute proteins. (shrink)

Understanding the operation and evolution of gene regulation networks is critical to understanding ontogeny and evolution. According to Stuart Kauffman's view, (1) each cell type cycles through its own repeated pattern of gene expression, (2) the order of ontogeny is dependent on these cycles being short, and (3) evolution is possible because these cycles mutate gradually. This view of gene regulation reflects Kauffman's view that ontogeny is fundamentally the process of cells repeating cycles of activity. (...) I criticize Kauffman's view of gene regulation networks and offer the connectionist theory of gene regulation as an alternative. On this view, the generic order of gene regulation mechanisms is due to the qualitatively consistent way that one gene product influences the expression of another. This allows networks to be stable and evolve to regulate accurately, allowing cells to react appropriately to their microenvironments, due to design by natural selection. 1. Introduction2. Kauffman's Model of Gene Regulation3. Explaining the Order of Kauffman's K = 2 Networks4. The Importance and Relevance of Kauffman's Explanations of the Order of Gene Regulation5. Additional Orderly Facts of Transcription6. The Order of Network Accuracy7. The Accuracy of Connectionist Networks8. The Evolvability of Gene Regulation Networks9. Laws of Structure. (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 (...) class='Hi'>gene variegation, pairing‐dependent effects and insertional targeting. (shrink)

Much research has focused on the effects of pathogenic mitochondrial mutations on health. Notwithstanding, the mechanisms regulating the link between these mutations and their effects remain elusive in several cases. Here, we propose that certain mitochondrial mutations may disrupt function of a set of mitochondrial‐transcribed small RNAs, perturbing communication between mitochondria and nucleus, leading to disease. Our hypothesis synthesises two lines of supporting evidence. First, several mitochondrial mutations cannot be directly linked to effects on energy production or protein synthesis. Second, (...) emerging studies have described the existence of small RNAs encoded by the mitochondria and proposed their involvement in RNA interference. We present a roadmap to testing this hypothesis. (shrink)

It has long been thought that gene expression is tightly regulated in multicellular eukaryotes, so that expression profiles match functional profiles. This conception emerged from the assumption that gene activity is synonymous with gene function. This paradigm was first challenged by comparative protein electrophoresis studies showing extensive differences in expression patterns among related species. The paradigm is now being challenged by evolutionary transcriptomics using microarray technologies. Most gene expression profiles display features that lack any obvious functional (...) significance. The so‐called “ectopic” expression refers to the expression of genes at times and locations where the target gene is not known to have a function. However, ectopic expression might be associated with genuine function even if this function is not essential or has yet to be ascertained. Alternatively, ectopic expression might come about as a superfluous by‐product of regulatory systems, which would call for a revision of prevailing ideas about the specificity of gene regulation. We herein review available evidence for ectopic expression and the hypotheses proposed for its origin and evolution. We propose that ectopic expression must be regarded as part of an integrated phenotypic whole. It seems likely that ectopic expression represents a leak in the evolution of regulatory systems, but one that is endowed with considerable evolutionary possibilities. BioEssays 27:592–601, 2005. © 2005 Wiley Periodicals, 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)

The coordinated expression of the Hox gene family encoding transcription factors is critical for proper embryonic development and patterning. Major efforts have thus been dedicated to understanding mechanisms controlling Hox expression. In addition to the temporal and spatial sequential activation of Hox genes, proper embryonic development requires that Hox genes get differentially silenced in a cell‐type specific manner as development proceeds. Factors contributing to Hox silencing include the polycomb repressive complexes (PRCs), which control gene expression through epigenetic modifications. (...) This review focuses on PRC‐dependent regulation of the Hox genes and is aimed at integrating the growing complexity of PRC functional properties in the context of Hox regulation. In particular, mechanisms underlying PRC binding dynamics as well as a series of studies that have revealed the impact of PRC on the 3D organization of the genome is discussed, which has a significant role on Hox regulation during development. (shrink)

Novel regulatory elements that enabled expression of pre‐existing immune genes in reproductive tissues and novel immune genes with pregnancy‐specific roles in eutherians have shaped the evolution of mammalian pregnancy by facilitating the emergence of novel mechanisms for immune regulation over its course. Trade‐offs arising from conflicting fitness effects on reproduction and host defenses have further influenced the patterns of genetic variation of these genes. These three mechanisms (novel regulatory elements, novel immune genes, and trade‐offs) played a pivotal role in (...) refining the regulation of maternal immune systems during pregnancy in eutherians, likely facilitating the establishment of prolonged direct maternal–fetal contact in eutherians without causing immunological rejection of the genetically distinct fetus. (shrink)

The sequencing of the human genome has opened the way for using bioinformatics to identify sets of genes controlled by specific regulatory signals. Here, we review the unexpected diversity of DNA response elements mediating transcriptional regulation by estrogen receptors (ERs), which control the broad physiological effects of estrogens. Consensus palindromic estrogen response elements are found in only a few known estrogen target genes, whereas most responsive genes contain only low‐affinity half palindromes, which may also control regulation by other (...) nuclear receptors. ERs can also regulate gene expression in the absence of direct interaction with DNA, via protein–protein interactions with other transcription factors or by modulating the activity of upstream signaling components, thereby significantly expanding the repertoire of estrogen‐responsive genes. These diverse mechanisms of action must be taken into account in screening for potential estrogen‐responsive sequences in the genome or in regulatory regions of target genes identified by expression profiling. BioEssays 24:244–254, 2002. © 2002 Wiley Periodicals, Inc.; DOI 10.1002/bies.10066. (shrink)

