Homology searches between DNA sequences of evolutionary distant species (phylogenetic footprinting) offer a fast detection method for regulatory sequences. Because of the small size of their genomes, tetraodontid species such as the Japanese pufferfish and green spotted pufferfish have become attractive models for comparative genomics. A disadvantage of the tetraodontid species is, however, that they cannot be bred and manipulated routinely under laboratory conditions, so these species are less attractive for developmental and genetic analysis. In contrast, an increasing arsenal of (...) transgene techniques with the developmental model species zebrafish and medaka are being used for functional analysis of cis regulatory sequences. The main disadvantage is the much larger genome. While comparison between many loci proved the suitability of phylogenetic footprinting using fish and mammalian sequences, fast rate of change in enhancer structure and gene duplication within teleosts may obscure detection of homologies. Here we discuss the contribution and potentials provided by different teleost models for the detection and functional analysis of conserved cis‐regulatory elements. BioEssays 24:564–572, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

This paper, in the form of a frequently asked questions page (FAQ), addresses outstanding questions about “shadow enhancers”, quasi‐redundant cis‐regulatory elements, and their proposed roles in transcriptional control. Questions include: What exactly are shadow enhancers? How many genes have shadow/redundant/distributed enhancers? How redundant are these elements? What is the function of distributed enhancers? How modular are enhancers? Is it useful to study a single enhancer in isolation? In addition, a revised definition of “shadow enhancers” is proposed, and (...) possible mechanisms of shadow enhancer function and evolution are discussed. (shrink)

Gene regulation involves various cis-regulatory elements that can act at a distance. They may physically interact each other or with their target genes to exert their effects. Such interactions are beginning to be uncovered in the imprinted Igf2/H19 domain.1 The differentially methylated regions (DMRs), containing insulators, silencers and activators, were shown to have physical contacts between them. The interactions were changeable depending on their epigenetic state, presumably enabling Igf2 to move between an active and a silent chromatin domain. The (...) study gives us a novel view on how regulatory elements influence gene expression and how epigenetic modifications modulate their long-range effects. (shrink)

Insulators play a central role in subdividing the chromosome into a series of discrete topologically independent domains and in ensuring that enhancers and silencers contact their appropriate target genes. In this review we first discuss the general characteristics of insulator elements and their associated protein factors. A growing collection of insulator proteins have been identified including a family of proteins whose expression is developmentally regulated. We next consider several unexpected discoveries that require us to completely rethink how insulators function (...) (and how they can best be assayed). These discoveries also require a reevaluation of how insulators might restrict or orchestrate (by preventing or promoting) interactions between regulatory elements and their target genes. We conclude by connecting these new insights into the mechanisms of insulator action to dynamic changes in the three‐dimensional topology of the chromatin fiber and the generation of specific patterns of gene activity during development and differentiation. (shrink)

High‐throughput genomic technologies are revolutionizing human genetics. So far the focus has been on the 1.5% of the genome, which is coding, in spite of the fact that the great majority of genomic variants fall outside the coding regions. Recent efforts to annotate the non‐coding sequence show that over 80% of the genome is biochemically active. The genome is divided into regulatory domains consisting of sequence regions that enhance and/or silence the expression of nearby genes and are, in some cases, (...) separated by boundaries with insulator activity. In this paper, we review the recent advances in the identification of variations that influence gene regulation and their consequences for human disease. We hypothesize that structural variations outside of the coding genome can interfere with normal gene regulation by disrupting the regulatory landscape. Therefore, the regulatory landscape of the genome has also to be taken into consideration when investigating the pathology of human disease. (shrink)

Precise spatiotemporal control of gene expression during normal development and cell differentiation is achieved by the combined action of proximal (promoters) and distal (enhancers) cis‐regulatory elements. Recent studies have reported that a subset of promoters, termed Epromoters, works also as enhancers to regulate distal genes. This new paradigm opened novel questions regarding the complexity of our genome and raises the possibility that genetic variation within Epromoters has pleiotropic effects on various physiological and pathological traits by differentially impacting multiple (...) proximal and distal genes. Here, we discuss the different observations pointing to an important role of Epromoters in the regulatory landscape and summarize the evidence supporting a pleiotropic impact of these elements in disease. We further hypothesize that Epromoter might represent a major contributor to phenotypic variation and disease. (shrink)

Cis‐regulatory elements govern gene expression programs to determine cell identity during development. Recently, the possibility that multiple enhancers are orchestrated in clusters of enhancers has been suggested. How these elements are arranged in the 3D space to control the activation of a specific promoter remains unclear. Our recent work revealed that the TGFβ pathway drives the assembly of enhancer clusters and precise gene activation during neurogenesis. We discovered that the TGFβ pathway coactivator JMJD3 was essential in maintaining (...) these structures in the 3D space. To do that, JMJD3 required an intrinsically disordered region involved in forming phase‐separated biomolecular condensates found in the enhancer clusters. Our data support the existence of a relationship between 3D‐conformation of the chromatin, biomolecular condensates, and TGFβ‐driven response during mammalian neurogenesis. In this review, we discuss how signaling (TGFβ), epigenetics (JMJD3), and biochemical properties (biomolecular condensates nucleation) are coordinated to modulate the genome structure to guarantee proper neural development. Moreover, we comment on the potential underlying mechanisms and implications of the enhancer‐mediated regulation. Finally, we point out the knowledge gaps that still need to be addressed. (shrink)

