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Nature Jul 2017Chromosomes in proliferating metazoan cells undergo marked structural metamorphoses every cell cycle, alternating between highly condensed mitotic structures that...
Chromosomes in proliferating metazoan cells undergo marked structural metamorphoses every cell cycle, alternating between highly condensed mitotic structures that facilitate chromosome segregation, and decondensed interphase structures that accommodate transcription, gene silencing and DNA replication. Here we use single-cell Hi-C (high-resolution chromosome conformation capture) analysis to study chromosome conformations in thousands of individual cells, and discover a continuum of cis-interaction profiles that finely position individual cells along the cell cycle. We show that chromosomal compartments, topological-associated domains (TADs), contact insulation and long-range loops, all defined by bulk Hi-C maps, are governed by distinct cell-cycle dynamics. In particular, DNA replication correlates with a build-up of compartments and a reduction in TAD insulation, while loops are generally stable from G1 to S and G2 phase. Whole-genome three-dimensional structural models reveal a radial architecture of chromosomal compartments with distinct epigenomic signatures. Our single-cell data therefore allow re-interpretation of chromosome conformation maps through the prism of the cell cycle.
Topics: Animals; Cell Compartmentation; Cell Cycle; Chromosomes, Mammalian; Epigenesis, Genetic; Haploidy; Imaging, Three-Dimensional; Mice; Mouse Embryonic Stem Cells; Reproducibility of Results; Single-Cell Analysis
PubMed: 28682332
DOI: 10.1038/nature23001 -
Cell Dec 2015Spatial genome organization and its effect on transcription remains a fundamental question. We applied an advanced chromatin interaction analysis by paired-end tag...
Spatial genome organization and its effect on transcription remains a fundamental question. We applied an advanced chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) strategy to comprehensively map higher-order chromosome folding and specific chromatin interactions mediated by CCCTC-binding factor (CTCF) and RNA polymerase II (RNAPII) with haplotype specificity and nucleotide resolution in different human cell lineages. We find that CTCF/cohesin-mediated interaction anchors serve as structural foci for spatial organization of constitutive genes concordant with CTCF-motif orientation, whereas RNAPII interacts within these structures by selectively drawing cell-type-specific genes toward CTCF foci for coordinated transcription. Furthermore, we show that haplotype variants and allelic interactions have differential effects on chromosome configuration, influencing gene expression, and may provide mechanistic insights into functions associated with disease susceptibility. 3D genome simulation suggests a model of chromatin folding around chromosomal axes, where CTCF is involved in defining the interface between condensed and open compartments for structural regulation. Our 3D genome strategy thus provides unique insights in the topological mechanism of human variations and diseases.
Topics: Animals; CCCTC-Binding Factor; Cell Cycle Proteins; Cell Line; Chromatin; Chromosomal Proteins, Non-Histone; Chromosomes; DNA Packaging; Genome, Human; Humans; RNA Polymerase II; Repressor Proteins; Salamandridae; Transcription, Genetic; Cohesins
PubMed: 26686651
DOI: 10.1016/j.cell.2015.11.024 -
Current Opinion in Structural Biology Dec 2022Eukaryotic DNA is packaged into nucleosomes, which further condenses into chromosomes. The telomeres, which form the protective end-capping of chromosomes, play a... (Review)
Review
Eukaryotic DNA is packaged into nucleosomes, which further condenses into chromosomes. The telomeres, which form the protective end-capping of chromosomes, play a pivotal role in ageing and cancer. Recently, significant advances have been made in understanding the nucleosomal and telomeric chromatin structure at the molecular level. In addition, recent studies shed light on the nucleosomal organisation at telomeres revealing its ultrastructural organisation, the atomic structure at the nucleosome level, its dynamic properties, and higher-order packaging of telomeric chromatin. Considerable advances have furthermore been made in understanding the structure, function and organisation of shelterin, telomerase and CST complexes. Here we discuss these recent advances in the organisation of telomeric nucleosomes and chromatin and highlight progress in the structural understanding of shelterin, telomerase and CST complexes.
Topics: Telomere; Nucleosomes; Chromatin; Telomerase; DNA
PubMed: 36335846
DOI: 10.1016/j.sbi.2022.102492 -
Current Opinion in Cell Biology Jun 2016During eukaryotic cell division, nuclear chromatin undergoes marked changes with respect to shape and degree of compaction. Although already significantly compacted... (Review)
Review
During eukaryotic cell division, nuclear chromatin undergoes marked changes with respect to shape and degree of compaction. Although already significantly compacted during interphase, upon entry into mitosis chromatin further condenses and individualizes to discrete chromosomes that are captured and moved independently by the mitotic spindle apparatus. Once segregated by the spindle, chromatin decondenses to re-establish its interphase structure competent for DNA replication and transcription. Although cytologically described a long time ago, the underlying molecular mechanisms of mitotic chromatin condensation and decondensation are still ill-defined. Here we summarize our current knowledge of mitotic chromatin restructuring and recent progress in the field.
