Genotoxic stress, arising from various environmental sources and endogenous cellular processes, pose a constant threat to genomic stability. Cells have evolved intricate mechanisms to detect and repair DNA damage, orchestrating a robust genotoxic stress response to safeguard the integrity of the genome. Recent research has shed light on the crucial role of co‐ and post‐transcriptional regulatory mechanisms in modulating the cellular response to genotoxic stress. Here we highlight recent advances illustrating the intricate interplay between pre‐mRNA processing, with a focus (...) on 3′‐end processing, and genotoxic stress response. (shrink)

Adipose tissue plays an important role in mammalian energy equilibrium not only as a lipid‐dissipating, i.e. energy‐storing, tissue (white adipose tissue), but also as an energy‐dissipating one (brown adipose tissue). Brown adipocytes have the ability of facultative heat production due to a unique mitochondrial protein, the uncoupling protein (UCP). Differentiation of white and (to a lesser extent) brown adipocytes has been studied in different cell culture systems, which has led to the identification of external inducers, second messenger pathways and (...) transcription factors involved in adipocyte differentiation. Functional differentiation of white adipocytes implies adipose conversion, whereas in brown adipocytes it insinuates additionally the development of a thermogenic function. This review discusses recent advances in the elucidation of the pathways responsible for, and the molecular bases of, adipose conversion on the one hand and development of the thermogenic properties of brown adipocytes on the other. (shrink)

Retrograde plastid‐to‐nucleus signaling plays a central role in coordinating nuclear and plastid gene expression. The gun (genomes uncoupled) mutants of Arabidopsis have been used to demonstrate that Mg‐protoporphyrin (Mg‐Proto) acts as a plastid signal to repress the transcription of nuclear photosynthesis genes.1 It is unclear how Mg‐Proto triggers repression, but several components of this pathway have been recently identified. These include the products of GUN4 and GUN5. GUN5 is the ChlH subunit of Mg‐chelatase, which produces Mg‐Proto, and GUN4 is a (...) regulator of ChlH activity.2 GUN4 might also play a role in photoprotection and in the trafficking of Mg‐Proto. BioEssays 25:631–636, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Almost all messenger RNAs carry a polyadenylate tail that is added in a post‐transcriptional reaction. In the nuclei of animal cells, the 3'‐end of the RNA is formed by endonucleolytic cleavage of the primary transcript at the site of poly (A) addition, followed by the polymerisation of the tail. The reaction depends on specific RNA sequences upstream as well as downstream of the polyadenylation site. Cleavage and polyadenylation can be uncoupled in vitro. Polyadenylation is carried out by poly(A) polymerase (...) with the aid of a specificity factor that binds the polyadenylation signal AAUAAA. Several aditional factors are required for the initial cleavage. A newly discovered poly(A)‐binding protein stimulates poly(A) tail synthesis and may be involved in the control of tail length. Polyadenylation reactions different from this scheme, either in other organisms or under special physiological circumstances, are discussed. (shrink)

Chromosomal origins of DNA replication in higher eukaryotes differ significantly from those of E. coli (oriC) and the tumor virus, SV40 (ori sequence). Initiation events appear to occur throughout broad zones rather than at specific origin sequences. Analysis of four chromosomal origin regions reveals that they share common modular sequence elements. These include DNA unwinding elements, pyrimidine tracts that may serve as strong DNA polymerase‐primase start sites, scaffold associated regions, transcriptional regulatory sequences, and, possibly, initiator protein binding sites and (...) inherently destabilized regions. Based on the novel organization of chromosomal origin regions, we propose a model for initiation of DNA replication in higher eukaryotes. Unwinding of duplex DNA during initiation may be uncoupled, both temporally and spatially, from DNA synthesis, resulting in transient single‐stranded intermediates that function in lieu of conventional replication forks during chromosomal DNA replication. DNA synthesis begins subsequently at multiple sites Within the unwound regions rather than at specific origin sequences. (shrink)

