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)

Histone acetylation is an important regulatory mechanism that controls transcription and diverse nuclear processes. While great progress has been made in understanding how localized acetylation and deacetylation control promoter activity, virtually nothing is known about the consequences of acetylation throughout entire chromosomal regions. An increasing number of genes have been found to reside in large chromatin domains that are controlled by regulatory elements many kilobases away. Recent studies have shown that broad histone acetylation patterns are hallmarks of chromatin domains. The (...) purpose of this review is to discuss how such patterns are established and their implications for regulating gene expression. BioEssays 23:820–830, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Post‐transcriptional regulation faces a distinctive challenge in gametes. Transcription is limited when the germ cells enter the division phase due to condensed chromatin, while gene expression during gamete maturation, fertilization, and early cleavage depends on existing mRNA post‐transcriptional coordination. The dynamics of the 3ʹ‐poly(A) tail play crucial roles in defining mRNA fate. The 3ʹ‐poly(A) tail is covered with poly(A)‐binding proteins (PABPs) that help to mediate mRNA metabolism and recent work has shed light on the number and function (...) of germ cell‐specific expressed PABPs. There are two structurally different PABP groups distinguished by their cytoplasmic and nuclear localization. Both lack catalytic activity but are coupled with various roles through their interaction with multifunctional partners during mRNA metabolism. Here, we present a synopsis of PABP function during gametogenesis and early embryogenesis and describe both conventional and current models of the functions and regulation of PABPs, with an emphasis on the physiological significance of how germ cell‐specific PABPs potentially affect human fertility. (shrink)

This paper argues that the “long 1970s” (1969–1983) is an important though often overlooked period in the development of a rich landscape in the research of metabolism, development, and evolution. The period is marked by: shrinking public funding of basic science, shifting research agendas in molecular biology, the incorporation of new phenomena and experimental tools from previous biological research at the molecular level, and the development of recombinant DNA techniques. Research was reoriented towards eukaryotic cells and development, and in (...) particular towards “giant” RNA processing and transcription. We will here focus on three different models of developmental regulation published in that period: the two models of eukaryotic genetic regulation at the transcriptional level that were developed by Georgii P. Georgiev on the one hand, and by Roy Britten and Eric Davidson on the other; and the model of genetic sufficiency and evolution of regulatory genes proposed by Emile Zuckerkandl. These three cases illustrate the range of exploratory hypotheses that characterised the challenging landscape of gene regulation in the 1970s, a period that in hindsight can be labelled as transitional, between the biology at the laboratory bench of the preceding period, and the biology of genetic engineering and intensive data-driven research that followed. (shrink)

The vertebrate immune system provides a remarkable showcase of the different ways the genome can be used to specify cellular identity and to mediate cellular function. It is arguably the leading mammalian system in which gene regulation programs that drive the acquisition of specific cell-type identities have been elucidated at the single cell level. More broadly for molecular genomics, the activation-induced gene expression pathways used in immune effector responses have provided textbook cases for fundamental elements of transcription factor assembly (...) at enhancers ; and immune system genes and gene clusters have provided key paradigms for the roles of long-range.. (shrink)

The fate of root epidermal cells is controlled by a complex interplay of transcriptional regulators, generating a genetically determined, position‐biased arrangement of root hair cells. This pattern is altered during postembryonic development and in response to environmental signals to confer developmental plasticity that acclimates the plant to the prevailing conditions. Based on the hypothesis that events downstream of this initial mechanism can modulate the pattern installed during embryogenesis, we have developed a reaction diffusion model that reproduces the root hair (...) patterning previously observed experimentally. Under all growth conditions, an almost equal spacing between root hair forming cells was observed both in vitro and in silico, indicating that long‐range intercellular communication is crucial for the trichoblasts' decision to form a root hair. We assume that a hair growth promoter (HGP) is upregulated in root‐hair‐forming cells by a trichoblast‐specific component. Once established, HGP production is self‐enhancing. The autocatalytic regulation of HGP is antagonized by an HGP‐produced hair growth inhibitor (HGI). HGI is exported from trichoblasts and diffuses to neighboring cells, where it inhibits further HGP production and promotes the non‐hair cell fate. Under conditions of phosphate deficiency, we hypothesise that HGP production is increased and HGI diffusion rate is reduced, leading to a position‐independent formation of extra root hairs. BioEssays 30:75–81, 2008. © 2007 Wiley Periodicals, Inc. (shrink)

A gene's “expression profile” denotes the number of transcripts present relative to all other transcripts. The overall rate of transcript production is determined by transcription and RNA processing rates. While the speed of elongating RNA polymerase II has been characterized for many different genes and organisms, gene‐architectural features – primarily the number and length of exons and introns – have recently emerged as important regulatory players. Several new studies indicate that rapidly cycling cells constrain gene‐architecture toward short genes with a (...) few introns, allowing efficient expression during short cell cycles. In contrast, longer genes with long introns exhibit delayed expression, which can serve as timing mechanisms for patterning processes. These findings indicate that cell cycle constraints drive the evolution of gene‐architecture and shape the transcriptome of a given cell type. Furthermore, a tendency for short genes to be evolutionarily young hints at links between cellular constraints and the evolution of animal ontogeny. (shrink)