Transposable elements (TEs) have emerged as important factors in establishing the cell type‐specific gene regulatory networks and evolutionary novelty of embryonic and placental development. Recently, studies on the role of TEs and their dysregulation in cancers have shed light on the transcriptional, transpositional, and regulatory activity of TEs, revealing that the activation of developmental transcriptional programs by TEs may have a role in the dedifferentiation of cancer cells to the progenitor‐like cell states. This essay reviews the recent evidence of (...) the cis‐regulatory TEs (henceforth crTE) in normal development and malignancy as well as the key transcription factors and regulatory pathways that are implicated in both cell states, and presents existing gaps remaining to be studied, limitations of current technologies, and therapeutic possibilities. (shrink)

Metazoan genomes contain thousands of protein‐coding and non‐coding RNA genes, most of which are differentially expressed, i.e., at different locations, at different times during development, or in response to environmental signals. Differential gene expression is achieved through complex regulatory networks that are controlled in part by two types of trans‐regulators: transcription factors (TFs) and microRNAs (miRNAs). TFs bind to cis‐regulatory DNA elements that are often located in or near their target genes, while miRNAs hybridize to cis‐regulatory RNA (...) elements mostly located in the 3′ untranslated region of their target mRNAs. Here, we describe how these trans‐regulators interact with each other in the context of gene regulatory networks to coordinate gene expression at the genome‐scale level, and discuss future challenges of integrating these networks with other types of functional networks. (shrink)

The genomes of vertebrates, flies, and nematodes contain highly conserved noncoding elements (CNEs). CNEs cluster around genes that regulate development, and where tested, they can act as transcriptional enhancers. Within an animal group CNEs are the most conserved sequences but between groups they are normally diverged beyond recognition. Alternative CNEs are, however, associated with an overlapping set of genes that control development in all animals. Here, we discuss the evidence that CNEs are part of the core gene regulatory networks (...) (GRNs) that specify alternative animal body plans. The major animal groups arose >550 million years ago. We propose that the cis‐regulatory inputs identified by CNEs arose during the “re‐wiring” of regulatory interactions that occurred during early animal evolution. Consequently, different animal groups, with different core GRNs, contain alternative sets of CNEs. Due to the subsequent stability of animal body plans, these core regulatory sequences have been evolving in parallel under strong purifying selection in different animal groups. (shrink)

The ability to transfer genes from one species to another provides a powerful method to study genetic regulatory differences between species in a homogeneous genetic background. A survey of several transgenic animal experiments indicates that the vast majority of regulatory differences observed between species are due to differences in the cis‐acting elements associated with the genes under study. A corollary is that in almost all cases the host species provides the necessary regulatory proteins for expression of the transgenes in (...) specific tissues in which the endogenous homolog is not expressed. Although the details of the cis‐acting differences are unknown for most cases, it appears that these differences may consist of the acquisition or loss of unique elements or subtle variation of conserved elements. It is unknown whether much of this variation is directly related to adaptive evolution. The identification of the promoter enhancer elements responsible for these differences is an important first step in examining the functional significance of this variation. (shrink)

The early discovery of cis‐regulatory elements able to promote transcription of genes over large distances led to the postulate that elements, termed insulators, should also exist that would limit the action of enhancers, LCRs and silencers to defined domains. Such insulators were indeed found during the past fifteen years in a wide range of organisms, from yeast to humans. Recent advances point to an important role of transcription factors in insulator activity and demonstrate that the operational observation (...) of an insulator effect relies on a delicate balance between the “efficiency” of the insulator and that of the element to be counteracted. In addition, genuine insulator elements now appear less common than initially envisaged, and they are only found at loci displaying a high density of coding or regulatory information. Where this is not the case, chromatin domains of opposing properties are thought to confront each other at “fuzzy” boundaries. In this article, we propose models for both fixed and fuzzy boundaries that incorporate probabilistic and dynamic parameters. BioEssays 26:523–532, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

One facet of the control of gene expression is long‐range promoter regulation by distant enhancers. It is an important component of the regulation of genes that control metazoan development and has been appreciated for some time but the molecular mechanisms underlying this regulation have remained poorly understood. A recent study by Cleard and colleagues1 reports the first in vivo evidence of chromatin looping and boundary element promoter interaction. Specifically, they studied the function of a boundary element within the cis‐regulatory (...) region of the Abdominal‐B (Abd‐B) gene of Drosophila melanogaster. BioEssays 29: 7–10, 2007. © 2006 Wiley Periodicals, Inc. (shrink)

The major challenge in complex disease genetics is to understand the fundamental features of this complexity and why functional alterations at multiple independent genes conspire to lead to an abnormal phenotype. We hypothesize that the various genes involved are all functionally united through gene regulatory networks (GRN), and that mutant phenotypes arise from the consequent perturbation of one or more rate‐limiting steps that affect the function of the entire GRN. Understanding a complex phenotype thus entails unraveling the details of each (...) GRN, namely, the transcription factors that bind to cis regulatory elements affected by sequence variants altering transcription of specific genes, and their mutual feedback relationships. These GRNs can be identified through their rate‐limiting steps and are best uncovered by genomic analyses of rare, extreme phenotype families, thus providing a coherent molecular basis to complex traits and disorders. (shrink)

