Histone H3.3 turnover displays distinct dynamics at various genomic elements such as promoters, enhancers, gene bodies, and heterochromatic regions, suggesting that it is differentially regulated according to chromatin context. Incorporation of variant histones into chromatin provides a mechanism to modulate chromatin states in addition to histone modifications. The replication‐independent deposition and replacement of histone variant H3.3, i.e. H3.3 turnover, is mainly associated with transcriptional activity. H3.3 or H3.3‐like histone turnover has been studied in various organisms from yeast to mammals. Here, (...) we review the recent progress on this topic. The diversified turnover profiles of H3.3, and their corresponding underlying mechanisms, may reflect distinct requirements for chromatin accessibility in different biological events. (shrink)

Pre‐existing but untranslated or ‘poised’ mRNA exists as a means to rapidly induce the production of specific proteins in response to stimuli and as a safeguard to limit the actions of these proteins. The translation of poised mRNA enables immune cells to express quickly genes that enhance immune responses. The molecular mechanisms that repress the translation of poised mRNA and, upon stimulation, enable translation have yet to be elucidated. They likely reflect intrinsic properties of the mRNAs and (...) their interactions with trans‐acting factors that direct poised mRNAs away from or into the ribosome. Here, I discuss mechanisms by which this might be regulated. (shrink)

Histone variant exchange is a novel epigenetic regulator of cognition. We speculate that H2A.Z, a variant of canonical histone H2A, exerts unique effects on transcription during distinct stages of memory formation, ultimately acting to maintain memory of previous transcriptional states and poise genes for re‐activation. Hippocampus‐dependent memory formation is initiated by transient expression of memory‐related genes, which support the storage of recently acquired memories. Soon after, memories undergo systems consolidation, which transfers memories from the hippocampus to the cortex for long‐term (...) storage, and requires ongoing re‐activation of memory‐related genes. We speculate that learning‐induced H2A.Z eviction from nucleosomes initially contributes to stimulus‐induced transcriptional induction needed for the initial process of memory consolidation. During systems consolidation, we speculate that delayed incorporation of H2A.Z into nucleosomes of memory‐related genes in the cortex is needed to poise genes for rapid re‐activation, thus supporting the long‐term process of memory stabilization.Also watch the Video Abstract. (shrink)

Bivalent chromatin with active H3K4me3 and repressive H3K27me3 was initially identified in embryonic stem cells (ESCs) to poise expression of developmental genes upon lineage commitment. Since then, many more different bivalent modifications have been demonstrated in both ESCs and fully differentiated cells. Bivalency not only spatiotemporally controls gene transcription but also acts to fine‐tune the level of transcription during development. Although increasing number of studies demonstrated the functional significance of bivalent chromatin, the molecular connection of bivalent chromatin and transcriptional regulation (...) remains largely elusive. Recently, we showed Spindlin1/C11orf84 complex prefers to recognize the non‐canonical histone H3K4me3K9me3 bivalent mark, which is required for timely ribosomal RNA transcription. Here, we hypothesize the recognition of K4me3 and K9me3 at the same histone tail by Spindlin1/C11orf84 complex may serve as a general mechanism of conversion from a repressed to an active chromatin structure for transcriptional activation. (shrink)

The DNase I hypersensitive sites (DHSs) of chromatin constitute one of the best landmarks of eukaryotic genes that are poised and/or activated for transcription. For over 35 years, the high‐mobility group nucleosome‐binding chromosomal proteins HMGN1 and HMGN2 have been shown to play a role in the establishment of these chromatin‐accessible domains at transcriptional regulatory elements, namely promoters and enhancers. The critical presence of HMGNs at enhancers, as highlighted by a recent publication, suggests a role for them in the structural (...) and functional fine‐tuning of the DHSs in vertebrates. As we review here, while preferentially out‐competing histone H1 binding and invading neighbor nucleosomes, HMGNs may also modulate histone H3 at serine 10 (H3S10ph), which plays an important role in enhancer function and transcriptional initiation. (shrink)