Gene transcription in eukaryotes is associated with conformational changes of a large area of chromatin adjacent to a gene. This rearrangement may involve the whole loop (topological domain) to which a given gene belongs.Regulatory events associated with activation or inactivation of transcription are found to act through relatively short nucleotide sequences, often located several thousand base pairs apart from gene. These sequences, termed enhancers may act independently on their distance from or orientation with respect to the gene.Both long‐range (...) conformational rearrangements of chromatin and any long distance effects of enhancers may be associated with elastic torsional strain in DNA, arising in transcriptionally active chromatin loops. Enhancer effects, in particular, may be associated with conformational transitions in DNA competing for the energy deposited in the elastic spring of the DNA. (shrink)

The Arf family proteins are best known for their roles in the vesicle biogenesis. However, they also play fundamental roles in a wide range of cellular regulation besides vesicular trafficking, such as modulation of lipid metabolic enzymes, cytoskeleton remodeling, ciliogenesis, lysosomal, and mitochondrial morphology and functions. Growing studies continue to expand the downstream effector landscape of Arf proteins, especially for the less‐studied members, revealing new biological functions, such as amino acid sensing. Experiments with cutting‐edge technologies and in vivo (...) functional studies in the last decade help to provide a more comprehensive view of Arf family functions. In this review, we summarize the cellular functions that are regulated by at least two different Arf members with an emphasis on those beyond vesicle biogenesis. (shrink)

A recurrent theme in eukaryotic genome regulation stipulates that the properties of DNA are strongly influenced by the nucleoprotein complex into which it is assembled. Methylation of cytosine residues in vertebrate genomes has been implicated in influencing the assembly of locally repressive chromatin architecture. Current models suggest that covalent modification of DNA results in heritable, long‐term transcriptional silencing. In October of 2003, two manuscripts1,2 were published that challenge important aspects of this model, suggesting that modulation of both (...) DNA methylation itself, as well as the machinery implicated in its interpretation, are involved in acute gene regulation. BioEssays 26:217–220, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Recently, transcriptome‐wide sequencing data have revealed the pervasiveness of intergenic long noncoding RNA (lncRNA) transcription. Subsets of lncRNAs have been demonstrated to crosstalk with and post‐transcriptionally regulate mRNAs in a microRNA (miRNA)‐dependent manner. Referred to as long noncoding competitive endogenous RNAs (lnceRNAs), these transcripts can contribute to diverse aspects of organismal and cellular biology, likely by providing a hitherto unrecognized layer of gene expression regulation. Here, we discuss the biological relevance of post‐transcriptional regulation by lnceRNAs, (...) provide insights on recent advances in the understanding of lnceRNA regulatory networks, and speculate on molecular factors that facilitate miRNA‐dependent crosstalk between lnceRNAs and other transcripts. (shrink)

Hedgehog (HH) signaling is a conserved pathway that drives developmental growth and is essential for the formation of most organs. The expression of HH target genes is regulated by a dual switch mechanism where GLI proteins function as bifunctional transcriptional activators (in the presence of HH signaling) and transcriptional repressors (in the absence of HH signaling). This results in a tight control of GLI target gene expression during rapidly changing levels of pathway activity. It has long been (...) presumed that GLI proteins also repress target genes prior to the initial expression of HH in a given tissue. This idea forms the basis for the limb bud pre‐patterning model for regulating digit number. Recent findings indicate that GLI repressor proteins are indeed present prior to HH signaling but contrary to this model, GLI proteins are inert as they do not regulate transcriptional responses or enhancer chromatin modifications at this time. These findings suggest that GLI transcriptional repressor activity is not a default state as assumed, but is itself regulated in an unknown fashion. We discuss these findings and their implications for understanding pre‐patterning, digit regulation, and HH‐driven disease. (shrink)

Numerous accessory factors modulate RNA polymerase response to regulatory signals and cellular cues and establish communications with co‐transcriptional RNA processing. Transcription regulators are astonishingly diverse, with similar mechanisms arising via convergent evolution. NusG/Spt5 elongation factors comprise the only universally conserved and ancient family of regulators. They bind to the conserved clamp helices domain of RNA polymerase, which also interacts with non‐homologous initiation factors in all domains of life, and reach across the DNA channel to form processivity clamps that enable (...) uninterrupted RNA chain synthesis. In addition to this ubiquitous function, NusG homologs exert diverse, and sometimes opposite, effects on gene expression by competing with each other and other regulators for binding to the clamp helices and by recruiting auxiliary factors that facilitate termination, antitermination, splicing, translation, etc. This surprisingly diverse range of activities and the underlying unprecedented structural changes make studies of these “transformer” proteins both challenging and rewarding. (shrink)

Ribosomal RNA transcription was one of the first model systems for molecular characterization of a transcription regulatory mechanism and certainly one of the best studied in the widest range of organisms. In multicellular organisms, however, the issue of cell‐type‐specific regulation of rRNA transcription has not been well addressed. Here I propose that a systematic study of cell‐type‐specific regulation of rRNA transcription may reveal new regulatory mechanisms that have not been previously realized. Specifically, issues concerning the cell‐type‐specific requirement (...) for rRNA production, the universality of Pol I transcription complex and the division of rDNA into regulatory subdomains are discussed. BioEssays 28: 719–725, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

A key challenge for understanding transcriptional regulation is being able to measure transcription factor (TF)‐DNA binding events with sufficient spatial and temporal resolution; that is, when and where TFs occupy their cognate sites. A recent study by Para et al. has highlighted the dynamics underlying the activation of gene expression by a master regulator TF. This study provides concrete evidence for a long‐standing hypothesis in biology, the “hit‐and‐run” mechanism, which was first proposed decades ago. That is, gene (...) expression is dynamically controlled by a TF that transiently binds and activates a target gene, which might stay in a transcriptionally active state after the initial binding event has ended. Importantly, the experimental procedure introduced, TARGET, provides a useful way for identifying multiple target genes transiently bound by their regulators, which can be used in conjunction with other well‐established methods to improve our understanding of transcriptional regulatory dynamics. (shrink)

