Transcription factor binding sites (TFBSs) on the DNA are generally accepted as the key nodes of gene control. However, the multitudes of TFBSs identified in genome‐wide studies, some of them seemingly unconstrained in evolution, have prompted the view that in many cases TF binding may serve no biological function. Yet, insights from transcriptional biochemistry, population genetics and functional genomics suggest that rather than segregating into ‘functional’ or ‘non‐functional’, TFBS inputs to their target genes may be generally cumulative, with varying (...) degrees of potency and redundancy. As TFBS redundancy can be diminished by mutations and environmental stress, some of the apparently ‘spurious’ sites may turn out to be important for maintaining adequate transcriptional regulation under these conditions. This has significant implications for interpreting the phenotypic effects of TFBS mutations, particularly in the context of genome‐wide association studies for complex traits. (shrink)

(NOTE: This is a transcript of the class. FOR THE FULL PAPER please click on "Maxson J McDowell" above.) An edited transcript of an experiment performed within a class on dream interpretation. Knowing only the dreamer’s age and gender, we interpreted his dream from its text. Our interpretation included predictions about the dreamer's psychological issues, and about his defenses. It also identified a series of jokes within the dream which would tend to penetrate the dreamer's defenses. When we had finished (...) our 'blind' interpretation, the bringer of the dream gave us more information about the dreamer against which we tested the accuracy of our predictions. A paper on this experiment has been submitted for publication. (shrink)

(NOTE: This is a transcript of the class. FOR THE FULL PAPER, please click on "Maxson J. McDowell".) A complete transcript of an experiment performed within a class on dream interpretation. Knowing only the dreamers age and gender, we interpreted his dream from its text. Our interpretation included predictions about the dreamer's psychological issues, and about his defenses. It also identified a series of jokes within the dream which would tend to penetrate the dreamer's defenses. When we had finished our (...) 'blind' interpretation, the bringer of the dream gave us more information about the dreamer against which we tested the accuracy of our predictions. A paper on this experiment has been submitted for publication. A link to an AUDIO-RECORDING of this class is given on the first page of this transcript. (shrink)

In eukaryotes, the messenger RNA (mRNA), the blueprint of a protein‐coding gene, is processed and packaged into a messenger ribonucleoprotein particle (mRNP) by mRNA‐binding proteins in the nucleus. The steps of mRNP formation – transcription, processing, packaging, and the orchestrated release of the export‐competent mRNP from the site of transcription for nuclear mRNA export – are tightly coupled to ensure a highly efficient and regulated process. The importance of highly accurate nuclear mRNP formation is illustrated by the fact (...) that mutations in components of this pathway lead to cellular inviability or to severe diseases in metazoans. We hypothesize that efficient mRNP formation is realized by a molecular mRNP packaging station, which is built by several recruitment platforms and coordinates the individual steps of mRNP formation. (shrink)

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

Transcriptional networks regulate cell fate decisions, which occur at the level of individual cells. However, much of what we know about their structure and function comes from studies averaging measurements over large populations of cells, many of which are functionally heterogeneous. Such studies conceal the variability between cells and so prevent us from determining the nature of heterogeneity at the molecular level. In recent years, many protocols and platforms have been developed that allow the high throughput analysis of gene expression (...) in single cells, opening the door to a new era of biology. Here, we discuss the need for single cell gene expression analysis to gain deeper insights into the transcriptional control of cell fate decisions, and consider the insights it has provided so far into transcriptional regulatory networks in development. (shrink)

Genome‐wide identification of transcription factor binding sites with the ChIP‐seq method is an extremely important scientific endeavor − one that should ideally be performed for every transcription factor in as many cell types as possible. A major hurdle on the way to this goal is the necessity for a specific, ChIP‐grade antibody for each transcription factor of interest, which is often not available. Here, we describe CETCh‐seq, a recently published method utilizing genome engineering with the CRISPR/Cas9 system (...) to circumvent the need for a specific antibody. Using the CETCh‐seq method, targeted genomic editing results in an epitope‐tagged transcription factor, which is recognized by a well‐characterized, standard antibody, efficacious for ChIP‐seq. We have used CETCh‐seq in human cancer cell lines as well as mouse embryonic stem cells. We find that roughly 60% of transcription factors tagged using CETCh‐seq produce a high quality ChIP‐seq map, a significant improvement over traditional antibody‐based methods. (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)

