The eukaryotic genome is packaged into a periodic nucleoprotein structure termed chromatin. The repeating unit of chromatin, the nucleosome, consists of DNA that is wound nearly two times around an octamer of histone proteins. To facilitate DNA‐directed processes in chromatin, it is often necessary to rearrange or to mobilize the nucleosomes. This remodeling of the nucleosomes is achieved by the action of chromatin‐remodeling complexes, which are a family of ATP‐dependent molecular machines. Chromatin‐remodeling factors share a (...) related ATPase subunit and participate in transcriptional regulation, DNA repair, homologous recombination and chromatin assembly. In this review, we provide an overview of chromatin‐remodeling enzymes and discuss two possible mechanisms by which these factors might act to reorganize nucleosome structure. BioEssays 25:1192–1200, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Here, the emerging data on DNA G‐quadruplexes (G4s) as epigenetic modulators are reviewed and integrated. This concept has appeared and evolved substantially in recent years. First, persistent G4s (e.g., those stabilized by exogenous ligands) were linked to the loss of the histone code. More recently, transient G4s (i.e., those formed upon replication or transcription and unfolded rapidly by helicases) were implicated in CpG island methylation maintenance and de novo CpG methylation control. The most recent data indicate that there are direct (...) interactions between G4s and chromatin remodeling factors. Finally, multiple findings support the indirect participation of G4s in chromatin reshaping via interactions with remodeling‐related transcription factors (TFs) or damage responders. Here, the links between the above processes are analyzed; also, how further elucidation of these processes may stimulate the progress of epigenetic therapy is discussed, and the remaining open questions are highlighted. (shrink)

The remodel the structure of chromatin (RSC) nucleosome remodeling complex is a conserved chromatin regulator with roles in chromatin organization, especially over nucleosome depleted regions therefore functioning in gene expression. Recent reports in Saccharomyces cerevisiae have identified specificities in RSC activity toward certain types of nucleosomes. RSC has now been shown to preferentially evict nucleosomes containing the histone variant H2A.Z in vitro. Furthermore, biochemical activities of distinct RSC complexes has been found to differ when their nucleosome substrate (...) is partially unraveled. Mammalian BAF complexes, the homologs of yeast RSC and SWI/SNF complexes, are also linked to nucleosomes with H2A.Z, but this relationship may be complex and extent of conservation remains to be determined. The interplay of remodelers with specific nucleosome substrates and regulation of remodeler outcomes by nucleosome composition are tantalizing questions given the wave of structural data emerging for RSC and other SWI/SNF family remodelers. (shrink)

Epigenetic control of gene expression by chromatin remodeling is critical for adult stem cell function. A decline in stem cell function is observed during aging, which is accompanied by changes in the chromatin structure that are currently unexplained. Here, we hypothesize that these epigenetic changes originate from the limited cellular capability to inherit epigenetic information. We suggest that spontaneous loss of histone modification, due to fluctuations over short time scales, gives rise to long‐term changes in DNA methylation and, (...) accordingly, in gene expression. These changes are assumed to impair stem cell function and, thus, to contribute to aging. We discuss cell replication as a major source of fluctuations in histone modification patterns. Gene silencing by our proposed mechanism can be interpreted as a manifestation of the conflict between the stem cell plasticity required for tissue regeneration and the permanent silencing of potentially deleterious genomic sequences. (shrink)

Transcription factor (TF) signaling regulates gene transcription and requires a complex network of proteins. This network includes co‐activators, co‐repressors, multiple TFs, histone‐modifying complexes, and the basal transcription machinery. It has been widely appreciated that pioneer factors, such as FoxA1 and GATA1, play an important role in opening closed chromatin regions, thereby allowing binding of a secondary factor. In this review we will focus on a newly proposed model wherein multiple TFs, such as steroid receptors (SRs), can function in a (...) pioneering role. This model, termed dynamic assisted loading, integrates data from widely divergent methodologies, including genome wide ChIP‐Seq, digital genomic footprinting, DHS‐Seq, live cell protein dynamics, and biochemical studies of ATP‐dependent remodeling complexes, to present a real time view of TF chromatin interactions. Under this view, many TFs can act as initiating factors for chromatin landscape programming. Furthermore, enhancer and promoter states are more accurately described as energy‐dependent, non‐equilibrium steady states. (shrink)