The germ lineage has been studied for a long time because of its crucial role in the propagation and survival of a species. While this lineage, in contrast to the soma, is clearly unique in its totipotent ability to produce a new organism, it has now been found also to have specific features at the cellular level. One feature, a period of transcriptional quiescence in the early germ cell precursors, has been observed in both Drosophila and C. elegans, (...) where it is essential for the formation and the survival of the germline. In addition, there are numerous instances where these early germ cells are reliant on translational regulation, especially in Drosophila. The genes that are important for these two functions, the mechanisms of their action, and studies in vertebrate organisms that reveal similarities as well as some potential differences in early germ cell development are discussed. BioEssays 25:326–335, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

New DNA sequencing technologies have provided novel insights into eukaryotic genomes, epigenomes, and the transcriptome, including the identification of new non‐coding RNA (ncRNA) classes such as promoter‐associated RNAs and long RNAs. Moreover, it is now clear that up to 90% of eukaryotic genomes are transcribed, generating an extraordinary range of RNAs with no coding capacity. Taken together, these new discoveries are modifying the status quo in genomic science by demonstrating that the eukaryotic gene pool is divided into two (...) distinct categories of transcripts: protein‐coding and non‐coding. The function of the majority of ncRNAs produced by the transcriptome is largely unknown; however, it is probable that many are associated with epigenetic mechanisms. The purpose of this review is to describe the most recent discoveries in the ncRNA field that implicate these molecules as key players in the epigenome. (shrink)

Understanding how transcription factor (TF) binding is related to gene regulation is a moving target. We recently uncovered genome‐wide evidence for a “Hit‐and‐Run” model of transcription. In this model, a master TF “hits” a target promoter to initiate a rapid response to a signal. As the “hit” is transient, the model invokes recruitment of partner TFs to sustain transcription over time. Following the “run”, the master TF “hits” other targets to propagate the response genome‐wide. As such, a TF may (...) act as a “catalyst” to mount a broad and acute response in cells that first sense the signal, while the recruited TF partners promote long‐term adaptive behavior in the whole organism. This “Hit‐and‐Run” model likely has broad relevance, as TF perturbation studies across eukaryotes show small overlaps between TF‐regulated and TF‐bound genes, implicating transient TF‐target binding. Here, we explore this “Hit‐and‐Run” model to suggest molecular mechanisms and its biological relevance. (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)

Common themes are emerging in the molecular mechanisms of long non‐coding RNA‐mediated gene repression. Long non‐coding RNAs (lncRNAs) participate in targeted gene silencing through chromatin remodelling, nuclear reorganisation, formation of a silencing domain and precise control over the entry of genes into silent compartments. The similarities suggest that these are fundamental processes of transcription regulation governed by lncRNAs. These findings have paved the way for analogous investigations on other lncRNAs and chromatin remodelling enzymes. Here we discuss these (...) common mechanisms and provide our view on other molecules that warrant similar investigations. We also present our concepts on the possible mechanisms that may facilitate the exit of genes from the silencing domains and their potential therapeutic applications. Finally, we point to future areas of research and put forward our recommendations for improvements in resources and applications of existing technologies towards targeted outcomes in this active area of research. (shrink)

Factors affecting transcriptional elongation have been characterized extensively in in vitro, single cell (yeast) and cell culture systems; however, data from the context of multicellular organisms has been relatively scarce. While studies in homogeneous cell populations have been highly informative about the underlying molecular mechanisms and prevalence of polymerase pausing, they do not reveal the biological impact of perturbing this regulation in an animal. The core components regulating pausing are expressed in all animal cells and are recruited to (...) the majority of genes, however, disrupting their function often results in discrete phenotypic effects. Mutations in genes encoding key regulators of transcriptional pausing have been recovered from several genetic screens for specific phenotypes or interactions with specific factors in mice, zebrafish and flies. Analysis of these mutations has revealed that control of transcriptional pausing is critical for a diverse range of biological pathways essential for animal development and survival. (shrink)

Sex‐specific transcriptional and epigenomic profiles are detectable in the embryo very soon after fertilization. I propose that in male (XY) and female (XX) pre‐implantation embryos sex chromosomes establish sexually dimorphic interactions with the autosomes, before overt differences become apparent and long before gonadogenesis. Lineage determination restricts expression biases between the sexes, but the epigenetic differences are less constrained and can be perpetuated, accounting for dimorphisms that arise later in life. In this way, sexual identity is registered in the (...) epigenome very early in development. As development progresses, sex‐specific regulatory modules are harbored within shared transcriptional networks that delineate common traits. In reviewing this field, I propose that analyzing the mechanisms for sexual dimorphisms at the molecular and biochemical level and incorporating developmental and environmental factors will lead to a greater understanding of sex differences in health and disease. (shrink)

An increasing number of transcription factors both from prokaryotic and eukaryotic sources are found to bend the DNA upon binding to their recognition site. Bending can easily be detected by the anomalous electrophoretic behaviour of the DNA‐protein complex or by increased cyclization of DNA fragments containing the protein‐induced bend. Induction of DNA bending by transcription factors could regulate transcription in various ways. Bending may bring distantly bound transcription factors closer together by facilitating DNA‐looping or it could mediate the interaction between (...) transcription factors and the general transcription machinery by formation of large nucleoprotein structures in which the DNA is wrapped around the protein complex. Alternatively, the energy stored in a protein‐induced bend could be used to favour formation of an open transcription complex or to dissociate the RNA polymerase in the transition from initiation to elongation. Modification of the bend angles and bending centers, caused by homodimerization or heterodimerization of transcription factors, may well turn out to be an important way to enlarge the range of interactions required for regulation of gene expression. (shrink)