The transcription of rat prolactin and growth hormone genes in vitro requires a pituitary transcription factor, specific to certain cell types in the pituitary, which currently appears to be the PUF‐I/Pit‐1/GHF‐1 protein. This factor binds to cis‐regulatory elements in the 5′ region of both genes and exerts a positive influence on transcription initiation presumably by interacting with general transcription factors. The PUF‐I/Pit‐1/GHF‐1 transcriptional regulatory protein probably has an important role in not only the differentiation of the pituitary lactotroph/somatotroph (...) cell lineage; it is also expressed in the early development of the nervous system but its function there is less well documented. It appears to be one member of a family of trans‐activator proteins involved in differential gene expression in several cell types. (shrink)

Embryonic stem cells are derived from the preimplantation embryo and can differentiate into virtually any other cell type, which is governed by lineage specific transcriptions factors binding to cis regulatory elements to mediate changes in gene expression. The reliance on transcriptional regulation to maintain pluripotency makes ESCs a valuable model to study the role of distal CREs such as enhancers in modulating gene expression to affect cell fate decisions. This review will highlight recent advance on transcriptional enhancers, focusing on (...) studies performed in ESCs. In addition, we argue that the Nanog locus, which encodes for an ESC-critical TF, is particularly informative because it contains multiple co-regulated genes and enhancers in close proximity to one another. The unique landscape at Nanog permits the study of ongoing questions including whether multiple enhancers function additively versus synergistically, determinants of gene specificity, and cell-to-cell variability in gene expression. Nanog encodes a transcription factor required to maintain ESC pluripotency. The Nanog locus is an ideal model to study enhancers because it contains multiple highly potent super-enhancers within a small region. Nanog and three super-enhancers are in close physical proximity but only two SEs are required for Nanog expression. (shrink)

The interactions between genetic and environmental risk factors contribute to the aetiology of complex human diseases. Genome‐wide association studies (GWAS) have revealed that most of the genetic variants associated with complex diseases are located in the non‐coding part of the genome, preferentially within enhancers. Enhancers are distal cis‐regulatory elements composed of clusters of transcription factors binding sites that positively regulate the expression of their target genes. The generation of genome‐wide maps for histone marks (e.g., H3K27ac), chromatin accessibility and (...) transcription factor and coactivator (e.g., p300) binding profiles have enabled the identification of enhancers across many human cell types and tissues. Nonetheless, the functional and pathological consequences of the majority of disease‐associated genetic variants located within enhancers seem to be rather minor under normal conditions, thus questioning their medical relevance. Here we propose that, due to the prevalence of enhancer redundancy, the pathological effects of many disease‐associated non‐coding genetic variants might be preferentially (or even only) manifested under environmental stress. (shrink)

There are two intriguing paradoxes in molecular biology-the inconsistent relationship between organismal complexity and (1) cellular DNA content and (2) the number of protein-coding genes-referred to as the C-value and G-value paradoxes, respectively. The C-value paradox may be largely explained by varying ploidy. The G-value paradox is more problematic, as the extent of protein coding sequence remains relatively static over a wide range of developmental complexity. We show by analysis of sequenced genomes that the relative amount of non-protein-coding sequence increases (...) consistently with complexity. We also show that the distribution of introns in complex organisms is non-random. Genes composed of large amounts of intronic sequence are significantly overrepresented amongst genes that are highly expressed in the nervous system, and amongst genes downregulated in embryonic stem cells and cancers. We suggest that the informational paradox in complex organisms may be explained by the expansion of cis-acting regulatory elements and genes specifying trans-acting non-protein-coding RNAs. (shrink)

Homeotic genes are subject to transcriptional silencing, which prevents their expression in inappropriate body regions. Here, we shall focus on Drosophila, as little is known about this process in other organisms. Evidence is accumulating that silencing of Drosophila homeotic genes is conferred by two types of cis‐regulatory sequences: initiation (SIL‐I) and maintenance (SIL‐M) elements. The former contain target sites for transient repressors with a highly localised distribution in the early embryo and the latter for constitutive repressors that are (...) likely to be present in all cells. We discuss how SIL‐I elements may cooperate with SIL‐M elements to promote formation of a silencing complex. We propose that this complex consists of specific non‐histone proteins, the so‐called Polycomb group proteins, and that it is anchored at SIL‐M elements and at the promoter. (shrink)

The DNA in a eukaryotic nucleus is packaged into a nucleosome array, punctuated by variations in the regular pattern. The local chromatin structure of inducible genes appears to fall into two categories: preset and remodeling. Preset genes are those in which the binding sites for trans‐acting factors are accessible (;i.e. in a non‐nucleosomal, DNase I hypersensitive configuration) prior to activation. In response to the activation signal, positive factors bind to cis‐acting regulatory elements and trigger transcription with no major alterations (...) in the chromatin structure of the promoter region. In contrast, remodeling genes are those in which some of the required cis‐acting regulatory elements are packaged into nucleosomes. The nucleosomes must be perturbed in response to an activation signal in order for the trans‐acting factors to gain access to cis‐acting elements; a chromatin remodeling process which forms DNase I hypersensitive sites must occur. In both cases, precise positioning of nucleosomes along the promoter region of a gene appears to be critical for appropriate regulation of expression. (shrink)

