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FEBS Letters Oct 2015Recent analysis of genome-wide epigenetic modification data, mean replication timing (MRT) profiles and chromosome conformation data in mammals have provided increasing... (Review)
Review
Recent analysis of genome-wide epigenetic modification data, mean replication timing (MRT) profiles and chromosome conformation data in mammals have provided increasing evidence that flexibility in replication origin usage is regulated locally by the epigenetic landscape and over larger genomic distances by the 3D chromatin architecture. Here, we review the recent results establishing some link between replication domains and chromatin structural domains in pluripotent and various differentiated cell types in human. We reconcile the originally proposed dichotomic picture of early and late constant timing regions that replicate by multiple rather synchronous origins in separated nuclear compartments of open and closed chromatins, with the U-shaped MRT domains bordered by "master" replication origins specified by a localized (∼200-300 kb) zone of open and transcriptionally active chromatin from which a replication wave likely initiates and propagates toward the domain center via a cascade of origin firing. We discuss the relationships between these MRT domains, topologically associated domains and lamina-associated domains. This review sheds a new light on the epigenetically regulated global chromatin reorganization that underlies the loss of pluripotency and the determination of differentiation properties.
Topics: Animals; Cell Nucleus; Chromatin; Chromatin Assembly and Disassembly; DNA Replication; Epigenesis, Genetic; Humans; Nucleic Acid Conformation; Regulatory Sequences, Nucleic Acid
PubMed: 25912651
DOI: 10.1016/j.febslet.2015.04.015 -
The FEBS Journal Sep 2018How did the nucleosome, the fundamental building block of all eukaryotic chromatin, evolve? This central question has been impossible to address because the four core... (Review)
Review
How did the nucleosome, the fundamental building block of all eukaryotic chromatin, evolve? This central question has been impossible to address because the four core histones that make up the protein core of the nucleosome are so highly conserved in all eukaryotes. With the discovery of small, minimalist histone-like proteins in most known archaea, the likely origin of histones was identified. We recently determined the structure of an archaeal histone-DNA complex, revealing that archaeal DNA topology and protein-DNA interactions are astonishingly similar compared to the eukaryotic nucleosome. This was surprising since most archaeal histones form homodimers which consist only of the minimal histone fold and are devoid of histone tails and extensions. Unlike eukaryotic H2A-H2B and H3-H4 heterodimers that assemble into octameric particles wrapping ~ 150 bp DNA, archaeal histones form polymers around which DNA coils in a quasi-continuous superhelix. At any given point, this superhelix has the same geometry as nucleosomal DNA. This suggests that the architectural role of histones (i.e. the ability to bend DNA into a nucleosomal superhelix) was established before archaea and eukaryotes diverged, while the ability to form discrete particles, together with signaling functions of eukaryotic chromatin (i.e. epigenetic modifications) were secondary additions.
Topics: Archaea; Chromatin; DNA, Archaeal; Histones; Nucleosomes
PubMed: 29729078
DOI: 10.1111/febs.14495 -
FEMS Microbiology Reviews Jul 1999A central problem in eukaryotic transcription is how proteins gain access to DNA packaged in nucleosomes. Research on the interplay between chromatin and transcription... (Review)
Review
A central problem in eukaryotic transcription is how proteins gain access to DNA packaged in nucleosomes. Research on the interplay between chromatin and transcription has progressed with the use of yeast genetics as a useful tool to characterize factors involved in this process. These factors have both positive and negative effects on the stability of nucleosomes, thereby controlling the role of chromatin in transcription in vivo. The negative effectors include the structural components of chromatin, the histones and non-histone chromatin associated proteins, as well as regulatory components like chromatin assembly factors and histone deacetylase complexes. The positive factors are involved in remodeling chromatin and several multiprotein complexes have been described: Swi/Snf, Srb/mediator and SAGA. The components of each of these complexes, as well as the functional relationships between them are covered by this review.
Topics: Chromatin; Gene Expression Regulation, Fungal; Histones; Saccharomyces cerevisiae; Transcription, Genetic
PubMed: 10422263
DOI: 10.1111/j.1574-6976.1999.tb00410.x -
Nucleus (Austin, Tex.) Mar 2017Mitosis in metazoans is characterized by abundant phosphorylation of histone H3 and involves the recruitment of condensin complexes to chromatin. The relationship... (Review)
Review
Mitosis in metazoans is characterized by abundant phosphorylation of histone H3 and involves the recruitment of condensin complexes to chromatin. The relationship between the 2 phenomena and their respective contributions to chromosome condensation in vivo remain poorly understood. Recent studies have shown that H3T3 phosphorylation decreases binding of histone readers to methylated H3K4 in vitro and is essential to displace the corresponding proteins from mitotic chromatin in vivo. Together with previous observations, these data provide further evidence for a role of mitotic histone H3 phosphorylation in blocking transcriptional programs or preserving the 'memory' PTMs. Mitotic protein exclusion can also have a role in depopulating the chromatin template for subsequent condensin loading. H3 phosphorylation thus serves as an integral step in the condensation of chromosome arms.