Epigenetic information is encoded by DNA methylation and by covalent modifications of histone tails. While defined epigenetic modification patterns have been frequently correlated with particular states of gene activity, very little is known about the integration level of epigenetic signals. Recent experiments have resulted in the characterization of several epigenetic adaptors that mediate interactions between distinct modifications. These adaptors include methyl‐DNA binding proteins, chromatin remodelling enzymes and siRNAs. Complex interactions between epigenetic modifiers and adaptors provide the foundation for the stability (...) of epigenetic inheritance. In addition, they also provide an explanation for the long‐range effects of epigenetic mechanisms. We propose that a major aspect of epigenetic regulation lies in the modification of chromosome architecture and that local changes in gene expression would be secondary consequences. This view is consistent with many results from recent genomic analyses. BioEssays 25:792–797, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

The landscapes of mammalian genomes are characterized by complex patterns of intersecting and overlapping sense and antisense transcription, giving rise to large numbers of coding and non‐protein‐coding RNAs (ncRNAs). A recent report by Kapranov and colleagues1 describes three potentially novel classes of RNAs located at the very edges of protein‐coding genes. The presence of RNAs from one of these classes appears to be correlated with the expression levels of their associated genes. These results suggest that a proportion of these RNAs (...) might have roles in the cis‐regulation of neighbouring protein‐coding genes' expression. BioEssays 29:1077–1080, 2007. © 2007 Wiley Periodicals, 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)

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)

BackgroundThe landscape of clinical research has evolved over the past decade. With technological advances, the practice of using electronic informed consent (eIC) has emerged. However, a number of challenges hinder the successful and widespread deployment of eIC in clinical research. Therefore, we aimed to investigate the views of various stakeholders on the potential advantages and challenges of eIC.MethodsSemi-structured interviews were conducted with 39 participants from 5 stakeholder groups from across 11 European countries. The stakeholder groups included physicians, patient organization representatives, (...) regulator representatives, ethics committee members, and pharmaceutical industry representatives, and all were involved in clinical research. Interviews were analyzed using the framework method.ResultsInterviewees identified that a powerful feature of eIC is its personalized approach as it may increase participant empowerment. However, they identified several ethical and practical challenges, such as ensuring research participants are not overloaded with information and offering the same options to research participants who would prefer a paper-based informed consent rather than eIC. According to the interviewees, eIC has the potential to establish efficient long-term interactions between the research participants and the research team in order to keep the participants informed during and after the study. Interviewees emphasized that a personal interaction with the research team is of utmost importance and this cannot be replaced by an electronic platform. In addition, interviewees across the stakeholder groups supported the idea of having a harmonized eIC approach across the European Member States.ConclusionsInterviewees reported a range of design and implementation challenges which needs to be overcome to foster innovation in informing research participants and obtaining their consent electronically. It was considered important that the implementation of eIC runs alongside the face-to-face contact between research participants and the research team. Moreover, interviewees expect that eIC could offer the opportunity to enable a personalized approach and to strengthen continuous communication over time. If successfully implemented, eIC may facilitate the engagement of research participants in clinical research. (shrink)

It is a long-standing view that global translation varies during the cell cycle and is much lower in mitosis than in other cell-cycle phases. However, the central papers in the literature are not in agreement about the extent of downregulation in mitosis, ranging from a dramatic decrease to only a marginal reduction. Herein, it is argued that the discrepancy derives from technical challenges. Cell-cycle-dependent variations are most conveniently studied in synchronized cells, but the synchronization methods by themselves often evoke (...) stress responses that, in turn, affect translation rates. Further, it is argued that previously reported cell-cycle-dependent changes in the global translation rate to a large extent reflect responses to the synchronization methods. Recent findings strongly suggest that the global translation rate is not regulated in a cell-cycle-dependent manner. Novel techniques allowing a genome-wide analysis of translational profiles suggest that the extent and importance of selective translational regulation associated with cell-cycle transitions have been underestimated. Therefore, the main question is which messenger RNAs (mRNAs) are translated, rather than whether the global translation rate is decreased. (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)