Uncoupling proteins (UCPs) regulate mitochondrial function, and thus cellular metabolism. Angiotensin‐converting enzyme (ACE) is the central component of endocrine and local tissue renin–angiotensin systems (RAS), which also regulate diverse aspects of whole‐body metabolism and mitochondrial function (partly through altering mitochondrial UCP expression). We show that ACE expression also appears to be regulated by mitochondrial UCPs. In genetic analysis of two unrelated populations (healthy young UK men and Scandinavian diabetic patients) serum ACE (sACE) activity was significantly higher amongst UCP3‐55C (rather (...) than T) and UCP2 I (rather than D) allele carriers. RNA interference against UCP2 in human umbilical vein endothelial cells reduced UCP2 mRNA sixfold (P < 0·01) whilst increasing ACE expression within a physiological range (<1·8‐fold at 48 h; P < 0·01). Our findings suggest novel hypotheses. Firstly, cellular feedback regulation may occur between UCPs and ACE. Secondly, cellular UCP regulation of sACE suggests a novel means of crosstalk between (and mutual regulation of) cellular and endocrine metabolism. This might partly explain the reduced risk of developing diabetes and metabolic syndrome with RAS antagonists and offer insight into the origins of cardiovascular disease in which UCPs and ACE both play a role. (shrink)

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)

Slaughter sets the debate about what is acceptable to do to animals at an extremely low bar. Recently, there has been considerable investment in developing cell-based meat, an alternative meat production process that does not require the raising and slaughtering of animals, instead using muscle cells cultivated in a bioreactor. We discuss the animal ethics impacts of cell-based and plant-based meat on human-animal interactions from animal welfare and rights perspectives, focusing on industrial meat production scenarios. Our hypothesis is that the (...) insertion of cell-based meat in the global meat market may alleviate farm animal suffering and potentially restore resources for wild fauna. We employed a conservative estimation of the cell-based meat contribution to the global meat market in the year 2040 to analyze the consequences for human-animal relationships for both wild animals and farmed domesticated animals. We discuss possible effects of an animal cell domestication process, previously described as the second domestication, on human-animal relationships. We consider its potential to reduce the impact of human demographic changes and land use on animal life, in particular whether there would be increased biomass availability and free land for wild animals. We anticipate a major reduction in animal suffering due to the decrease in the number of individual animals involved in food production, which justifies the adoption of cell-based meat from a utilitarian perspective. For the conventional animal food production that remains, further consideration is needed to understand which systems, either high or low welfare, will be retained and the impact of the innovation on the average farm animal welfare. Additionally, it seems likely that there will be less acceptance of the necessity of animal suffering in farming systems when meat production is uncoupled from animal raising and slaughter, supported by a deontological perspective of animal ethics. Consequent to this is anticipated the mitigation of relevant barriers to animal protection and to the recognition of animals as subjects by legislation. Thus, the development of the alternative meats may be related to a significant change in our relationship with non-human animals, with greater benefits than the prima facie effects on farm animals. (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)

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)

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)

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)

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)

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)

Speech-to-Text applications have made dazzling progress in recent years (e.g. Whisper). However, since they are usually intended to generate texts conform to written standards, they tend to blur marks of an oral nature (e.g. repetitions, pauses in the stream of words, phatics like er…). Thus, even if such applications suggest huge benefits in terms of working time as well as transcription accuracy, they remain inadequate for verbal exchanges analysis. Relying on a sample of transcripts from medical consultations anticipating an awake (...) brain-surgery (a research now in progress), this study aims at three goals: (i) drawing up an inventory of difficulties revealed by the use of Whisper from a speech analyst perspective; (ii) clarifying the origins of these difficulties; (iii) suggesting ways to overcome them. (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)

The philosophical discussion of emergence is often focused on properties of ‘wholes’ that are evaluated as emergent with respect to the properties of ‘parts’. Downward causation is, consequently, evaluated as some kind of causal influence of whole properties over parts properties. Yet, several important cases in scientific practice seem to be pursuing hypotheses of parts properties emerging from wholes properties, inverting the instinctive association of emergence with wholes. Furthermore, some areas of reflection which are very important for emergence, e.g., the (...) philosophy of consciousness, do not allow mapping properties onto part-whole organizations. The conceptual puzzle is solved by constructing a framework that disentangles the mereological dimension from the superventional dimension. By liberalizing the spatio-temporal allocation of emergent properties, the proposed dual framework could better capture the way in which emergence and downward causation are addressed in scientific 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)

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)

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)

(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.