The most striking region of structural differentiation of a eukaryotic chromosome is the kinetochore. This chromosomal domain plays an integral role in the stability and propagation of genetic material to the progeny cells during cell division. The DNA component of this structure, which we refer to as the centromere, has been localized to a small region of 220–250 base pairs within the chromosomes from the yeast Saccharomyces cerevisiae. The centromere DNA (CEN) is organized in a unique structure in the cell (...) nucleus and is required for chromosome stability during both mitotic and meiotic cell cycles. The centromeres from one chromosome can stabilize small circular minichromosomes or other yeast chromosomes. The centromeres may therefore interact with the same components of the segregation apparatus regardless of the chromosome in which they reside. The CEN DNA does not encode any regulatory RNAs or proteins, but rather is a cis‐acting element that provides genetic stability to adjacent DNA sequences. (shrink)

Transposable elements (TEs) are sequences currently or historically mobile, and are present across all eukaryotic genomes. A growing interest in understanding the regulation and function of TEs has revealed seemingly dichotomous roles for these elements in evolution, development, and disease. On the one hand, many gene regulatory networks owe their organization to the spread of cis‐elements and DNA binding sites through TE mobilization during evolution. On the other hand, the uncontrolled activity of transposons can generate mutations and (...) contribute to disease, including cancer, while their increased expression may also trigger immune pathways that result in inflammation or senescence. Interestingly, TEs have recently been found to have novel essential functions during mammalian development. Here, the function and regulation of TEs are discussed, with a focus on LINE1 in mammals. It is proposed that LINE1 is a beneficial endogenous dual regulator of gene expression and genomic diversity during mammalian development, and that both of these functions may be detrimental if deregulated in disease contexts. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Legitimacy, Performance, and Political Realism:Response to Ben CrossJiwei Ci (bio)Ben Cross raises important issues in his article and provides a much appreciated occasion for me to join the discussion. He targets his trenchant critique at what he calls Weberian sources of legitimacy, treating my view as a distinctive variation on the Weberian account. I am not sure that the issues on which we differ are most economically framed by (...) drawing Weber so prominently into the debate. Since Cross has already framed the issues in this way, however, I think I can best contribute to the exchange by accepting his terms of reference wherever appropriate and trying to work as fruitfully as possible within them. I will respectfully not take up any of the issues raised in the fourth section of the article, because Cross's use of the notion of civic agency there is so far removed from mine as to leave little room for productive engagement.As Cross notes, Weber identifies three distinct sources of legitimacy (or three types of authority): legality, the traditional, and the charismatic. This, however, is only a typology of specific sources and an incomplete one at that, for it does not cover the two sources that I happen to find most relevant in Democracy in China.1 The teleological legitimacy much discussed in chapter 1 of my book does not come under any of Weber's ideal types and seems to constitute another, distinct ideal type. Nor is the democratic legitimacy based on popular sovereignty that is proposed in chapter 3 as an alternative to teleological legitimacy quite the same as legal authority. It is thus easy to see that—and why—I do not avail myself of what Cross calls the Weberian sources of legitimacy. As a matter of fact, I do not [End Page 149] regard Weber's tripartite classification, regardless of whether it is exhaustive, as the conceptual core of his idea of legitimacy.Cross moves closer to that core when he notes the difference between the type of motive (i.e., non-expedient) that the three Weberian sources of legitimacy are supposed to have in common and the motive of pure expediency. This difference is important because, as Weber puts it in a well-known statement quoted by Cross, "Purely material interests and calculations of advantages as the basis of solidarity between the chief and his administrative staff result, in this as in other connexions, in a relatively unstable situation." Based on Weber's concern with the lack of stability characteristic of relations of pure expediency, Cross is then able to speak of a "Weber-inspired rejection of performance legitimacy." This conclusion, if not exactly mistaken, is nevertheless reached without adequately bringing out the issues involved.Take a close look at the passage in Economy and Society from which the above quote is taken:Purely material interests and calculations of advantages as the basis of solidarity between the chief and his administrative staff result, in this as in other connexions, in a relatively unstable situation. Normally other elements, affectual and ideal, supplement such interests. In certain exceptional cases the former alone may be decisive. In everyday life these relationships, like others, are governed by custom and material calculation of advantage. But custom, personal advantage, and purely affectual or ideal motives of solidarity do not form a sufficiently reliable basis for a given domination. In addition there is normally a further element, the belief in legitimacy.2Here it becomes clear that Weber, even in emphasizing the indispensable role of belief in legitimacy, argues his case much more cautiously and subtly than Cross gives one to understand. To begin with we see Weber take the trouble to stress "purely." We then find three qualifications in a row before Weber allows himself to conclude, as an empirical observation, that "custom, personal advantage, purely affectual or ideal motives of solidarity, do not form a sufficiently reliable basis for a given domination," from which he is apparently compelled to draw the inference that "there is normally a further element, the belief in legitimacy." In an earlier section of Economy and Society Weber makes similar allowances for the empirical proximity of motives... (shrink)