In this commentary, I consider variability as an ordinary and irremediable feature related to the indexicality not only of transcripts but first of all of transcribing. In this sense, it is not just a characteristic of transcripts as texts, which can be assessed in a kind of philological comparison comparing formal features of autonomous and fixed textual objects, but a characteristic of transcribing as a situated practice. Practices are irremediably indexical, reflexively tied to the context of their production and to (...) the practical purposes of their accomplishment. Thus, a transcript is an evolving flexible object; it changes as the transcriber engages in listening and looking again at the tape, endlessly checking, revising, reformatting it. Transcribing relies in a fundamental way not only on the possibility of fixing the relevant details in a complex multilayered representation but also on the possibility of manipulating them, playing them again and again, at different paces, positions, fragments, while transcribing their finely tuned coordination, their synchronization, the fine articulation between different projections and sequential implicativenesses. These manipulations are one of the ways in which transcribing is accomplished as a situated practice. (shrink)

Transcription phonétique des grands corpus littéraires. Les règles du jeu Le perfectionnement des phonétiseurs permet aujourd'hui d'envisager la transcription phonétique de grands ensembles textuels et, par conséquent, de doter la stylométrie de nouvelles capacités dans le domaine de l'analyse des effets sonores. Cet article montre, sur l'exemple d'une étude de La Règle du jeu de Michel Leiris menée à l'aide de LAIPTTS-SpeechMill (Université de Lausanne) et Mbrola (Faculté Polytechnique de Mons), quelles procédures et quelles précautions on se doit (...) d'associer à de telles entreprises. Le repérage et l’étude des allitérations et des assonances, des homophones, la détermination de la tonalité phonique d’une partie du texte montrent tout à la fois les perspectives et les limites de ce type d'approche du texte littéraire. (shrink)

Transcription phonétique des grands corpus littéraires. Les règles du jeu Le perfectionnement des phonétiseurs permet aujourd'hui d'envisager la transcription phonétique de grands ensembles textuels et, par conséquent, de doter la stylométrie de nouvelles capacités dans le domaine de l'analyse des effets sonores. Cet article montre, sur l'exemple d'une étude de La Règle du jeu de Michel Leiris menée à l'aide de LAIPTTS-SpeechMill (Université de Lausanne) et Mbrola (Faculté Polytechnique de Mons), quelles procédures et quelles précautions on se doit (...) d'associer à de telles entreprises. Le repérage et l’étude des allitérations et des assonances, des homophones, la détermination de la tonalité phonique d’une partie du texte montrent tout à la fois les perspectives et les limites de ce type d'approche du texte littéraire. (shrink)

Seed development in this paper has been classified into the three landmark stages of cell division, organ initiation and maturation, based on morphological changes, and the available literature. The entire process proceeds at the behest of an interplay of various specific and general transcription factors (TFs). Monocots and dicots utilize overlapping, as well as distinct, TF networks during the process of seed development. The known TFs in rice and Arabidopsis have been chronologically categorized into the three stages. The main (...) regulators of seed development contain B3 or HAP3 domains. These interact with bZIP and AP2 TFs. Other TFs that play an indispensable role during the process contain homeobox‐, NAC‐, MYB‐, or ARF‐domains. This paper is a comprehensive analysis of the TFs essential for seed development and their interactions. An understanding of this interplay will not only help unravel an integrated developmental process, but will also pave the way for biotechnological applications. (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)

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)

The complexity of organisms is not simply determined by the number of their genes, but to a large extent by how gene expression is controlled. In addition to transcriptional regulation, this involves several layers of post‐transcriptional control, such as translational repression, microRNA‐mediated mRNA degradation and translational inhibition, alternative splicing, and the regulated generation of functionally distinct gene products from a single mRNA through alternative use of translation initiation sites. Much progress has been made in describing the molecular basis for these (...) gene regulatory mechanisms. However, it is now a major challenge to translate this knowledge into deeper understanding of the physiological processes, both normal and pathological, that they govern. Using the C/EBP family of transcription factors as an example, the present review describes recent genetic experiments addressing this general problem and discusses how the physiological importance of newly discovered regulatory mechanisms might be determined. (shrink)