Improvements in deep sequencing, together with methods to rapidly deplete essential transcription factors (TFs) and chromatin remodelers, have recently led to a more detailed picture of promoter nucleosome architecture in yeast and its relationship to transcriptional regulation. These studies revealed that ∼40% of all budding yeast protein‐coding genes possess a unique promoter structure, where we propose that an unusually unstable nucleosome forms immediately upstream of the transcription start site (TSS). This “fragile” nucleosome (FN) promoter architecture relies on the (...) combined action of the essential RSC (Remodels Structure of Chromatin) nucleosome remodeler and pioneer transcription factors (PTFs). FNs are associated with genes whose expression is high, coupled to cell growth, and characterized by low cell‐to‐cell variability (noise), suggesting that they may promote these features. Recent studies in metazoans suggest that the presence of dynamic nucleosomes upstream of the TSS at highly expressed genes may be conserved throughout evolution. (shrink)

During early embryonic development in several metazoans, accurate DNA replication is ensured by high number of replication origins. This guarantees rapid genome duplication coordinated with fast cell divisions. In Xenopus laevis embryos this program switches to one with a lower number of origins at a developmental stage known as mid‐blastula transition (MBT) when cell cycle length increases and gene transcription starts. Consistent with this regulation, somatic nuclei replicate poorly when transferred to eggs, suggesting the existence of an epigenetic memory suppressing (...) replication assembly origins at all available sites. Recently, it was shown that histone H1 imposes a non‐permissive chromatin configuration preventing replication origin assembly on somatic nuclei. This somatic state can be erased by SSRP1, a subunit of the FACT complex. Here, we further develop the hypothesis that this novel form of epigenetic memory might impact on different areas of vertebrate biology going from nuclear reprogramming to cancer development. (shrink)

Activation of gene transcription in vivo is accompanied by an alteration of chromatin structure. The specific binding of transcriptional activators disrupts nucleosomal arrays, suggesting that the primary steps leading to transcriptional initiation involve interactions between activators and chromatin. The affinity of transcription factors for nucleosomal DNA is determined by the location of recognition sequences within nucleosomes, and by the cooperative interactions of multiple proteins targeting binding sites contained within the same nucleosomes. In addition, two distinct types of enzymatic (...) complexes facilitate binding of transcription factors to nucleosomal DNA. These include type A histone acetyltransferases (e.g. GCN5/ADA transcriptional adaptor complex) and ATP‐driven molecular machines that disrupt histone‐DNA interactions (e.g. SWI/SNF and NURF complexes). These observations raise the important question of what happens to the histones during chromatin remodeling. We discuss evidence supporting the retention of histones at transcription factorbound sequences as well as two alternative pathways of histone loss from gene control elements upon transcription factor binding: histone octamer sliding and histone dissociation. (shrink)

We present a molecular model of eukaryotic gene transcription. For the β‐globin locus, we hypothesise that a transcription machine composed of multiple RNA polymerase II (PolII) assembles using the locus control region as a foundation. Transcription and locus remodelling can be achieved by pulling DNA through this multi‐PolII ‘reading head’. Once a transcription complex is formed, it may engage an active gene in several rounds of transcription. Observed intergenic sense and antisense transcripts may be the result of PolII pulling the (...) DNA through the reading head whilst searching for the promoter of a gene. Support for this hypothesis is provided using various data from the literature. In the model, DNA is packed in a 30‐nm chromatin fibre, thus gene regulatory regions separated by kilobases are close in space. This, and the need to store transcription‐induced supercoiling, may explain why functionally interacting regions are often separated by many kilobases. (shrink)

In this review, we discuss a novel on‐site remodeling function that is mediated by the H2A‐ubiquitin binding protein ZRF1. ZRF1 facilitates the remodeling of multiprotein complexes at chromatin and lies at the heart of signaling processes that occur at DNA damage sites and during transcriptional activation. In nucleotide excision repair ZRF1 remodels E3 ubiquitin ligase complexes at the damage site. During embryonic stem cell differentiation, it contributes to retinoic acid‐mediated gene activation by altering the subunit composition of the Mediator (...) complex. We postulate that ZRF1 operates in conjunction with cellular remodeling machines and suggest that on‐site remodeling might be a hallmark of many chromatin‐associated signaling pathways. We discuss yet unexplored functions of ZRF1‐mediated remodeling in replication and double strand break repair. In conclusion, we postulate that on‐site remodeling of multiprotein complexes is essential for the timing of chromatin signaling processes. (shrink)