In this article, the views of Yusuf al-Qaradawi (d. 2022) on the change of the fatwa are discussed. Other issues of the fatwa method are generally excluded from the scope. At the point of solving new problems, the change of the fatwa is important. The aim of the study is to reveal al-Qaradawi's contribution to the issue of changing the fatwa. In this study, in which the qualitative research method was used, thematic reading was made. As it is known, scholars (...) have adopted the idea that the provisions open to ijtihad can be changed. According to al-Qaradawi, there is even a consensus on this. Likewise, there is a consensus that the final provisions are not subject to change. al-Qaradawi mentioned that independent ijtihad activities should continue. Because only in this way can fiqh remain alive and dynamic. Therefore, it can solve new problems. Therefore, the idea that the door of ijtihad is closed cannot be accepted. On the other hand, scholars should take into account the ancient jurisprudence. It should contribute to this information by adding or correcting it. The principles that allow the change of the fatwa are four in the form of time, place, situation and custom. al-Qaradawi stated that he added six new elements to these. These are as follows: The change of information, the change of people's needs, the change of people's power and possibilities, umumu'l-balwa, the change of social, economic and political conditions, the change of opinion and idea. The author has reached these six elements as a result of a deep research. Muftis should take these factors into consideration when issuing a fatwa. Because the maslahah of the servants and the principle of convenience require this. (shrink)

Recent studies indicate that mammalian chromosomes contain discretecis‐acting loci that control replication timing, mitotic condensation, and stability of entire chromosomes. Disruption of the large non‐coding RNA gene ASAR6 results in late replication, an under‐condensed appearance during mitosis, and structural instability of human chromosome 6. Similarly, disruption of the mouse Xist gene in adult somatic cells results in a late replication and instability phenotype on the X chromosome. ASAR6 shares many characteristics with Xist, including random mono‐allelic expression and asynchronous replication timing. (...) Additional “chromosome engineering” studies indicate that certain chromosome rearrangements affecting many different chromosomes display this abnormal replication and instability phenotype. These observations suggest that all mammalian chromosomes contain “inactivation/stability centers” that control proper replication, condensation, and stability of individual chromosomes. Therefore, mammalian chromosomes contain four types ofcis‐acting elements, origins, telomeres, centromeres, and “inactivation/stability centers”, all functioning to ensure proper replication, condensation, segregation, and stability of individual chromosomes. (shrink)

The stable differentiation of cells into other cell types typically involves dramatic reorganization of cellular structures and functions. This often includes remodeling of the cell cycle and the apparatus that controls it. Here we review our understanding of the role and regulation of cell cycle control elements during cell differentiation in the yeast, Saccharomyces cerevisiae. Although the process of differentiation may be more overtly obvious in metazoan organisms, those systems are by nature more difficult to study at a mechanistic (...) level. We consider the relatively well‐understood mechanisms by which mating‐type switching and the pheromone‐induced differentiation of gametes are coupled to the cell cycle as well as the more obscure mechanisms that govern the remodeling of the cell cycle during meiosis and filamentous growth. In some cases, the cell cycle is a primary stimulus for differentiation whereas, in other cases, the signals that promote differentiation alter the cell cycle. Thus, despite relative simplicity of these processes in yeast, the nature of the interplay between the cell cycle and differentiation is diverse. BioEssays 25:856–867, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

BACKGROUND: Alzheimer's disease is intimately tied to amyloid-beta peptide. Extraneuronal brain plaques consisting primarily of Abeta aggregates are a hallmark of AD. Intraneuronal Abeta subunits are strongly implicated in disease progression. Protein sequence mutations of the Abeta precursor protein account for a small proportion of AD cases, suggesting that regulation of the associated gene may play a more important role in AD etiology. The APP promoter possesses a novel 30 nucleotide sequence, or "proximal regulatory element" , at -76/-47, from the (...) +1 transcription start site that confers cell type specificity. This PRE contains sequences that make it vulnerable to epigenetic modification and may present a viable target for drug studies. We examined PRE-nuclear protein interaction by gel electrophoretic mobility shift assay and PRE mutant EMSA. This was followed by functional studies of PRE mutant/reporter gene fusion clones. RESULTS: EMSA probed with the PRE showed DNA-protein interaction in multiple nuclear extracts and in human brain tissue nuclear extract in a tissue-type specific manner. We identified transcription factors that are likely to bind the PRE, using competition gel shift and gel supershift: Activator protein 2 , nm23 nucleoside diphosphate kinase/metastatic inhibitory protein , and specificity protein 1 . These sites crossed a known single nucleotide polymorphism . EMSA with PRE mutants and promoter/reporter clone transfection analysis further implicated PuF in cells and extracts. Functional assays of mutant/reporter clone transfections were evaluated by ELISA of reporter protein levels. EMSA and ELISA results correlated by meta-analysis. CONCLUSIONS: We propose that PuF may regulate the APP gene promoter and that AD risk may be increased by interference with PuF regulation at the PRE. PuF is targeted by calcium/calmodulin-dependent protein kinase II inhibitor 1, which also interacts with the integrins. These proteins are connected to vital cellular and neurological functions. In addition, the transcription factor PuF is a known inhibitor of metastasis and regulates cell growth during development. Given that APP is a known cell adhesion protein and ferroxidase, this suggests biochemical links among cell signaling, the cell cycle, iron metabolism in cancer, and AD in the context of overall aging. (shrink)