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)

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)

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)

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)

The small ubiquitin‐like modifier SUMO regulates many aspects of cellular physiology to maintain cell homeostasis, both under normal conditions and during cell stress. Components of the transcriptional apparatus and chromatin are among the most prominent SUMO substrates. The prevailing view is that SUMO serves to repress transcription. However, as we will discuss in this review, this model needs to be refined, because recent studies have revealed that SUMO can also have profound positive effects on transcription.

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)

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)

Transcription is a potential threat to genome integrity, and transcription‐associated DNA damage must be repaired for proper messenger RNA (mRNA) synthesis and for cells to transmit their genome intact into progeny. For a wide range of structurally diverse DNA lesions, cells employ the highly conserved nucleotide excision repair (NER) pathway to restore their genome back to its native form. Recent evidence suggests that NER factors function, in addition to the canonical DNA repair mechanism, in processes that facilitate mRNA synthesis or (...) shape the 3D chromatin architecture. Here, these findings are critically discussed and a working model that explains the puzzling clinical heterogeneity of NER syndromes highlighting the relevance of physiological, transcription‐associated DNA damage to mammalian development and disease is proposed. (shrink)

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)

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)

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

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)

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)

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)

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 spatial organization of genomes is becoming increasingly understood. In mammals, where it is most investigated, this organization ties in with transcription, so an important research objective is to understand whether gene activity is a cause or a consequence of genome folding in space. In this regard, the phenomena of X‐chromosome inactivation and reactivation open a unique window of investigation because of the singularities of the inactive X chromosome. Here we focus on the cause–consequence nexus between genome conformation and transcription (...) and explain how recent results about the structural changes associated with inactivation and reactivation of the X chromosome shed light on this problem. (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)

It is proposed that the multiple enhancer elements associated with locus control regions and super‐enhancers recruit RNA polymerase II and efficiently assemble elongation competent transcription complexes that are transferred to target genes by transcription termination and transient looping mechanisms. It is well established that transcription complexes are recruited not only to promoters but also to enhancers, where they generate enhancer RNAs. Transcription at enhancers is unstable and frequently aborted. Furthermore, the Integrator and WD‐domain containing protein 82 mediate transcription termination at (...) enhancers. Abortion and termination of transcription at the multiple enhancers of locus control regions and super‐enhancers provide a large pool of elongation competent transcription complexes. These are efficiently captured by strong basal promoter elements at target genes during transient looping interactions. -/- . (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)

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.

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.

Tri‐methylation of lysine 4 on histone H3 (H3K4me3) is a near‐universal chromatin modification at the transcription start site of active genes in eukaryotes from yeast to man and its levels reflect the amount of transcription. Because of this association, H3K4me3 is often described as an ‘activating’ histone modification and assumed to have an instructive role in the transcription of genes, but the field is lacking a conserved mechanism to support this view. The overwhelming finding from genome‐wide studies is that actually (...) very little transcription changes upon removal of most H3K4me3 under steady‐state or dynamically changing conditions, including at mammalian CpG island promoters. Instead, rather than a major role in instructing transcription, time‐resolved experiments provide more evidence supporting the deposition of H3K4me3 into chromatin as a result of transcription, influencing processes such as memory of previous states, transcriptional consistency between cells in a population and transcription termination. -/- . (shrink)

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)

(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)

(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)

Studies of transcriptional control sequences responsible for regulated and basal‐level RNA synthesis from promoters of Drosophila melanogaster retrotransposons reveal novel aspects of gene regulation and lead to identification of trans‐acting factors that can be involved in RNA polymerase II transcription not only of retrotransposons, but of many other cellular genes. Comparisons between promoters of retrotransposons and some other Drosophila genes demonstrate that there is a greater variety in basal promoter structure than previously thought and that many promoters may contain (...) essential sequences downstream from the RNA start site. (shrink)