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

Disruptions in chromatin regulator genes are frequently the cause of neurodevelopmental and neuropsychiatric disorders. Chromatin regulators are widely expressed in the brain, yet symptoms suggest that specific circuits can be preferentially altered when they are mutated. Using Drosophila allows targeted manipulation of chromatin regulators in defined neuronal classes, lineages, or circuits, revealing their roles in neuronal precursor self‐renewal, dendrite and axon targeting, neuron diversification, and the tuning of developmental signaling pathways. Phenotypes arising from chromatin regulator disruption (...) are context dependent – defined by interaction networks between the regulators, transcription factors, and chromatin remodeling complex partners. Future challenges are to determine the complexity of partner interactions, and to ascertain the degree to which cognitive deficits are due to loss of chromatin regulator activity in building a circuit or in maintaining homeostasis and activity within it. (shrink)

Recently, there has been a convergence of fields studying the processing of DNA, such as transcription, replication, and repair. This convergence has been centered around the packaging of DNA in chromatin. Chromatin structure affects all aspects of DNA processing because it modulates access of proteins to DNA. Therefore, a central theme has become the mechanism(s) for accessing DNA in chromatin. It seems likely that mechanisms involved in one of these processes may also be used in others. For (...) example, the discovery of transcriptional coactivators with histone acetyltransferase activity and chromatin remodeling complexes has provided possible mechanisms required for efficient repair of DNA in chromatin. BioEssays 21:596–603, 1999. © 1999 John Wiley & Sons, Inc. (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)

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

It is increasingly clear that chromatin is not just a device for packing DNA within the nucleus but also a dynamic material that changes as cellular environments alter. The precise control of chromatin modification in response to developmental and environmental cues determines the correct spatial and temporal expression of genes. Here, we review exciting discoveries that reveal chromatin participation in many facets of plant development. These include: chromatin modification from embryonic and meristematic development to flowering and (...) seed formation, the involvement of DNA methylation and chromatin in controlling invasive DNA and in maintenance of epigenetic states, and the function of chromatin modifying and remodeling complexes such as SWI/SNF and histone acetylases and deacetylases in gene control. Given the role chromatin structure plays in every facet of plant development, chromatin research will undoubtedly be integral in both basic and applied plant biology. BioEssays 24:234–243, 2002. © 2002 Wiley Periodicals, Inc.; DOI 10.1002/bies.10055. (shrink)

Controversy has reigned for some time over the biological connection between DNA methylation and cancer. For this reason, the methylation mechanism responsible for increased cancer risk has received greater attention in recent years. Tumor suppressor genes are often hypermethylated resulting in gene silencing. Although some have questioned this interpretation of the link between methylation and cancer, it appears that both hypermethylation and hypomethylation events can create epigenetic changes that can contribute to cancer development. Recent studies have shown that the methyltransferases (...) DNMT1 and DNMT3b cooperatively maintain DNA methylation and gene silencing in human cancer cells. Disruption of the human DNMT3b only slightly reduces the overall global DNA methylation; however, demethylation was markedly potentiated when both DNMT1 and DNMT3b were simultaneously deleted. The results to these experiments provide compelling evidence towards a role for DNA methylation in cancer. This review discusses the current understanding of cancer‐epigenetic information and highlights recent studies that connect the methylation machinery and chromatin remodelling with cancer susceptibility. BioEssays 25:1071–1084, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

The organization of eukaryotic genomes as chromatin provides the framework within which regulated transcription occurs in the nucleus. The association of DNA with chromatin proteins required to package the genome into the nucleus is, in general, inhibitory to transcription, and therefore provides opportunities for regulated transcriptional activation. Granting access to the cis‐acting elements in DNA, a prerequisite for any further action of the trans‐acting factors involved, requires the establishment of local heterogeneity of chromatin and, in some cases, (...) extensive remodeling of nucleosomal structures. Challenging problems relate to the establishment of this heterogeneity at the level of the single nucleosome and to the mechanisms that operate when nucleosomal arrays are reorganized. Recent developments indicate that chromatin reconstitution in cell‐free systems allows the biochemical analysis of the interplay between transcription factors and chromatin components that brings about regulated transcription. (shrink)