Transposable elements are no longer considered to be “junk” DNA. Here, we review how TEs can impact gene regulation systematically. TEs encode various regulatory elements that enables them to regulate gene expression. RJ Britten and EH Davidson hypothesized that TEs can integrate the function of various transcriptional regulators into gene regulatory networks. Uniquely TEs can deposit regulatory sites across the genome when they transpose, and thereby bring multiple genes under control of the same regulatory logic. Several studies together (...) have robustly established that TEs participate in embryonic development and oncogenesis. We discuss the regulatory characteristics of TEs in context of evolution to understand the extent of their impact on gene networks. Understanding these features of TEs is central to future investigations of TEs in cellular processes and phenotypic presentations, which are applicable to development and disease studies. We re-visit the Britten–Davidson “gene-battery” model and understand the genetic and transcriptional impact of TEs in innovating gene regulatory networks. Transposable elements are exogenous sequences that have either been co-opted or repurposed for host functions. The vast amounts of TE sequence in the genome provides raw material for gene expression regulation, and still remains to be fully understood; the “gene-battery” model provides the basis for understanding this. (shrink)

DNA with a curved trajectory of its helix axis is called bent DNA, or curved DNA. Interestingly, biologically important DNA regions often contain this structure, irrespective of the origin of DNA. In the last decade, considerable progress has been made in clarifying one role of bent DNA in prokaryotic transcription and its mechanism of action. However, the role of bent DNA in eukaryotic transcription remains unclear. Our recent study raises the possibility that bent DNA is implicated in the “functional packaging” (...) of transcriptional regulatory regions into chromatin. In this article, I review recent progress in bent DNA research in eukaryotic transcription, and summarize the history of bent DNA research and several subjects relevant to this theme. Finally, I propose a hypothesis that bent DNA structures that mimic a negative supercoil, or have a right‐handed superhelical writhe, organize local chromatin infrastructure to help the very first interaction between cis‐acting DNA elements and activators that trigger transcription. BioEssays 23:708–715, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

The cis-regulatory hypothesis is one of the most important claims of evolutionary developmental biology. In this paper I examine the theoretical argument for cis-regulatory evolution and its role within evolutionary theorizing. I show that, although the argument has some weaknesses, it acts as a useful example for the importance of current scientific debates for science education.

The article analyses the legal status of the natural gas market regulatory institutions in Lithuania and in the member states of the European Union. First, the authors assess the most important elements of the legal status of the natural gas market regulators in the EU member states, namely, the degree of autonomy (type of institution, appointment and dismissal procedures of management, duration of the terms of office, sources of funding) and the measures aimed at ensuring accountability, transparency, and prevention (...) of conflicts of interest. Second, the legal status of the National Control Commission for Prices and Energy, which carries out functions of regulation and control of the natural gas sector in Lithuania, is examined. Finally, the authors conclude that the imperfections in the regulation of the legal status of the Commission result in several negative effects and provide reasoned proposals regarding the improvement of the legal status of the Commission. (shrink)

Theories of the genetics underlying punctuated equilibrium (PE) have been vague to date. Here the developmental gene hypothesis is proposed, which states that: 1) developmental regulatory (DevReg) genes are responsible for the orchestration of metazoan morphogenesis and their extreme conservation and mutation intolerance generates the equilibrium or stasis present throughout much of the fossil record and 2) the accumulation of regulatory elements and recombination within these same genes—often derived from transposable elements—drives punctuated bursts of morphological divergence and speciation (...) across metazoa. This two‐part hypothesis helps to explain the features that characterize PE, providing a theoretical genetic basis for the once‐controversial theory. Also see the video abstract here https://youtu.be/C-fu-ks5yDs. (shrink)

The generation of patterns and the diversity of cell types in a multicellular organism require differential gene regulation. At the heart of this process are enhancers or cis‐regulatory modules (CRMs), genomic regions that are bound by transcription factors (TFs) that control spatio‐temporal gene expression in developmental networks. To date, only a few CRMs have been studied in detail and the underlying cis‐regulatory code is not well understood. Here, we review recent progress on the genome‐wide identification of CRMs with (...) chromatin immunoprecipitation of TF‐DNA complexes followed by microarrays (ChIP‐on‐chip). We focus on two computational approaches that have succeeded in predicting the expression pattern driven by a CRM either based on TF binding site preferences and their expression levels, or quantitative analysis of CRM occupancy by key TFs. We also discuss the current limits of these methods and highlight some of the key problems that have to be solved to gain a more complete understanding of the structure and function of CRMs. (shrink)

Super commentaries on Pañcīkaraṇa by Śaṅkarācārya, and Pañcīkaraṇavārttika by Surēśvarācārya, verse works on the apparent manifestation of the Absolute (Brahman) in the phenomenal world through the five basic elements (Pañcamahābhūtās).

Zeins are a group of alcohol‐soluble proteins that are synthesized in the endosperm of developing maize seeds. These proteins are encoded by a large number of genes located on several chromosomes; based upon the number of mutants that have been isolated, zein gene regulation is complex. Comparisons of gene flanking regions reveal conserved sequences that may be important for their regulation. Studies of transformed plant tissues support the assertion that cis‐acting elements with the 5′ flanking regions of zein genes (...) are required for accurate transcription. Although the genes are transcribed in transgenic tobacco and petunia plants, they are not properly regulated. This appears to be due to transcriptional effects rather than protein or mRNA instability. (shrink)