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 lieu of an abstract, here is a brief excerpt of the content:Reviewed by:Laws, & Gods: Magistrates & Ceremony in the Regulation of Public Lands in Republican RomeT. Corey BrennanGargola, D. J. Lands, Laws, & Gods: Magistrates & Ceremony in the Regulation of Public Lands in Republican Rome. Chapel Hill: University of North Carolina Press, 1995. x 1 270 pp. Cloth, $43.95. (Studies in the History of Greece and Rome)“Nothing could have contributed more to the safety, strength and (...) profit of the state.” Thus Niccolò Machiavelli (Disc. II 6), one of the first of a long line of moderns to expatiate on the phenomenon of Roman Republican colonization. The latest (at time of writing) is D. J. G[argola], with his learned Lands, Laws, & Gods, which has its origins in the author’s 1989 University of North Carolina dissertation. The book takes as its general subject not just Republican colonization but also another well-trod area of Roman public policy—the agrarian legislation that distributed state land and regulated its use—as well as the religious and technical aspects of Roman land definition.Can we really expect much new on these traditional topics? Perhaps not, [End Page 143] especially now that we have Dieter Flach’s Römische Agrargeschichte (Handbuch der Altertumswissenschaft 3.9, Munich 1990)—a masterly synthesis that G. oddly has missed. Yet G. independently manages to come up with a work of value. The bulk of G.’s book (chapters 2–7) consists of detailed reconstructions, especially from the evidence of Livy 21–45 (not much used by Flach), of how colonies were established, viritane plots assigned, and land sold or leased in the mid-Republic. Here G. has sifted through a small mountain of difficult evidence (and bibliography) of widely varying worth and succeeded in shaping a coherent narrative. He has a keen eye for technical and conventional language, and sound judgment on the limits of applying evidence from the various Gromatici (none of whom were writing much before the second century a.d.) to the Republican situation. In short, G. in these pages has crafted a reliable and readable English language work of reference on all sorts of res agrariae.The emphasis in chapters 2–7 is not so much on evolution in the administration of agrarian and colonial legislation—G. argues (somewhat provocatively) that there was not much development of institutions within this period—but on creating a composite picture of how things worked. G. realizes “the result is necessarily an idealized portrait,” in which the system appears more regular than it perhaps was (10–11). One additional trouble, however, is that this approach sometimes flattens potentially significant details. Take for instance the two commissions of colonial IIIviri created under a lex Aelia of late 194 (Liv. 34.53.1–2), one of which went on to found Copia (193), the other Valentia (192). Now, the reported terms of this law provided that the commissioners hold imperium—quite striking, though G. misses that detail—for three years (i.e., 193–91) to colonize the ‘ager Thurinus’ and the ‘Bruttii’ respectively. G. is over-optimistic in calling these territories “stable, long pacified regions” (63). If so, why the imperium? One possible explanation. The territorial parameters placed on each of these commissions (especially ‘the Bruttii’) were quite loose. Those IIIviri may have been expected to take wide-ranging measures to strengthen Roman control over dissidents in this area (cf. App. Hann. 61.252–53), even after they established their colonies. (Note that each of these commissions completed their ostensible tasks before their triennium expired.) If true, how many other colonial commissions were like these?It is only in chapters 8 and 9, where G. surveys agrarian programs from the Gracchi to the end of the Republic, that we see an attempt to show real development. The Gracchi in their agrarian legislation sought to achieve broader effects than any of their predecessors, argues G. in chapter 8, and so introduced agrarian laws that “ended the rigid separation of categories found in mid-Republican legislation” (176). Consider the lex Sempronia agraria of 133, which, in its final form, established IIIviri a(gris) i(udicandis) a(dsignandis) to settle coloni on public land taken from illegal possessores. In this law... (shrink)

Polycomb group proteins are evolutionary conserved chromatin‐modifying complexes, essential for the regulation of developmental and cell‐identity genes. Polycomb‐mediated transcriptional regulation is provided by two multi‐protein complexes known as Polycomb repressive complex 1 (PRC1) and 2 (PRC2). Recent studies positioned PRC1 as a foremost executer of Polycomb‐mediated transcriptional control. Mammalian PRC1 complexes can form multiple sub‐complexes that vary in their core and accessory subunit composition, leading to fascinating and diverse transcriptional regulatory mechanisms employed by PRC1 complexes. (...) These mechanisms include PRC1‐catalytic activity toward monoubiquitination of histone H2AK119, a well‐established hallmark of PRC1 complexes, whose importance has been long debated. In this review, the central roles that PRC1‐catalytic activity plays in transcriptional repression are emphasized and the recent evidence supporting a role for PRC1 complexes in gene activation is discussed. (shrink)

Abstract3′ untranslated regions (3′ UTRs) of mRNAs have many functions, including mRNA processing and transport, translational regulation, and mRNA degradation and stability. These different functions require cis‐elements in 3′ UTRs that can be either sequence motifs or RNA structures. Here we review the role of secondary structures in the functioning of 3′ UTRs and discuss some of the trans‐acting factors that interact with these secondary structures in eukaryotic organisms. We propose potential participation of 3′‐UTR secondary structures in cytoplasmic polyadenylation (...) in the model organism Drosophila melanogaster. Because the secondary structures of 3′ UTRs are essential for post‐transcriptional regulation of gene expression, their disruption leads to a wide range of disorders, including cancer and cardiovascular diseases. Trans‐acting factors, such as STAU1 and nucleolin, which interact with 3′‐UTR secondary structures of target transcripts, influence the pathogenesis of neurodegenerative diseases and tumor metastasis, suggesting that they are possible therapeutic targets. (shrink)

Although the promyelocytic leukemia (PML) protein is renowned for regulating a wide range of cellular processes and as an essential component of PML nuclear bodies (PML‐NBs), the mechanisms through which it exerts its broad physiological impact are far from fully elucidated. Here, we review recent studies supporting an emerging view that PML's pleiotropic effects derive, at least partially, from its role in regulating histone H3.3 chromatin assembly, a critical epigenetic mechanism. These studies suggest that PML maintains heterochromatin organization by (...) restraining H3.3 incorporation. Examination of PML's contribution to H3.3 chromatin assembly in the context of the cell cycle and PML‐NB assembly suggests that PML represses heterochromatic H3.3 deposition during S phase and that transcription and SUMOylation regulate PML's recruitment to heterochromatin. Elucidating PML’ s contributions to H3.3‐mediated epigenetic regulation will provide insight into PML's expansive influence on cellular physiology and open new avenues for studying oncogenesis linked to PML malfunction. (shrink)

Graphical AbstractA recent study reported that longevity in Caenorhabditits elegans can be inherited over several generations. This is probably achieved through the following epigenetic mechanism: inherited demethylated histones at some central loci, such as miRNA, transcription factors or signaling regulators affect the expression of certain genes leading to the longevity phenotype.