Chromatin structure and dynamics regulate key cellular processes such as DNA replication, transcription, repair, remodeling, and gene expression, wherein different protein factors interact with the nucleosomes. In these events, DNA and RNA polymerases, chromatin remodeling enzymes and transcription factors interact with nucleosomes, either in a DNA‐sequence‐specific manner and/or by recognizing different structural features on the nucleosome. The molecular details of the recognition of a nucleosome by different viral proteins, remodeling enzymes, histone post‐translational modifiers, and RNA polymerase II, have (...) been explored in the recent past. The present review puts forth critical insights into the basic mechanisms of nucleosome recognition by the various protein factors and the role of distinct surface epitopes on a nucleosome. These determinants of the underlying specificity include features such as the acidic patch, arginine anchor, histone post‐translational modifications, core DNA, DNA lesions, and linker DNA. (shrink)

RNA polymerase II (RNAP II) non‐coding transcription is now known to cover almost the entire eukaryotic genome, a phenomenon referred to as pervasive transcription. As a consequence, regions previously thought to be non‐transcribed are subject to the passage of RNAP II and its associated proteins for histone modification. This is the case for the nucleosome‐depleted regions (NDRs), which provide key sites of entry into the chromatin for proteins required for the initiation of coding gene transcription and DNA replication. In (...) this review, recent data on the effects of pervasive transcription through NDRs are summarized and a model is proposed to explain how RNAP II‐driven transcription is able to modify the nucleosomes flanking the NDRs, leading to nucleosome repositioning and NDR closure. Even though much of the mechanistic detail underlying these events remains to be elucidated, such a model provides a basis to explain how non‐coding transcription through NDRs can regulate the initiation of coding gene expression and DNA replication. (shrink)

Histone variants are specialized histones which replace their canonical counterparts in specific nucleosomes. Together with histone post‐translational modifications and DNA methylation, they contribute to the epigenome. Histone variants are incorporated at specific locations by the concerted action of histone chaperones and ATP‐dependent chromatin remodelers. Recent studies have shown that the histone chaperone FACT plays key roles in preventing pervasive incorporation of two histone variants: H2A.Z and CenH3/CENP‐A. In addition, Spt6, another histone chaperone, was also shown to be important (...) for appropriate H2A.Z localization. FACT and Spt6 are both associated with elongating RNA polymerase II. Based on these two examples, we propose that the establishment and maintenance of histone variant genomic distributions depend on a transcription‐coupled epigenome editing (or surveillance) function of histone chaperones. (shrink)

DREAM complexes are transcriptional regulators that control the expression of hundreds to thousands of target genes involved in the cell cycle, quiescence, differentiation, and apoptosis. These complexes contain many subunits that can vary according to the considered target genes. Depending on their composition and the nature of the partners they recruit, DREAM complexes control gene expression through diverse mechanisms, including chromatin remodeling, transcription cofactor and factor recruitment at various genomic binding sites. This complexity is particularly high in mammals. Since (...) the discovery of the first dREAM complex (drosophila Rb, E2F, and Myb) in Drosophila melanogaster, model organisms such as Caenorhabditis elegans, and plants allowed a deeper understanding of the processes regulated by DREAM‐like complexes. Here, we review the conservation of these complexes. We discuss the contribution of model organisms to the study of DREAM‐mediated transcriptional regulatory mechanisms and their relevance in characterizing novel activities of DREAM complexes. (shrink)

This review explores the hypothesis that regulation of nucleocytoplasmic shuttling is a means of driving differentiation, using spermatogenesis as a model. The transition from undifferentiated spermatogonial stem cell to terminally differentiated spermatozoon is, at its most basic, a change in the repertoire of expressed genes. To effect this, the complement of nuclear proteins, such as transcription factors and chromatin remodelling components must change. Current knowledge of the nuclear proteins and nucleocytoplasmic transport machinery relevant to spermatogenesis is consolidated in this (...) review, and their functional linkages are highlighted not only as a means of regulating nuclear protein composition, but also as a key mechanism regulating gene transcription and hence cell fate. Through this, we hypothesize that male germ cell differentiation is mediated through regulation of nuclear transport machinery components, and thereby of the access of critical factors to the nucleus. The importance of nucleocytoplasmic trafficking to male germ cell differentiation is discussed, using the sex-determining factors Sry and SOX9, cell cycle regulators, CREM and cofactors and the Smads as specific examples, together with the roles in gametogenesis for particular nuclear transport factors in Caenorhabditis elegans and Drosophila. BioEssays 27:1011–1025, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