Iron uptake and storage in mammalian cells is at least partly regulated at a posttranscriptional level by the iron regulatory proteins (IRP‐1 and IRP‐2). These cytoplasmic regulators share 79% similarity in protein sequence and bind tightly to conserved mRNA stem‐loops, named iron‐responsive elements (IREs). The IRP:IRE interaction underlies the regulation of translation and stability of several mRNAs central to iron metabolism. The question of why the cell requires two such closely related regulatory proteins may be resloved as we learn (...) more about the expression and regulation of these proteins. It is evident so far that, despite similarities, the IRPs differ in several important respects. They are coordinately regulated by cellular iron, but whereas IRP‐1 is inactivated by high iron levels, IRP‐2 is rapidly degraded. Further differences arise in their expression and RNA‐binding specificity. The two proteins each recognise a large repertoire of IRE‐like sequences, including a small group of exclusive RNA targets. These findings hint that IRP‐1 and IRP‐2 may bind preferenitially to certain mRNAs in vivo, possibly extending their known functions beyond the regulation of intracellular iron homeostasis. (shrink)

Evolution is frequently concentrated in bursts of rapid morphological change and speciation followed by long‐term stasis. We propose that this pattern of punctuated equilibria results from an evolutionary tug‐of‐war between host genomes and transposable elements (TEs) mediated through the epigenome. According to this hypothesis, epigenetic regulatory mechanisms (RNA interference, DNA methylation and histone modifications) maintain stasis by suppressing TE mobilization. However, physiological stress, induced by climate change or invasion of new habitats, disrupts epigenetic regulation and unleashes TEs. With their (...) capacity to drive non‐adaptive host evolution, mobilized TEs can restructure the genome and displace populations from adaptive peaks, thus providing an escape from stasis and generating genetic innovations required for rapid diversification. This “epi‐transposon hypothesis” can not only explain macroevolutionary tempo and mode, but may also resolve other long‐standing controversies, such as Wright's shifting balance theory, Mayr's peripheral isolates model, and McClintock's view of genome restructuring as an adaptive response to challenge. (shrink)

Transposable elements (TEs) are mobile genomic elements constituting a big fraction of eukaryotic genomes. They ignite an evolutionary arms race with host genomes, which in turn evolve strategies to restrict their activity. Despite being tightly repressed, TEs display precisely regulated expression patterns during specific stages of mammalian development, suggesting potential benefits for the host. Among TEs, the long interspersed nuclear element (LINE‐1 or L1) has been found to be active in neurons. This activity prompted extensive research into its (...) possible role in cognition. So far, no specific cause‐effect relationship between L1 retrotransposition and brain functions has been conclusively identified. Nevertheless, accumulating evidence suggests that interactions between L1 RNAs and RNA/DNA binding proteins encode specific messages that cells utilize to activate or repress entire transcriptional programs. We summarize recent findings highlighting the activity of L1 RNAs at the non‐coding level during early embryonic and brain development. We propose a hypothesis suggesting a mutualistic relationship between L1 mRNAs and the host cell. In this scenario, cells tolerate a certain rate of retrotransposition to leverage the regulatory effects of L1s as non‐coding RNAs on potentiating their mitotic potential. In turn, L1s benefit from the cell's proliferative state to increase their chance to mobilize. (shrink)

Comme l’attestent les textes relatifs à la cosmologie de Bardesane, le monde est venu à l’existence à partir des esṭuksē / ītyē, qui correspondraient aux éléments primordiaux de la tradition philosophique grecque. Bien que la cosmologie de Bardesane soit déjà étudiée, les témoignages au sujet des esṭuksē / ītyē contiennent des contradictions difficiles à expliquer. Le présent article propose une nouvelle interprétation de la doctrine de Bardesane, fondée sur la comparaison avec la cosmologie d’Aristote. L’approche aristotélicienne du mouvement des éléments, (...) de leurs qualités et leurs actions réciproques, donne une meilleure compréhension des points obscurs de la doctrine bardesanite et permet de retrouver la cohérence de celle-ci. En outre, le débat engagé par Aristote avec les théories atomistes aide à comprendre la place des perdē – atomes – dans le système de Bardesane. (shrink)

The ontogeny of the vertebrate retina has been a topic of interest to developmental biologists and human geneticists for many decades. Understanding the unfolding of the genetic program that transforms a field of progenitors cells into a functionally complex and multi‐layered sensory organ is a formidable challenge. Although classical genetic studies succeeded in identifying the key regulators of retina specification, understanding the architecture of their gene network and predicting their behavior are still a distant hope. The emergence of next‐generation sequencing (...) platforms revolutionized the field unlocking the access to genome‐wide datasets. Emerging techniques such as RNA‐seq, ChIP‐seq, ATAC‐seq, or single cell RNA‐seq are used to characterize eye developmental programs. These studies provide valuable information on the transcriptional and cis‐regulatory profiles of precursors and differentiated cells, outlining the trajectories that connect each intermediate state. Here, recent systems biology efforts are reviewed to understand the genetic programs shaping the vertebrate retina. (shrink)

Advaita verse work, with the supplement by Sureśvarācārya, about the apparent manifestation of the Absolute (Brahman) into the phenomenal world through the five primary elements.