Topics: Chromatin; Chromosome Segregation; Epigenesis, Genetic; Humans; Mitosis
PubMed: 28045584
DOI: 10.1080/19491034.2016.1276144 -
Biomedicine & Pharmacotherapy =... Jun 2021In the physical sciences, solid, liquid, and gas are the most familiar phase states, whose essence is their existence reflecting the different spatial distribution of... (Review)
Review
In the physical sciences, solid, liquid, and gas are the most familiar phase states, whose essence is their existence reflecting the different spatial distribution of molecular components. The biological molecules in the living cell also have differences in spatial distribution. The molecules organized in the form of membrane-bound organelles are well recognized. However, the biomolecules organized in membraneless compartments called biomolecular condensates remain elusive. The liquid-liquid phase separation (LLPS), as a new emerging scientific breakthrough, describes the biomolecules assembled in special distribution and appeared as membraneless condensates in the form of a new "phase" compared with the surrounding liquid milieu. LLPS provides an important theoretical basis for explaining the composition of biological molecules and related biological reactions. Mounting evidence has emerged recently that phase-separated condensates participate in various biological activities. This article reviews the occurrence of LLPS and underlying regulatory mechanisms for understanding how multivalent molecules drive phase transitions to form the biomolecular condensates. And, it also summarizes recent major progress in elucidating the roles of LLPS in chromatin organization and provides clues for the development of new innovative therapeutic strategies for related diseases.
Topics: Animals; Biophysical Phenomena; Chromatin; Humans; Liquid-Liquid Extraction; Organelles; Phase Transition
PubMed: 33765580
DOI: 10.1016/j.biopha.2021.111520 -
Blood Apr 2013Complex developmental processes such as hematopoiesis require a series of precise and coordinated changes in cellular identity to ensure blood homeostasis. Epigenetic... (Review)
Review
Complex developmental processes such as hematopoiesis require a series of precise and coordinated changes in cellular identity to ensure blood homeostasis. Epigenetic mechanisms help drive changes in gene expression that accompany the transition from hematopoietic stem cells to terminally differentiated blood cells. Genome-wide profiling technologies now provide valuable glimpses of epigenetic changes that occur during normal hematopoiesis, and genetic mouse models developed to investigate the in vivo functions of chromatin-modifying enzymes clearly demonstrate significant roles for these enzymes during embryonic and adult hematopoiesis. Here, we will review the basic science aspects of chromatin modifications and the enzymes that add, remove, and interpret these epigenetic marks. This overview will provide a framework for understanding the roles that these molecules play during normal hematopoiesis. Moreover, many chromatin-modifying enzymes are involved in hematologic malignancies, underscoring the importance of establishing and maintaining appropriate chromatin modification patterns to normal hematology.
Topics: Amino Acid Sequence; Animals; Chromatin; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Hematologic Neoplasms; Hematopoiesis; Humans; Molecular Sequence Data
PubMed: 23287864
DOI: 10.1182/blood-2012-10-451237 -
Genome Apr 2021In recent years, our perception of chromatin structure and organization in the cell nucleus has changed in fundamental ways. The 30 nm chromatin fiber has lost its... (Review)
Review
In recent years, our perception of chromatin structure and organization in the cell nucleus has changed in fundamental ways. The 30 nm chromatin fiber has lost its status as an essential in vivo structure. Hi-C and related biochemical methods, advanced electron and super-resolved fluorescence microscopy, together with concepts from soft matter physics, have revolutionized the field. A comprehensive understanding of the structural and functional interactions that regulate cell cycle and cell type specific nuclear functions appears within reach, but it requires the integration of top-down and bottom-up approachs. In this review, I present an update on nuclear architecture studies with an emphasis on organization and the controversy regarding the physical state of chromatin in cells.