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

Despite the progress achieved over the last decade after the birth of the first cloned mammal, the efficiency of reproductive cloning remains invariably low. However, research aiming at the use of nuclear transfer for the production of patient‐tailored stem cells for cell/tissue therapy is progressing rapidly. Yet, reproductive cloning has many potential implications for animal breeding, transgenic research and the conservation of endangered species. In this article we suggest that the changes in the epi‐/genotype observed in cloned embryos arise from (...) unbalanced nuclear reprogramming between parental chromosomes. It is probable that the oocyte reprogramming machinery, devised for resident chromosomes, cannot target the paternal alleles of somatic cells. We, therefore, suggest that a reasonable approach to balance this asymmetry in nuclear reprogramming might involve the transient expression in donor cells of chromatin remodelling proteins, which are physiologically expressed during spermatogenesis, in order to induce a male‐specific chromatin organisation in the somatic cells before nuclear transfer. BioEssays 30:66–74, 2008. © 2007 Wiley Periodicals, Inc. (shrink)

Graphical AbstractCurrent differentiation therapies for cancer may not be effective because it might not be enough to only use molecules targeting chromatin remodelers. It may also be necessary to stabilize the re-expressed genes to convert malignant cells into benign ones.

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

The gelsolin gene family encodes a number of higher eukaryotic actin-binding proteins that are thought to function in the cytoplasm by severing, capping, nucleating or bundling actin filaments. Recent evidence, however, suggests that several members of the gelsolin family may have adopted unexpected nuclear functions including a role in regulating transcription. In particular, flightless I, supervillin and gelsolin itself have roles as coactivators for nuclear receptors, despite the fact that their divergence appears to predate the evolutionary appearance of nuclear receptors. (...) Flightless I has been shown to bind both actin and the actin-related BAF53a protein, which are subunits of SWI/SNF-like chromatin remodelling complexes. The primary sequences of some actin-related proteins such as BAF53a exhibit conservation of residues that, in actin itself, are known to interact with gelsolin-related proteins. In summary, there is a growing body of evidence supporting a biological role in the nucleus for actin, Arps and actin-binding proteins and, in particular, the gelsolin family of actin-binding proteins. (c) 2005 Wiley Periodicals, Inc. (shrink)

Since its original identification as a component of the heterogeneous nuclear ribonucleoprotein (hnRNP) complex, K protein has been found not only in the nucleus but also in the cytoplasm and mitochondria and is implicated in chromatin remodeling, transcription, splicing and translation processes. K protein contains multiple modules that, on one hand, bind kinases while, on the other hand, recruit chromatin, transcription, splicing and translation factors. Moreover, the K‐ protein‐mediated interactions are regulated by signaling cascades. These observations are consistent (...) with K protein acting as a docking platform to integrate signaling cascades by facilitating cross‐talk between kinases and factors that mediate nucleic‐acid‐directed processes. Comparison of K across species reveals that it is an essential factor in metazoans, but not in yeast. Although some of the K protein interactions and functions are conserved in eukaryotes from yeast to man, the mammalian protein seems to play a wider role. The greater diversity of mammalian K protein interactions and function may reflect gain of novel docking sites and expansion evolutionary of gene expression networks. BioEssays 26:629–638, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Gestational factors play a role in the development of several neuropsychiatric disorders including schizophrenia and autism. In utero conditions influence future mental health through epigenetic mechanisms, which alter gene expression without affecting DNA coding sequence. Environmental factors account for at least 60% of the risk for developing major depression, and earlier onset of depressive illness has been observed over the past decades. I speculate that gestational factors may play a greater role in programing depression than previously recognized. Here, I examine (...) recent evidence for a role for gestational factors in programing mood disorders, and how epigenetic mechanisms mediate this effect. (shrink)

Expression of sexually dimorphic behaviors critical for reproduction depends on the organizational actions of steroid hormones on the developing brain. We offer the new hypothesis that transcriptional activities in brain regions executing these sexually dimorphic behaviors are modulated by estrogen‐induced modifications of histone proteins. Specifically, in preoptic nerve cells responsible for facilitating male sexual behavior in rodents, gene expression is fostered by increased histone acetylation and reduced methylation (Me), and, that the opposite set of histone modifications will be found in (...) females. Conversely, in ventromedial hypothalamic neurons that are responsible for coordinating female sexual behavior, transcriptional activities in genetic females are fostered by increased histone acetylation and reduced Me, and, further, that the opposite set of histone modifications will be found in males. Thus, these epigenetic events will guarantee that effects of sex hormone exposure during the neonatal critical period will be translated into lasting sex differences in adult reproductive behaviors. (shrink)