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) can self‐renew indefinitely and contribute to all tissue types of the adult organism. Stem cell‐based therapeutic approaches hold enormous promise for the cure of regenerative diseases. Over the last few years, several studies have attempted to decipher the important role of transcription factor networks and epigenetic regulatory signals in the maintenance of ESC pluripotency, but the exact underlying mechanisms have yet to be identified. Among the epigenetic factors, chromatin dynamics and (...) structure have been found to contribute greatly to maintenance of pluripotency and regulation of differentiation in ESCs. These modifications include: covalent histone acetylation and methylation, histone bivalents and chromatin remodeling, and DNA methylation. Studies in ESCs have shown that genes associated with early development are arranged within a bivalent chromatin structure. This is thought to be a “poised yet repressed” situation, which can be activated upon differentiation. The breakthrough of iPSCs has opened a new era in stem cell biology. During reprogramming, the chromatin state of differentiated cells is reset to an embryonic form via a largely unknown mechanism. In this review, the fundamental impact of chromatin dynamic in ESCs as well as its critical role in the generation of iPSCs is discussed. (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)

The urban poise is dependent on a particular notion of urban planning: a myriad of actions that can adjust civic life in many places to provoke it towards greater self-esteem. Urban planning is not consecrated by a drawing in the shape of a plan alone, but it must respect the elevation of the stance of an urban spectacle as seen from the sidewalk. The coercion of civic indicators is reappraised by delighting in the figurative stance of the informant city. Small (...) things are done in the city within its existing urban structure so that an edge is applied to what already exists. City blocks might be fractionally altered, holes in the skyline reamed out smooth, and points located strategically so that they can carry their attendant responsibilities. The method is marginally parasitic, for it exists by requiring something else to exist that it cannot readily harbor.Ten points and places of vulnerability have been chosen in the city that poke at its underbelly. Whilst the poises are given names and specific sites, their viability could be felt equally in a different city using changed names. The Appliance House franchises its intention to various matters of civic consequence, ranging from the weather to shopping to the monumental respect for the dead. Each poise is considered integrally related to the wholeness of the city. If any of the Poises becomes disassociated from the city or from other Poises, the prime tenet of urban existence will have been ignored: the over-exertion of one component of urban life will take place at the expense of somebody else. Ben Nicholson is studio professor of architecture at the Illinois Institute of Technology. His Appliance House will be published later this year. (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)

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)

This paper explores a line of argument against the classical paradigm in cognitive science that is based upon properties of non-linear dynamical systems, especially in their chaotic and near-chaotic behavior. Systems of this kind are capable of generating information-rich macro behavior that could be useful to cognition. I argue that a brain operating at the edge of chaos could generate high-complexity cognition in this way. If this hypothesis is correct, then the symbolic processing methodology in cognitive science faces serious obstacles. (...) A symbolic description of the mind will be extremely difficult, and even if it is achieved to some approximation, there will still be reasons for rejecting the hypothesis that the brain is in fact a symbolic processor. (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)

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)

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)

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)

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)

How do we ready ourselves to intervene responsively in the contingent situations that arise in co-designing to make change? How do we attune to group dynamics and respond ethically to unpredictable developments when working with 'community'? Participatory Design can contribute to social transitions, yet its focus is often tightly tuned to technique for designing ICT at the cost of participatory practice. We challenge PD conventions by addressing what happens as we step into a situation to alter it with others, an (...) aspect of practice that cannot be replicated or interchanged. We do so to argue that practices of readiness are constituted by personal histories, experiences, philosophies and culture. We demonstrate this political argument by giving reflexive accounts of our dimensions of preparation. The narratives here are distinct, yet reveal complementary theories and worldviews that shape PD ontologies. We have organized these around the qualities of punctuation and poise as a way to draw out some less easily articulated aspects of PD practice. (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)

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)

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)

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)

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.

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)

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)

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)

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)

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)

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)

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)

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)

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)

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.

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)