Measurements of open chromatin in specific cell types are widely used to infer the spatiotemporal activity of transcriptional enhancers. How reliable are these predictions? In this review, it is argued that the relationship between the accessibility and activity of an enhancer is insufficiently described by simply considering open versus closed chromatin, or active versus inactive enhancers. Instead, recent studies focusing on the quantitative nature of accessibility signal reveal subtle differences between active enhancers and their different inactive counterparts: the closed silenced (...) state and the accessible primed and repressed states. While the open structure as such is not a specific indicator of enhancer activity, active enhancers display a higher degree of accessibility than the primed and repressed states. Molecular mechanisms that may account for these quantitative differences are discussed. A model that relates molecular events at an enhancer to changes in its activity and accessibility in a developing tissue is also proposed. (shrink)

Establishment of cell lineage identity from multipotent progenitors is controlled by cooperative actions of lineage‐specific and stably expressed transcription factors, combined with input from environmental signals. Lineage‐specific master transcription factors activate and repress gene expression by recruiting consistently expressed transcription factors and chromatin modifiers to their target loci. Recent technical advances in genome‐wide and multi‐omics analysis have shed light on unexpected mechanisms that underlie more complicated actions of transcription factors in cell fate decisions. In this review, (...) we discuss functional dynamics of stably expressed and continuously required factors, Notch and Runx family members, throughout developmental stages of early T cell development in the thymus. Pre‐ and post‐commitment stage‐specific transcription factors induce dynamic redeployment of Notch and Runx binding genomic regions. Thus, together with stage‐specific transcription factors, shared transcription factors across distinct developmental stages regulate acquisition of T lineage identity. (shrink)

The Myelin Regulator Factor (MYRF) is a master regulator governing myelin formation and maintenance in the central nervous system. The conservation of MYRF across metazoans and its broad tissue expression suggest it has functions extending beyond the well‐established role in myelination. Loss of MYRF results in developmental lethality in both invertebrates and vertebrates, and MYRF haploinsufficiency in humans causes MYRF‐related Cardiac Urogenital Syndrome, underscoring its importance in animal development; however, these mechanisms are largely unexplored. MYRF, an unconventional transcription factor, (...) begins embedded in the membrane and undergoes intramolecular chaperone mediated trimerization, which triggers self‐cleavage, allowing its N‐terminal segment with an Ig‐fold DNA‐binding domain to enter the nucleus for transcriptional regulation. Recent research suggests developmental regulation of cleavage, yet the mechanisms remain enigmatic. While some parts of MYRF's structure have been elucidated, others remain obscure, leaving questions about how these motifs are linked to its intricate processing and function. (shrink)

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

(2000). Full transcript of inaugural AARST Science Policy Forum, New York Hilton, Friday 20 November 1998, 7?9 pm. Social Epistemology: Vol. 14, No. 2-3, pp. 131-180.

Many nuclear proteins have been found recently to interact with short conserved sequences which are involved in regulating the transcription of various genes. Nuclear transcription factors may be arbitrarily subdivided into two groups, ubiquitous and tissue‐specific. The transcription of one gene is usually regulated by several factors which interact with different sequences located either in the promoter region of the gene or outside it. The appearance or disappearance of transcription factors for some genes corresponds to certain (...) phases of cell differentiation or dedifferentiation and even to individual stages of the cell cycle. (shrink)