The acidic (leucine‐rich) nuclear phosphoprotein 32 kDa (ANP32) family is composed of small, evolutionarily conserved proteins characterized by an N‐terminal leucine‐rich repeat domain and a C‐terminal low‐complexity acidic region. The mammalian family members (ANP32A, ANP32B, and ANP32E) are ascribed physiologically diverse functions including chromatin modification and remodelling, apoptotic caspase modulation, protein phosphatase inhibition, as well as regulation of intracellular transport. In addition to reviewing the widespread literature on the topic, we present a concept of the ANP32s as having a (...) whip‐like structure. We also present hypotheses that ANP32C and other intronless sequences should not currently be considered bona fide family members, that their disparate necessity in development may be due to compensatory mechanisms, that their contrasting roles in cancer are likely context‐dependent, along with an underlying hypothesis that ANP32s represent an important node of physiological regulation by virtue of their diverse biochemical activities. (shrink)

The chromodomain is a highly conserved sequence motif that has been identified in a variety of animal and plant species. In mammals, chromodomain proteins appear to be either structural components of large macromolecular chromatin complexes or proteins involved in remodelling chromatin structure. Recent work has suggested that apart from a role in regulating gene activity, chromodomain proteins may also play roles in genome organisation. This article reviews progress made in characterising mammalian chromodomain proteins and emphasises their emerging role (...) in the regulation of gene expression and genome organisation. BioEssays 22:124–137, 2000. ©2000 John Wiley & Sons, Inc. (shrink)

Every cell, tissue, organ and organism is competent to use signs to exchange information reaching common coordinations and organisations of both single cell and group behavior. These sign-mediated interactions we term biological communication. The regulatory system that works in development, morphology, cell fate and identity, physiology, genetic instructions, immunity, memory/learning, physical and mental disease depends on epigenetic marks. The communication of cells, persistent viruses and their defectives such as mobile genetic elements and RNA networks ensures both the transport of regulatory (...) instructions and the reprogramming of these instructions. But how are the different states of the epigenome orchestrated? The epigenetic pathways respond to various signaling cues such as DNA methylation, histone variants, histone modifications, chromatin structure, nucleosome remodeling, and epigenetic interactions. Epigenetic signals are responsible for the establishment, maintenance and reversal of transcriptional states that are fundamental for the cell's ability to memorize past events, such as changes in the external environment, socio-sphere or developmental cues. External signals trigger changes in the epigenome, allowing cells to respond dynamically. Internal signals direct activities that are necessary for body maintenance, and repairing damaged tissues and organs. With the emergence of epigenetic memory, organisms can fix historical and context dependent impressive experiences. Evolution from now on learnt to learn. Learning means organisms can avoid reproduction of always the same. This is key to adaptation. However, inheritance of acquired characteristics is only one of the many examples of the explanatory power of epigenetics. Behavioral epigenetics demonstrates the way in which environmental and social experiences produce individual differences in behaviour, cognition, personality, and mental health. This book assembles experts to outline the various motifs of all kinds of epigenetic regulation of cells throughout their lives. (shrink)

The most enigmatic feature of polytene chromosomes is their banding pattern, the genetic organization of which has been a very attractive puzzle for many years. Recent genome‐wide protein mapping efforts have produced a wealth of data for the chromosome proteins of Drosophila cells. Based on their specific protein composition, the chromosomes comprise two types of bands, as well as interbands. These differ in terms of time of replication and specific types of proteins. The interbands are characterized by their association with (...) “active” chromatin proteins, nucleosome remodeling, and origin recognition complexes, and so they have three functions: acting as binding sites for RNA pol II, initiation of replication and nucleosome remodeling of short fragments of DNA. The borders and organization of the same band and interband regions are largely identical, irrespective of the cell type studied. This demonstrates that the banding pattern is a universal principle of the organization of interphase polytene and non‐polytene chromosomes.Editor's suggested further reading in BioEssaysCaught in the act: Rapid, symbiont‐driven evolution AbstractFunction and evolution of sex determination mechanisms, genes and pathways in insects Abstract. (shrink)