When state regulations prevent owners from certain uses of their property, is this action of the state a taking of property which requires compensation? One way of answering this problem, within a framework viewing property as a bundle of rights, is to inquire into whether the incident of use is an essential element of the bundle making up the property. Given the difficulties with figuring out what is essential and what is not, I propose an alternative solution, which does not (...) give up the bundle-of-rights framework, but which, while assuming all incidents to be equally essential, it concentrates, instead, upon the legal entitlements conveying those incidents. I begin by arguing that while the incident of possession may be expressed by a right to exclude, the incident of use is expressed by a Hohfeldian liberty, and then I consider the consequences of this argument for the question of regulatory takings. I argue that while the liberty to use does not render the incident of use meaningless (at least, insofar as regulation of property use is concerned), there is nonetheless a significant distinction between transgressing a right and transgressing a liberty, and this implies that what it takes for an infringement of the right to exclude to be translated into a taking of the (whole) property is less than what it takes for the infringement of the liberty to use to be translated into a taking of property. As I show in the paper, we can achieve this result either by means of an argument from ‘constitutional residue’ or by means of an argument from the specification of constitutional rights. (shrink)

We give in this paper indications about the dynamical impact coming from the main sources of perturbation in biological regulatory networks. First, we define the boundary of the interaction graph expressing the regulations between the main elements of the network . Then, we search what changes in the state values on the boundary could cause some changes of states in the core of the system . After, we analyse the role of the mode of updating on the asymptotics of (...) the network, essentially on the occurrence of limit cycles . Finally, we show the influence of some topological changes on the dynamical behaviour of the system. (shrink)

Transparency is a salutary value in our constitutional architecture. It has also been described as a necessary element in promoting accountability in the regulatory aspects of essential medicines. Despite its several incarnations, the Medicines and Related Substances Act (Medicines Act) retains a provision headed 'Preservation of secrecy' (section 34). This contributionseeks to evaluate section 34 in the context of transparency and ascertain whether it is in conflict with other legislation pertaining to the promotion of access to information and, in particular, (...) whether it is consistent with the Constitution of the Republic of South Africa. (shrink)

Cellular differentiation and multicellular development require the programmed expression of coregulated suites of genetic loci dispersed throughout the genome. How do functionally diverse loci come to share common regulatory motifs? A new paper finds that retrotransposons (RTEs) may play a role in providing common regulation to a group of functions expressed during the development of oocytes and preimplantation embryos. Examining cDNA libraries, Peaston et al.1 find that 13% of all processed transcripts in full-grown mouse oocytes contain RTE sequences, mostly from (...) the MT family of retroviral-like elements. Smaller but still significant percentages of RTE sequences are found in cDNA libraries from 2-cell embryos and blastocysts. A quarter of these RTE sequences are at the 5′ ends of chimeric transcripts that also contain exons from endogenous mouse loci. These chimeric transcripts display restricted expression in oocytes and preimplantation embryos and presumably originate from developmentally regulated LTR promoters. Some, but not all, chimeric transcripts encode novel protein products. BioEssays 27:122–125, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

We discuss here a series of testable hypotheses concerning the role of chromosome folding into topologically associating domains (TADs). Several lines of evidence suggest that segmental packaging of chromosomal neighborhoods may underlie features of chromatin that span large domains, such as heterochromatin blocks, association with the nuclear lamina and replication timing. By defining which DNA elements preferentially contact each other, the segmentation of chromosomes into TADs may also underlie many properties of long‐range transcriptional regulation. Several observations suggest that TADs (...) can indeed provide a structural basis to regulatory landscapes, by controlling enhancer sharing and allocation. We also discuss how TADs may shape the evolution of chromosomes, by causing maintenance of synteny over large chromosomal segments. Finally we suggest a series of experiments to challenge these ideas and provide concrete examples illustrating how they could be practically applied. (shrink)

Sont ici étudiés (sur un corpus d’articles scientifiques) les éléments initiaux dans les énoncés comportant une inversion du sujet – inversion (simple ou complexe) du sujet pronominal, et inversion (complète ou absolue) du sujet nominal. Dans la perspective macro-syntaxique adoptée, il est montré que, selon le type d’inversion du sujet et la nature des éléments initiaux, ceux-ci sont tantôt des périphériques extra-prédicatifs préfixés au noyau, tantôt des constituants intra-prédicatifs du noyau.

In 2013, controversy sparked student protests, campus debates, and national attention when Smith College denied admittance to Calliope Wong—a trans woman. Since then, eight women’s colleges have revised their admissions policies to include different gender identities such as trans women and genderqueer people. Given the recency of such policies, we interrogate the ways the category “woman” is determined through certain alignments of biology-, legal-, and identity-based criteria. Through an inductive analysis of administrative scripts appearing both in student newspapers and in (...) trans admittance policies, we highlight two areas U.S. women’s colleges straddle while creating these policies: inclusion/exclusion scripts of self-identification and legal documentation, and tradition-/activism-speak. Through these tensions, women’s college admittance policies not only construct “womanhood” but also serve as regulatory norms that redo gender as a structuring agent within the gendered organization. (shrink)

Consolidation of long-term memory is a highly and precisely regulated multistep process. The transcription regulator cAMP response element-binding protein (CREB) plays a key role in initiating memory consolidation. With time processing, first the cofactors are changed and, secondly, CREB gets dispensable. This ultimately changes the expressed gene program to genes required to maintain the memory. Regulation of memory consolidation also requires epigenetic mechanisms and control at the RNA level. At the neuronal circuit level, oscillation in the activity of CREB and (...) downstream factor define engram cells. Together the combination of all regulation mechanisms allows correct memory processing while keeping the process dynamic and flexible to adjust to different contexts. Also see the video abstract here https://youtu.be/BhSCSmorpEc. (shrink)