Evidence from Drosophila and also vertebrates predicts that two different sets of instructions may determine the development of the rostral and caudal parts of the body. This implies different cellular and inductive processes during gastrulation, whose genetic requirements remain to be understood. To date, four genes encoding transcription factors expressed in the presumptive vertebrate head during gastrulation have been studied at the functional level: Lim‐1, Otx‐2, HNF‐3β and goosecoid. We discuss here the potential functions of these genes in the (...) formation of rostral head as compared to posterior head and trunk, and in the light of recent fate map and expression analyses in mouse, chick, Xenopus and zebrafish. These data indicate that Lim‐1, Otx‐2 and HNF‐3β may be involved in the same genetic pathway controlling the formation of the prechordal mesendoderm, which is subsequently required for rostral head development. goosecoid may act in a parallel pathway, possibly in conjunction with other, yet unidentified, factors. (shrink)

Abstractftz is one of the ‘pair rule’ segmentation genes of Drosophila melanogaster, and is an important component of the segmentation process in the fruit fly. We discuss the transcriptional mechanism which causes ftz to be expressed in a seven stripe pattern during embryogenesis.

In this paper, I examine the views of contemporary aesthetician of music Stephen Davies about musical transcriptions as special forms of classical music and try to apply his theoretical views to remixing as a musical practice that is primarily related to contemporary electronic music. Using the theoretical approaches of Davies’ aesthetics of music, I point out the similarities between the creative attitudes of a musician in transcribing and remixing, similarities that can be found in the way these musical forms relate (...) to the original composition on which transcriptions or remixes are based. Comparisons between transcription and remix are further investigated by considering the various roles that these musical practices fulfil in various cultural contexts. (shrink)

Editor's suggested further reading in BioEssays ftz Evolution: Findings, hypotheses and speculations (response to DOI 10.1002/bies.201100019) AbstractOn the border of the homeotic function: Re‐evaluating the controversial role of cofactor‐recruiting motifs AbstractControl of DNA replication: A new facet of Hox proteins? AbstractClassification of sequence signatures: a guide to Hox protein function Abstract.

Echoes of a philosophy -- Strategic considerations -- Cultural evolution -- Communication -- A cultural technology -- Unique function of the library -- Stewardship of the social transcript -- Sounding for the embedded philosophy.

Two mechanisms are available for the repair of DNA double‐strand breaks (DSBs) in eukaryotic cells: homology directed repair (HDR) and non‐homologous end‐joining (NHEJ). While NHEJ is not restricted to a particular phase of the cell cycle, it is incapable of accurately repairing DBSs that have suffered a loss or gain of nucleotide sequence information. In contrast, HDR achieves accurate repair of such DSBs by use of a sister chromatid as a DNA template, but is restricted to cell cycle phases (S/G2) (...) when such templates are available. In this scheme, G1 cells appear to lack a mechanism for the accurate repair of certain DSBs, and an ability to use alternative templates would be highly advantageous. Considered here, therefore, is the possibility that RNA transcripts are used as templates for HDR. Potential mechanisms for transcript‐templated HDR, and ways in which it might be detected, are presented. BioEssays 28:78–83, 2006. © 2005 Wiley Periodicals, Inc. (shrink)

Developmental processes in complex animals are directed by a hardwired genomic regulatory code, the ultimate function of which is to set up a progression of transcriptional regulatory states in space and time. The code specifies the gene regulatory networks (GRNs) that underlie all major developmental events. Models of GRNs are required for analysis, for experimental manipulation and, most fundamentally, for comprehension of how GRNs work. To model GRNs requires knowledge of both their overall structure, which depends upon linkage amongst regulatory (...) genes, and the modular building blocks of which GRNs are heirarchically constructed. The building blocks consist of basic transcriptional control processes executed by one or a few functionally linked genes. We show how the functions of several such building blocks can be considered in mathematical terms, and discuss resolution of GRNs by both “top down” and “bottom up” approaches. BioEssays 24:1118–1129, 2002. © 2002 Wiley‐Periodicals, Inc. (shrink)

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

The 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)