Acetylation of internal lysine residues of core histone N-terminal domains has been found correlatively associated with transcriptional activation in eukaryotes for more than three decades. Recent discoveries showing that several transcriptional regulators possess intrinsic histone acetyltransferase (HAT) and deacetylase (HDAC) activities strongly suggest that histone acetylation and deacetylation each plays a causative role in regulating transcription. Intriguingly, several HATs have been shown an ability to acetylate nonhistone protein substrates (e.g., transcription factors) in vitro as well, suggesting the possibility that internal (...) lysine acetylation of multiple proteins exists as a rapid and reversible regulatory mechanism much like protein phosphorylation. This article reviews recent developments in histone acetylation and transcriptional regulation. We also discuss several important, yet unanswered, questions. BioEssays 20:615–626, 1998. © 1998 John Wiley & Sons Inc. (shrink)

In mice, dosage compensation of X‐linked gene expression is achieved through the inactivation of one of the two X‐chromosomes in XX female cells. The complex epigenetic process leading to X‐inactivation is largely controlled by Xist and Tsix, two non‐coding genes of opposing function. Xist RNA triggers X‐inactivation by coating the inactive X, while Tsix is critical for the designation of the active X‐chromosome through cis‐repression of Xist RNA accumulation. Recently, a plethora of trans‐acting factors and cis‐regulating elements have been (...) suggested to act as key regulators of either Xist, Tsix or both; these include ubiquitous factors such as Yy1 and Ctcf, developmental proteins such as Nanog, Oct4 and Sox2, and X‐linked regulators such as Rnf12. In this paper we summarise recent advances in our knowledge of the regulation of Xist and Tsix in embryonic stem (ES) and differentiating ES cells. (shrink)

The process by which the genetically identical cell lineages of a multicellular organism acquire the propensity to express distinct arrays of gene products is among the most significant and fascinating questions in modern biology. Not surprisingly, this complex process requires control at several levels, each level providing a condition that is necessary but not sufficient for transcription to occur. Evidence suggests that one level of control concerns a region of DNA much larger than the transcription unit itself – the (...) chromatin domain. This domain must be in a specific chromatin conformation in order to permit transcription; other control mechanisms may be required to bring about overt transcription. A hypothesis concerning the nature of chromatin domains and the relationship between early replication and transcription potential is presented. (shrink)

For the purposes of conservation or suppression of species, gene drive technology has significant potential. Theoretically speaking, with the release of even relatively few animals with gene drive systems in an ecosystem, beneficial or harmful genes could be introduced into the entire wild-type population of that species. Given the profound impact that gene drives could have on species and ecosystems, their use is a highly contentious issue. Communities and groups have differing beliefs about nature and its conservation (...) or preservation, as well as concerns about the ecological safety of the eradication, replacement or enhancement of particular species of animals by means of genetic engineering. For all those reasons, the rigorous regulation of insects and other animals with gene drive systems is crucial. In this paper, we consider the question of whether the United States Food and Drug Administration is prepared to effectively regulate insects and other animals with gene drives. (shrink)

Major hallmarks of Alzheimer's disease include brain deposition of the amyloid-beta peptide , which is proteolytically cleaved from a large Abeta precursor protein by beta and gamma- secretases. A transmembrane aspartyl protease, beta-APP cleaving enzyme , has been recognized as the beta-secretase. We review the structure and function of the BACE1 protein, and of 4129 bp of the 5'-flanking region sequence of the BACE1 gene and its interaction with various transcription factors involved in cell signaling. The promoter region and (...) 5'-untranslated region contain multiple transcription factor binding sites, such as AP-1, CREB and MEF2. A 91 bp fragment is the shortest region with significant reporter gene activity and constitutes the minimal promoter element for BACE1. The BACE1 promoter contains six unique functional domains and three structural domains of increasing sequence complexity as the "ATG" start codon is approached. Notably, the BACE1 gene promoter contains basal regulatory elements, inducible features and sites for regulation by various important transcription factors. Herein, we also discuss and speculate how the interaction of these transcription factors with the BACE1 promoter can modulate synaptic plasticity, neuronal apoptosis and oxidative stress, which are pertinent to the pathogenesis and progression of AD. (shrink)

Zygotic gene activation (ZGA) is the critical event that governs the transition from maternal to embryonic control of development. In the mouse, ZGA occurs during the 2‐cell stage and appears to be regulated by the time following fertilization, i.e. a zygotic clock, rather than by progression through the first cell cycle. The onset of ZGA must depend on maternally inherited proteins, and post‐translational modification of these maternally derived proteins is likely to play a role in ZGA. Consistent with this (...) prediction is that protein phosphorylation catalyzed by the cAMP‐dependent protein kinase is involved in ZGA and that protein synthesis is not required for ZGA. Recent results suggest that ZGA may occur earlier than previously thought, i.e. not during the 2‐cell stage, but rather in G2 of the 1‐cell embryo. Thus ZGA may comprise a period of minor gene activation in the 1‐cell embryo that is followed by a period of major gene activation in the 2‐cell embryo. Following ZGA, the expression of constitutively activated genes may require an enhancer. (shrink)