The molecular mechanism of temperature‐dependent sex determination (TSD) is a long‐standing mystery. How is the thermal signal sensed, captured and transduced to regulate key sex genes? Although there is compelling evidence for pathways via which cells capture the temperature signal, there is no known mechanism by which cells transduce those thermal signals to affect gene expression. Here we propose a novel hypothesis we call 3D‐TSD (the three dimensions of thermolabile sex determination). We postulate that the genome has capacity to remodel (...) in response to temperature by changing 3D chromatin conformation, perhaps via temperature‐sensitive transcriptional condensates. This could rewire enhancer–promoter interactions to alter the expression of key sex‐determining genes. This hypothesis can accommodate monogenic or multigenic thermolabile sex‐determining systems, and could be combined with upstream thermal sensing and transduction to the epigenome to commit gonadal fate. (shrink)

The chromodomain is a highly conserved sequence motif that has been identified in a variety of animal and plant species. In mammals, chromodomain proteins appear to be either structural components of large macromolecular chromatin complexes or proteins involved in remodelling chromatin structure. Recent work has suggested that apart from a role in regulating gene activity, chromodomain proteins may also play roles in genome organisation. This article reviews progress made in characterising mammalian chromodomain proteins and emphasises their emerging role (...) in the regulation of gene expression and genome organisation. BioEssays 22:124–137, 2000. ©2000 John Wiley & Sons, Inc. (shrink)

Proteins with seven conserved “helicase domains” play essential roles in all aspects of nucleic acid metabolism. Deriving energy from ATP hydrolysis, helicases alter the structure of DNA, RNA, or DNA:RNA duplexes, remodeling chromatin and modulating access to the DNA template by the transcriptional machinery. This review focuses on the diverse functions of these proteins in the process of RNA polymerase II transcription in eukaryotes. Known or putative helicases are required for general transcription initiation and for transcription-coupled DNA repair, and (...) may play important roles in elongation, termination, and transcript stability. Recent evidence suggests that helicase-domain-containing proteins are also involved in complexes that facilitate the activity of groups of seemingly unrelated genes. BioEssays 20:634–641, 1998. © 1998 John Wiley & Sons Inc. (shrink)

In this essay, I propose that DNA‐binding anti‐cancer drugs work more via chromatin disruption than DNA damage. Success of long‐awaited drugs targeting cancer‐specific drivers is limited by the heterogeneity of tumors. Therefore, chemotherapy acting via universal targets (e.g., DNA) is still the mainstream treatment for cancer. Nevertheless, the problem with targeting DNA is insufficient efficacy due to high toxicity. I propose that this problem stems from the presumption that DNA damage is critical for the anti‐cancer activity of these drugs. (...) DNA in cells exists as chromatin, and many DNA‐targeting drugs alter chromatin structure by destabilizing nucleosomes and inducing histone eviction from chromatin. This effect has been largely ignored because DNA damage is seen as the major reason for anti‐cancer activity. I discuss how DNA‐binding molecules destabilize chromatin, why this effect is more toxic to tumoral than normal cells, and why cells die as a result of chromatin destabilization. (shrink)

The organization of the genome into topologically associated domains (TADs) appears to be a fundamental process occurring across a wide range of eukaryote organisms, and it likely plays an important role in providing an architectural foundation for gene regulation. Initial studies emphasized the remarkable parallels between TAD organization in organisms as diverse as Drosophila and mammals. However, whereas CCCTC‐binding factor (CTCF)/cohesin loop extrusion is emerging as a key mechanism for the formation of mammalian topological domains, the genome organization in Drosophila (...) appears to depend primarily on the partitioning of chromatin state domains. Recent work suggesting a fundamental conserved role of chromatin state in building domain architecture is discussed and insights into genome organization from recent studies in Drosophila are considered. (shrink)

Eukaryotic genomes are packaged into a nucleoprotein complex known as chromatin. The term was introduced in 1879 by German cytologist Walther Flemming. While observing the processes of mitosis in a light microscope, Flemming coined the term to describe the easily stainable threads in the nucleus. He predicted that it would not have a long life: “The word chromatin may serve until its chemical nature is known, and meanwhile stands for that substance in the cell nucleus which is readily (...) stained”. However, Flemming’s prediction did not come true. Although the chemical nature of chromatin—a complex of nucleic acid and proteins—was already elucidated at the end of the 19th century, the.. (shrink)

Chromatin composition differs across the genome, with distinct compositions characterizing regions associated with different properties and functions. Whereas many histone modifications show local enrichment over genes or regulatory elements, marking can also span large genomic intervals defining broad chromatin domains. Here we highlight structural and functional features of chromatin domains marked by histone modifications, with a particular emphasis on the potential roles of H3K27 methylation domains in the organization and regulation of genome activity in metazoans. Chromatin (...) domains are extended genomic regions defined by the continuous enrichment of a given histone modification. Here, we review recent work highlighting the presence of chromatin domains in multiple species, their structural aspects in the context of chromatin architecture, and their potential role on the regulation of genome activity. (shrink)