The plant hormones auxin and brassinosteroid are both essential regulators of plant growth and known to influence both cell division and cell elongation in various developmental contexts. These physiological effects of auxin and brassinosteroid have been known for many years. Based on observations from external simultaneous application of both hormones to plant tissues, it has been suggested that they act in an interdependent and possibly synergistic manner. Recent work in the model plant Arabidopsis thaliana suggests that, at the molecular level, (...) auxin–brassinosteroid synergism manifests itself in the regulation of the expression of common target genes. However, whether this reflects genuine hormone pathway‐dependent crosstalk modulation of the transcription machinery or rather indirect effects of hormone action on other cellular activities, such as hormone biosynthesis or the polar transport of auxin, is not entirely clear. This article reviews the evidence for transcriptional crosstalk between auxin and brassinosteroid and its molecular basis. BioEssays 29:1115–1123, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

The chromosomes of eukaryotic cells possess many potential DNA replication origins, of which a subset is selected in response to the cellular environment, such as the developmental stage, to act as active replication start sites. The mechanism of origin selection is not yet fully understood. In this review, we summarize recent observations regarding replication origins and initiator proteins in various organisms. These studies suggest that the DNA‐binding specificities of the initiator proteins that bind to the replication origins and promote DNA (...) replication are primarily responsible for origin selection. We particularly focus on the importance of transcription factors in the origin selection process. We propose that transcription factors are general regulators of the formation of functional complexes on the chromosome, including the replication initiation complex. We discuss the possible mechanisms by which transcription factors influence the selection of particular origins. BioEssays 27:1107–1106, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Two groups of plant viruses have DNA in their genomes. One group, the caulimoviruses, are non‐integrating retroviruses that package dsDNA in virions. The other group, the geminiviruses, package small circular ssDNA and include the only DNA viruses known with bipartite genomes. The regulation of transcription of these viruses is not well characterized, but recent work is beginning to yield interesting results. Regulatory sequences from these viruses function in cells of species that are not hosts of the virus and are (...) finding use in constitutive expression of chimeric genes in transformed plants. Development of vectors based on plant viruses requires further characterization at the molecular level of viral life cycles. (shrink)

As cells approach S phase, many changes occur to create an environment conducive for DNA synthesis and commitment to cell division. The transcription rate of many genes encoding enzymes involved in DNA synthesis, including the dihydrofolate reductase (dhfr) gene, increases at the G1/S boundary of the cell cycle. Although a number of transcription factors interact to finely tune the levels of dhfr RNA produced, two families of transcription factors, Sp1 and E2F, play central roles in modulating dhfr (...) levels. A region containing several Sp1‐binding sites is required for both regulated and basal transcription levels. In contrast, the E2F‐binding sites near the transcription start site are required only for regulated transcription. A model is presented for the regulation of the dhfr gene which may also pertain to other cell cycle‐associated genes. (shrink)

This response picks up on the four key points developed in `Variation in Transcription'. The focus is on how transcription practices are implicated in extended histories of data processing by arguing for a wider take on the `dyad' of researcher and represented voice. The article addresses the relevance of historically specific contexts of `hearing' and interpretative-analytical appropriation, the practical exigencies of publication and how these have shifted over time, the contemporary challenges posed by transcription-in-translation, as well as (...) the affordances and constraints of past and current technologies. (shrink)

Recent evidence from studies on DNA repair systems that are implicated in accelerated aging syndromes, have revealed a mechanism through which low levels of persistent damage might exert beneficial effects for both cancer prevention and longevity assurance. Beneficial effects of adaptive responses to low doses of insults that in higher concentrations show adverse effects are generally referred to as hormesis. There are numerous examples of hormetic effects ranging from mild stresses of irradiation to heat stress, hypergravity, pro‐oxidants, or food restriction. (...) Although the notion of hormesis is supported by many observations in various organisms, at least two major caveats have thus far prevented the application of hormesis for disease prevention in humans. First, the very nature of hormesis using toxins as a treatment regimen harbors the inherent danger of detrimental consequences. Second, the molecular mechanisms through which insults might exert beneficial effects have thus far remained elusive. Here, I discuss a mechanistic basis for hormesis and its implications for cancer prevention and healthy aging. (shrink)