The BTB domain is a protein–protein interaction motif that is found throughout eukaryotes. It determines a unique tri‐dimensional fold with a large interaction surface. The exposed residues are highly variable and can permit dimerization and oligomerization, as well as interaction with a number of other proteins. BTB‐containing proteins are numerous and control cellular processes that range from actin dynamics to cell‐cycle regulation. Here, we review findings in the field of transcriptional regulation to illustrate how the high (...) variability of the BTB has allowed related transcription factors to evolve different functional abilities. We then report how recent work has showed that, in spite of their high sequence divergence and apparently unrelated functions, many BTB‐containing proteins have at least one shared role: the recruitment of degradation targets to E3 ubiquitin ligase complexes. Taken together, these findings illustrate diverse and convergent functions of a versatile protein–protein interaction domain. BioEssays 28: 1194–1202, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:46. HUME AND THE FUTURE OF THE SOCIETY OF NATIONS In the section of Hume's Treatise of Human Nature entitled Of the laws of nations (Section XI of Book III) he says: Political writers tell us, that in every kind of intercourse, a body politic is to be consider 'd as one person; and indeed this assertion is so far just, that different nations, as well as private persons, (...) require mutual assistance; at the same time that their selfishness and ambition are perpetual sources of war and discord.But tho' nations in this particular resemble individuals, yet as they are very different in other respects, no wonder they regulate themselves by different maxims, and give rise to a new set of rules, which we call the laws of nations. 1 He goes on to give examples of such laws:the sacredness of the persons of ambassadors, the declaration of war, the abstaining from poison'd arms, with other duties of that kind, which are evidently calculated for the commerce, that is peculiar to different.societies. (T 567) Hume then tells us in the next paragraph that such laws of nations may be added to the three laws of nature (that possessions should be stable, that possessions should be transferable by consent, and that promises or contracts should be kept) but that these laws of nations do not supersede the laws of nature; that is, they do not make the laws of nature irrelevant to relations among nation-states. In fact, the morality among nation-states involves the same kinds of obligations as morality among private persons, but the obligations are not as binding. The obligations of nation-states to each other can more readily be overridden by concerns of self-interest than would be legitimate in the case of private persons because nation-states are more nearly able to maintain themselves without external assistance than are individual persons. In Hume's words,... tho' the 47. morality of princes has the same extent, yet it has not the same force as that of private persons (T 558) because tho' the intercourse of different states be advantageous, and even sometimes necessary, yet it is not so necessary nor advantageous as that among individuals, without which 'tis utterly impossible for human nature ever to subsist. (T 569) In the last paragraph of this section Hume addresses himself to the question of the proportion these two species of morality bear to each other. (T 569) He says that we can never give any precise answer (T 569) and that the proper proportion is exhibited in the actual practice of the world. He takes this fact as showing that all men recognize that the rules of morality, both among private individuals and among nation-states, arise from human conventions, and from the interest, which we have in the preservation of peace and order. (T 569) When discussing the same issue in his Enquiry concerning the Principles of Morals Hume is more succinct. The observance of justice, though useful among them [nations], is not guarded by so strong a necessity as among individuals; and the moral obligation holds proportion with the usefulness. 2 """ The moral obligations of individuals to each other is thus greater than that of nations to each other because keeping the rules of justice is inore useful in the former case than in the latter. But Hume did not live in an age of atomic weapons, long-range missiles, and precision-guided munitions. Furthermore, the nations of the world are now much more interdependent than in his day, not only with regard to where they get the resources they need but also with regard to what they do with their wastes. There seems to be little roo.? _or dtubt that the utility of following the rules of justice among nations is much greater now than it was in the eighteenth 48. century. Since a nuclear war might mean the end of the human species, the utility of justice among nations seems to be approaching, perhaps even surpassing, the utility which moral rules have at the level of private persons. In view of this changed situation, I intend to review what Hume has... (shrink)

MYC is a transcription factor, which not only directly modulates multiple aspects of transcription and co‐transcriptional processing (e.g. RNA‐Polymerase II initiation, elongation, and mRNA capping), but also indirectly influences several steps of RNA metabolism, including both constitutive and alternative splicing, mRNA stability, and translation efficiency. As MYC is an oncoprotein whose expression is deregulated in multiple human cancers, identifying its critical downstream activities in tumors is of key importance for designing effective therapeutic strategies. With this knowledge and recent technological (...) advances, we now have multiple angles to reach the goal of targeting MYC in tumors, ranging from the direct reduction of MYC levels, to the dampening of selected house‐keeping functions in MYC‐overexpressing cells, to more targeted approaches based on MYC‐induced secondary effects. (shrink)