Eukaryotic genome DNA is wrapped around core histones and forms a nucleosome structure. Together with associated proteins and RNAs, these nucleosomes are organized three‐dimensionally in the cell as chromatin. Emerging evidence demonstrates that chromatin consists of rather irregular and variable nucleosome arrangements without the regular fiber structure and that its dynamic behavior plays a critical role in regulating various genome functions. Single‐nucleosome imaging is a promising method to investigate chromatin behavior in living cells. It reveals local (...) class='Hi'>chromatin motion, which reflects chromatin organization not observed in chemically fixed cells. The motion data is like a gold mine. Data analyses from many aspects bring us more and more information that contributes to better understanding of genome functions. In this review article, we describe imaging of single‐nucleosomes and their tracked behavior through oblique illumination microscopy. We also discuss applications of this technique, especially in elucidating nucleolar organization in living cells. (shrink)

Remodel[l]ing Reality is an inquiry into Wittgenstein's notion of übersichtliche Darstellung and the phenomenon of installation in visual art. In a sense, both provide a perspicuous overview of a particular part of our complex world, but the nature of the overview differs. Although both generate knowledge, philosophy via the übersichtliche Darstellung gives us a view of how things stand for us, while the installation shows an unexpected, exiting point of view. The obvious we tend to forget and the ambiguity of (...) reality are related to each other in a dynamic way. It is in this reflexive dynamics that we constantly remodel our reality. Tools we use are our creative abilities and our powers of imagination. In our choices and solutions we show which aspects of reality we find important and how we communicate these values. The outcome of this investigation is a new perspective on the art of installation and a new insight in Wittgenstein's notion of übersichtliche Darstellung. Because of this combination, the book is itself an artwork: an InstallationPackage. The book is distributed by Ideabooks Amsterdam, Isbn 978 90 804240 3 6. Remodel[l]ing Reality is included in Special Collections, Allard Pierson Museum Amsterdam. (shrink)

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

The process of chromatin diminution in Parascaris and Ascaris is a developmentally controlled genome rearrangement, which results in quantitative and qualitative differences in DNA content between germ line and somatic cells. Chromatin diminution involves chromosomal breakage, new telomere formation and DNA degradation. The programmed elimination of chromatin in presomatic cells might serve as an alternative way of gene regulation. We put forward a new hypothesis of how an ancient partial genome duplication and chromatin diminution may have (...) served to maintain the genetic balance in somatic cells and simultaneously endowed the germ line cells with a selective advantage. (shrink)

Eukaryotic genomes are packaged into nucleosomal chromatin, and genomic activity requires the precise localization of transcription factors, histone modifications and nucleosomes. Classic work described the progressive reassembly and maturation of bulk chromatin behind replication forks. More recent proteomics has detailed the molecular machines that accompany the replicative polymerase to promote rapid histone deposition onto the newly replicated DNA. However, localized chromatin features are transiently obliterated by DNA replication every S phase of the cell cycle. Genomic strategies now (...) observe the rebuilding of locus‐specific chromatin features, and reveal surprising delays in transcription factor binding behind replication forks. This implies that transient chromatin disorganization during replication is a central juncture for targeted transcription factor binding within genomes. We propose that transient occlusion of regulatory elements by disorganized nucleosomes during chromatin maturation enforces specificity of factor binding. (shrink)

Just as the faithful replication of DNA is an essential process for the cell, chromatin structures of active and inactive genes have to be copied accurately. Under certain circumstances, however, the activity pattern has to be changed in specific ways. Although analysis of specific aspects of these complex processes, by means of model systems, has led to their further elucidation, the mechanisms of chromatin replication in vivo are still controversial and far from being understood completely. Progress has been (...) achieved in understanding: 1. The initiation of chromatin replication, indicating that a nucleosome‐free origin is necessary for the initiation of replication; 2. The segregation of the parental nucleosomes, where convincing data support the model of random distribution of the parental nucleosomes to the daughter strands; and 3. The assembly of histones on the newly synthesized strands, where growing evidence is emerging for a two‐step mechanism of nucleosome assembly, starting with the deposition of H3/H4 tetramers onto the DNA, followed by H2A/H2B dimers. (shrink)