The proteins that are implicated in the basal transcription of protein coding genes have now been identified. Although little is known about their function, recent data demonstrate the ability of these proteins, previously called class II transcription factors, to participate in other reactions: TBP, the TATA‐box binding factor, is involved in class I and III transcription, while TFIIH has been shown to possess components that are involved in the DNA repair mechanism. The involvement of some if not (...) all of the TFIIH subunits in transcription and repair may explain the heterogeneity of the various and sometimes completely unrelated symptoms observed in xeroderma pigmentosum, Cockayne Syndrome and trichothiodystrophy disorders. (shrink)

Recently discovered transcription‐independent features of p53 involve the choice of DNA damage repair pathway after PARylation, and p53's complex formation with phosphoinositide lipids, PI(4,5)P2. PARylation‐mediated rapid accumulation of p53 at DNA damage sites is linked to the recruitment of downstream repair factors and tumor suppression. This links p53's capability to sense damaged DNA in vitro and its relevant functions in cells. Further, PI(4,5)P2 rapidly accumulates at damage sites like p53 and complexes with p53, while it is required for ATR (...) recruitment. These findings help explain how p53 and PI(4,5)P2 maintain genome stability by directing DNA repair pathway choice. Additionally, there is a strong correlation between p53 sequence homology, genome mutation rates as well as lifespans across various mammalian species. Further investigation is required to better understand the connections between genome stability, tumor suppression, longevity and the transcriptional‐independent function of p53. (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)

Cyclin-dependent kinase 5 has been implicated in Alzheimer's disease pathogenesis. Here, we demonstrate that overexpression of p25, an activator of cdk5, led to increased levels of BACE1 mRNA and protein in vitro and in vivo. A p25/cdk5 responsive region containing multiple sites for signal transducer and activator of transcription was identified in the BACE1 promoter. STAT3 interacts with the BACE1 promoter, and p25-overexpressing mice had elevated levels of pSTAT3 and BACE1, whereas cdk5-deficient mice had reduced levels. Furthermore, mice with (...) a targeted mutation in the STAT3 cdk5 responsive site had lower levels of BACE1. Increased BACE levels in p25 overexpressing mice correlated with enhanced amyloidogenic processing that could be reversed by a cdk5 inhibitor. These data demonstrate a pathway by which p25/cdk5 increases the amyloidogenic processing of APP through STAT3-mediated transcriptional control of BACE1 that could have implications for AD pathogenesis. (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)

Methylation of cytosine DNA residues is a well‐studied epigenetic modification with important roles in formation of heterochromatic regions of the genome, and also in tissue‐specific repression of transcription. However, we recently found that the ciliate Oxytricha uses methylcytosine in a novel DNA elimination pathway important for programmed genome restructuring. Remarkably, mounting evidence suggests that methylcytosine can play a dual role in ciliates, repressing gene expression during some life‐stages and directing DNA elimination in others. In this essay, I describe these (...) recent advances in the DNA methylation field and discuss whether this unexpected novel role for methylcytosine in DNA elimination might be more widely conserved in eukaryotic biology, particularly in apoptotic pathways. (shrink)

One of the central issue of developmental biology concerns the molecular mechanisms whereby a multipotent cell gives rise to distinct differentiated progeny. Differences between specialised cell types reflect variations in their patterns of gene expression. The regulation of transcription initiation is an important control point for gene expression and it is, therefore, not surprising that transcription factors play a pivotal role in mammalian development and differentiation.Haemopoiesis offers a uniquely tractable system for the study of lineage commitment and differentiation. (...) The importance of transcription factor in the normal regulation of haemopoiesis is underlined by the frequency with which transcription factors are targeted by leukaemogenic mutations. Studies of the function and regulation of haemopoietic transcription factors, especially those expressed in lineage‐restricted patterns, should greatly increase our understanding of the molecular control of haemopoiesis. In this review we have focused on insights provided by recent studies of the GATA and SCL proteins. (shrink)

This section provides the first full edited transcription—from Latin and Italian vernacular language—of the Opera geometrica. Further, as above said, facsimile texts are added, including our critical comments as footnotes to this chapter.

This section provides information and background on the selection of Opera geometrica (Fig. 1). We have worked on transcription from Latin and Italian vernacular language, which is the original language of the Torricelli’s text. Further facsimile texts are added for readers and our critical comments can be found as footnotes to this chapter.

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