It is often overlooked that, in addition to the integrity of protein‐coding sequences (PCSs), human health is crucially linked to the normal expression of genes by cis‐regulatory sequences (CRSs). These CRSs often lie at some considerable distance from the PCSs whose expression they control and often within other genes. The resulting gene interdigitation can make long‐range CRS identification and characterisation difficult. We propose that the need to conserve long‐range CRSs in cis with their target PCSs through (...) evolution, in combination with gene interdigitation and co‐regulation of many genes by individual CRSs, has contributed to the persistence of conserved synteny blocks between diverse species. We further hypothesise that examination of the varying extents of synteny blocks between multiple species in combination with phylogenetic footprinting to find CRSs might provide important clues to the existence of crucial functional CRS–PCS linkages. Identifying CRS–PCS linkages crucial to human health will lead to a better understanding of how their disruption by CRS mutation or chromosome translocation might contribute to many distressing human diseases. BioEssays 26:1217–1224, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Basic proteins and nucleic acids are assembled into complexes in a reaction that must be facilitated by nuclear chaperones in order to prevent protein aggregation and formation of non‐specific nucleoprotein complexes. The nucleophosmin/nucleoplasmin (NPM) family of chaperones [NPM1 (nucleophosmin), NPM2 (nucleoplasmin) and NPM3] have diverse functions in the cell and are ubiquitously represented throughout the animal kingdom. The importance of this family in cellular processes such as chromatin remodeling, genome stability, ribosome biogenesis, DNA duplication and transcriptional regulation has (...) led to the rapid growth of information available on their structure and function. The present review covers different aspects related to the structure, evolution and function of the NPM family. Emphasis is placed on the long‐term evolutionary mechanisms leading to the functional diversification of the family members, their role as chaperones (particularly as it pertains to their ability to aid in the reprogramming of chromatin), and the importance of NPM2 as an essential component of the amphibian chromatin remodeling machinery during fertilization and early embryonic development. BioEssays 29: 49–59, 2007. © 2006 Wiley Periodicals, Inc. (shrink)

The paper addresses the formation of striking patterns within originally near-homogenous tissue, the process prototypical for embryology, and represented in particularly purist form by cut sections of hydra regenerating, by internal reorganisation of the pre-existing tissue, a complete animal with head and foot. The essential requirements are autocatalytic, self-enhancing activation, combined with inhibitory or depletion effects of wider range – “lateral inhibition”. Not only de-novo-pattern formation, but also well known, striking features of developmental regulation such as induction, inhibition, (...) and proportion regulation can be explained on this basis. The theory provides a mathematical recipe for the construction of molecular models with criteria for the necessary non-linear interactions. It has since been widely applied to different developmental processes. (shrink)

Alzheimer's disease is the most common form of dementia that gradually disrupts the brain network to impair memory, language and cognition. While the amyloid hypothesis remains the leading proposed mechanism to explain AD pathophysiology, anti-amyloid therapeutic strategies have yet to translate into useful therapies, suggesting that amyloid β-protein and its precursor, the amyloid precursor protein are but a part of the disease cascade. Further, risk of AD can be modulated by a number of factors, the most impactful being the ɛ4 (...) isoform of apolipoprotein E. A recent study reported a novel isoform-dependent transcriptional regulation of APP by apoE. These interesting new results add to the myriad of mechanisms that have been proposed to explain how apoE4 enhances AD risk, highlighting the complexities of not only apoE and AD pathophysiology, but also of disease itself. Also see the video abstract here: https://youtu.be/yd14MBdPkCY APP transcription is differentially modulated by apoE and its isoforms: how does this novel mechanism fit with the existing hypotheses? (shrink)

What I have tried to do here is to provide a historical example of the interdependence between nature and culture that is one of the themes of this conference. To sum up: Scientific descriptions of the world emerge out of a complex interaction between nature, economic production, and the legal system. “Science” consists of a struggle among scientists, and between scientists and citizens, over what counts as “reality.” Lawmaking, in turn, consists of a struggle between people who want to allocate (...) access to resources for particular purposes, whether for commercial use, recreational use, or “natural” uses. Production, for its part, is a complicated function of technology, the sociology of user groups, the structure of legal entitlements to access, and the availability of resources. Nature, finally, is at any point, to no small degree, the product of past and present human impacts on it — which impacts, in turn, are determined in no small way by the sociology and the legal structure of the market.Each process takes place in continual conversation with all the others. As John Muir put it, “When we try to pick out anything by itself, we find it hitched to everything else in the universe.”45 Historically, resource managers have gotten into trouble when they have unconsciously assumed that such is not the case — yet such, assumptions are powerful because they are made instinctively, unthinkingly, at the level of people's basic understanding of the world and their place in it. Lots of them persist.On the other hand, in a few experimental cases in the United States and Canada where government and users have shared power and responsibility for resources management, including long-range planning for recovery and enhancement, here have been some notable improvements. The strategy goes under the name of “co-management” and involves negotiated agreements for shared decision-making between central authority and local groups. Typically, both government and industry resist such arrangements because they involve restructuring the power relations between different sectors in the industry; the result is that the few experiments in co-management that we have seen in the United States have come in areas, typically fisheries and wildlife, where the resource is in serious crisis and all of the parties to the agreement have had to abandon the positions they held previously.Examples of successful co-management regimes include those among American tribes in the Pacific Northwest, among commercial salmon fishers in Alaska, and in a project to rehabilitate the clam industry in New Jersey. Government employees and local groups share responsibility for gathering scientific data about the resources, for developing plans to manage them, and for enforcing regulations. Successful experiments at co-management seem to generate better scientific data about their resources than traditional management regimes do; they significantly reduce enforcement costs; and they enhance the economic power of the resource users. Most importantly, they nurture among the user groups a sense of control over their own destinies, and a willingness to share both costs and benefits of managing the resources rationally and to develop lasting, stable mechanisms for conflict resolution. The process is both democratic and ecologically rational. The key is to link the day-to-day work of producers to their long-range interests as residents in their communities and as working parts of the ecological systems in which they live.45At a minimum, it is clear that objective certainty about the state of the resources or the likely effect of whatever regulations we do impose is simply not attainable. This is partly because of the important role that random shocks play in the environment (and should play in our thinking about it), and also because of the sheer complexity of the system in which we are embedded. There will always be something that even the most complete model leaves out; and in any event the total system of ecology, production, and management will change every time something changes in any part of it.The policy lesson to be derived from all of this, finally, is that what we ought to sustain when we approach conservation problems is not the size of a particular resource, or even the prosperity of a particular harvesting group, but the long-term health of the interaction between nature, the economy, and the political system. We can recognize that the balance of the system, our attempted insurance against an uncertain future, democracy among user groups, and our moral duty to avoid extinguishing species — all of these things being difficult to quantify — do play integral roles in the conversation between nature and humankind, and perhaps more significant roles than the more objective measures to which we usually look for guidance. We can recognize, as John Muir did, that because everything in the universe is hitched to everything else, every step we take will change the total system in some way. When we make choices, then, we can keep an eye on what kind of conversation we want to have with the rest of Creation and make our choices accordingly. *** DIRECT SUPPORT *** A8402064 00014 *** DIRECT SUPPORT *** A8402064 00015. (shrink)