Topics: Cell Cycle; Cell Nucleus; Chromatin; Chromosomes; Eukaryotic Cells; Humans
PubMed: 33306433
DOI: 10.1139/gen-2020-0132 -
Viruses Apr 2023Epstein-Barr Virus (EBV) is a human gamma-herpesvirus that is widespread worldwide. To this day, about 200,000 cancer cases per year are attributed to EBV infection. EBV... (Review)
Review
Epstein-Barr Virus (EBV) is a human gamma-herpesvirus that is widespread worldwide. To this day, about 200,000 cancer cases per year are attributed to EBV infection. EBV is capable of infecting both B cells and epithelial cells. Upon entry, viral DNA reaches the nucleus and undergoes a process of circularization and chromatinization and establishes a latent lifelong infection in host cells. There are different types of latency all characterized by different expressions of latent viral genes correlated with a different three-dimensional architecture of the viral genome. There are multiple factors involved in the regulation and maintenance of this three-dimensional organization, such as CTCF, PARP1, MYC and Nuclear Lamina, emphasizing its central role in latency maintenance.
Topics: Humans; Herpesvirus 4, Human; Epstein-Barr Virus Infections; Virus Latency; Gene Expression Regulation, Viral; Genome, Viral; Chromatin
PubMed: 37243174
DOI: 10.3390/v15051088 -
Molecular Metabolism Aug 2018To maintain homeostasis, cells need to coordinate the expression of their genes. Epigenetic mechanisms controlling transcription activation and repression include DNA... (Review)
Review
BACKGROUND
To maintain homeostasis, cells need to coordinate the expression of their genes. Epigenetic mechanisms controlling transcription activation and repression include DNA methylation and post-translational modifications of histones, which can affect the architecture of chromatin and/or create 'docking platforms' for multiple binding proteins. These modifications can be dynamically set and removed by various enzymes that depend on the availability of key metabolites derived from different intracellular pathways. Therefore, small metabolites generated in anabolic and catabolic processes can integrate multiple external and internal stimuli and transfer information on the energetic state of a cell to the transcriptional machinery by regulating the activity of chromatin-modifying enzymes.
SCOPE OF REVIEW
This review provides an overview of the current literature and concepts on the connections and crosstalk between key cellular metabolites, enzymes responsible for their synthesis, recycling, and conversion and chromatin marks controlling gene expression.
MAJOR CONCLUSIONS
Whereas current evidence indicates that many chromatin-modifying enzymes respond to alterations in the levels of their cofactors, cosubstrates, and inhibitors, the detailed molecular mechanisms and functional consequences of such processes are largely unresolved. A deeper investigation of mechanisms responsible for altering the total cellular concentration of particular metabolites, as well as their nuclear abundance and accessibility for chromatin-modifying enzymes, will be necessary to better understand the crosstalk between metabolism, chromatin marks, and gene expression.
Topics: Animals; Chromatin; Epigenesis, Genetic; Histone Code; Humans; Second Messenger Systems
PubMed: 29397344
DOI: 10.1016/j.molmet.2018.01.007 -
Biophysical Journal May 2018The mechanism by which the "beads-on-a-string" nucleosome chain folds into various higher-order chromatin structures in eukaryotic cell nuclei is still poorly... (Review)
Review
The mechanism by which the "beads-on-a-string" nucleosome chain folds into various higher-order chromatin structures in eukaryotic cell nuclei is still poorly understood. The various models depicting higher-order chromatin as regular helical fibers and the very opposite "polymer melt" theory imply that interactions between nucleosome "beads" make the main contribution to the chromatin compaction. Other models in which the geometry of linker DNA "strings" entering and exiting the nucleosome define the three-dimensional structure predict that small changes in the linker DNA configuration may strongly affect nucleosome chain folding and chromatin higher-order structure. Among those studies, the cross-disciplinary approach pioneered by Jörg Langowski that combines computational modeling with biophysical and biochemical experiments was most instrumental for understanding chromatin higher-order structure in vitro. Strikingly, many recent studies, including genome-wide nucleosome interaction mapping and chromatin imaging, show an excellent agreement with the results of three-dimensional computational modeling based on the primary role of linker DNA geometry in chromatin compaction. This perspective relates nucleosome array models with experimental studies of nucleosome array folding in vitro and in situ. I argue that linker DNA configuration plays a key role in determining nucleosome chain flexibility, topology, and propensity for self-association, thus providing new implications for regulation of chromatin accessibility to DNA binding factors and RNA transcription machinery as well as long-range communications between distant genomic sites.
Topics: Animals; Chromatin; DNA; Humans; Nucleic Acid Conformation; Nucleosomes
PubMed: 29628212
DOI: 10.1016/j.bpj.2018.03.009