Cell membranes experience frequent stretching and poking: from cytoskeletal elements, from osmotic imbalances, from fusion and budding of vesicles, and from forces from the outside. Are the ensuing changes in membrane tension localized near the site of perturbation, or do these changes propagate rapidly through the membrane to distant parts of the cell, perhaps as a mechanical mechanism of long‐range signaling? Literature statements on the timescale for membrane tension to equilibrate across a cell vary by a factor of (...) ≈106. This study reviews and discusses how apparently contradictory findings on tension propagation in cells can be evaluated in the context of 2D hydrodynamics and poroelasticity. Localization of tension in the cell membrane is likely critical in governing how membrane forces gate ion channels, set the subcellular distribution of vesicle fusion, and regulate the dynamics of cytoskeletal growth. Furthermore, in this study, it is proposed that cells can actively regulate the degree to which membrane tension propagates by modulating the density and arrangement of immobile transmembrane proteins. Also see the video abstract here https://youtu.be/T6K7AIAqqBs. (shrink)

The enactive approach conceives of cognition as acts of sense-making. A requirement of sense-making is adaptivity, i.e., the agent’s capacity to actively monitor and regulate its own trajectories with respect to its viability constraints. However, there are examples of sense-making, known as ultrafast cognition, that occur faster than the time physiologically required for the organism to centrally monitor and regulate movements, for example, via long-range neural feedback mechanisms. These examples open a clarificatory challenge for the enactive approach with (...) respect to how to operationalize monitoring and regulation, and with respect to the temporal scale of sense-making, which has traditionally been limited to the here-and-now in accordance with the axiom of structural determinism. We explore possible responses to this challenge and suggest that this axiom should be explicitly rejected, in particular, we suggest that adaptivity is a property of organism–environment interactions over a time span that includes both present and past conditions. Ultrafast performances are thus no longer a challenge for the enactive approach, because the constitutive basis of their normativity is spatiotemporally extensive. This is in agreement with recent developments in different varieties of enactivism, which all converge toward assigning a constitutive role to an agent’s history of interactions. (shrink)

The development of T cells and B cells from pluripotent hematopoietic precursors occurs through a stepwise narrowing of developmental potential that ends in lineage commitment. During this process, lineage-specific genes are activated asynchronously, and lineage-inappropriate genes, although initially expressed, are asynchronously turned off. These complex gene expression events are the outcome of the changes in expression of multiple transcription factors with partially overlapping roles in early lymphocyte and myeloid cell development. Key transcription factors promoting B-cell development and candidates for this (...) role in T-cell development are discussed in terms of their possible modes of action in fate determination. We discuss how a robust, stable, cell-type–specific gene expression pattern may be established in part by the interplay between endogenous transcription factors and signals transduced by cytokine receptors, and in part by the network of effects of particular transcription factors on each other. BioEssays 21:726–742, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Eukaryotic genes are divided into three categories according to the machineries by which they are transcribed. Ribosomal RNA genes (rDNA) are the only ones that are transcribed by RNA polymerase I and are under different control from other genes transcribed by RNA polymerase II or III. None the less, the regulation of rDNA is of prime interest in view of its close relationship to cell growth and differentiation. In this review I shall discuss the recent progress in the study (...) of transcription mechanisms of rDNA by the RNA polymerase I system. The structure of the rDNA promoter and the presence of possible upstream enhancer regions will be described. In addition, factors involved in the transcription initiation of this gene will be discussed with special reference to the formation of an initiation complex. (shrink)

Long-range correlation, a property of time series exhibiting long-term memory, is mainly studied in the statistical physics domain and has been reported to exist in natural language. Using a state-of-the-art method for such analysis, long-range correlation is first shown to occur in long CHILDES data sets. To understand why, Bayesian generative models of language, originally proposed in the cognitive scientific domain, are investigated. Among representative models, the Simon model was found to exhibit surprisingly good (...) long-range correlation, but {\em not} the Pitman-Yor model. Since the Simon model is known not to correctly reflect the vocabulary growth of natural language, a simple new model is devised as a conjunct of the Simon and Pitman-Yor models, such that long-range correlation holds with a correct vocabulary growth rate. The investigation overall suggests that uniform sampling is one cause of long-range correlation and could thus have a relation with actual linguistic processes. (shrink)