Topics: Animals; Chromatin; Chromosomes; DNA Replication; Eukaryotic Cells; Interphase; Mitosis; Spindle Apparatus
PubMed: 26895139
DOI: 10.1016/j.ceb.2016.01.013 -
Nucleus (Austin, Tex.) Dec 2024Heterochromatin is an organizational property of eukaryotic chromosomes, characterized by extensive DNA and histone modifications, that is associated with the silencing... (Review)
Review
Heterochromatin is an organizational property of eukaryotic chromosomes, characterized by extensive DNA and histone modifications, that is associated with the silencing of transposable elements and repetitive sequences. Maintaining heterochromatin is crucial for ensuring genomic integrity and stability during the cell cycle. During meiosis, heterochromatin is important for homologous chromosome synapsis, recombination, and segregation, but our understanding of meiotic heterochromatin formation and condensation is limited. In this review, we focus on the dynamics and features of heterochromatin and how it condenses during meiosis in plants. We also discuss how meiotic heterochromatin influences the interaction and recombination of homologous chromosomes during prophase I.
Topics: Heterochromatin; Centromere; Meiosis; Chromosome Pairing
PubMed: 38488152
DOI: 10.1080/19491034.2024.2328719 -
Annual Review of Genomics and Human... Aug 2022Virtually all cell types have the same DNA, yet each type exhibits its own cell-specific pattern of gene expression. During the brief period of mitosis, the chromosomes... (Review)
Review
Virtually all cell types have the same DNA, yet each type exhibits its own cell-specific pattern of gene expression. During the brief period of mitosis, the chromosomes exhibit changes in protein composition and modifications, a marked condensation, and a consequent reduction in transcription. Yet as cells exit mitosis, they reactivate their cell-specific programs with high fidelity. Initially, the field focused on the subset of transcription factors that are selectively retained in, and hence bookmark, chromatin in mitosis. However, recent studies show that many transcription factors can be retained in mitotic chromatin and that, surprisingly, such retention can be due to nonspecific chromatin binding. Here, we review the latest studies focusing on low-level transcription via promoters, rather than enhancers, as contributing to mitotic memory, as well as new insights into chromosome structure dynamics, histone modifications, cell cycle signaling, and nuclear envelope proteins that together ensure the fidelity of gene expression through a round of mitosis.
Topics: Chromatin; Chromosomes; Histone Code; Humans; Mitosis; Transcription Factors
PubMed: 35440147
DOI: 10.1146/annurev-genom-121321-094603 -
FEMS Microbiology Reviews Nov 2020Chromosomes are dynamic entities, whose organization and structure depend on the concerted activity of DNA-binding proteins and DNA-processing enzymes. In bacteria,... (Review)
Review
Chromosomes are dynamic entities, whose organization and structure depend on the concerted activity of DNA-binding proteins and DNA-processing enzymes. In bacteria, chromosome replication, segregation, compaction and transcription are all occurring simultaneously, and to ensure that these processes are appropriately coordinated, all bacteria employ a mix of well-conserved and species-specific proteins. Unusually, Streptomyces bacteria have large, linear chromosomes and life cycle stages that include multigenomic filamentous hyphae and unigenomic spores. Moreover, their prolific secondary metabolism yields a wealth of bioactive natural products. These different life cycle stages are associated with profound changes in nucleoid structure and chromosome compaction, and require distinct repertoires of architectural-and regulatory-proteins. To date, chromosome organization is best understood during Streptomyces sporulation, when chromosome segregation and condensation are most evident, and these processes are coordinated with synchronous rounds of cell division. Advances are, however, now being made in understanding how chromosome organization is achieved in multigenomic hyphal compartments, in defining the functional and regulatory interplay between different architectural elements, and in appreciating the transcriptional control exerted by these 'structural' proteins.
Topics: Bacterial Proteins; Chromosomes, Bacterial; Streptomyces
PubMed: 32658291
DOI: 10.1093/femsre/fuaa028 -
Current Biology : CB Dec 2012The processes underlying the large-scale reorganisation of chromatin in mitosis that form compact mitotic chromosomes and ensure the fidelity of chromosome segregation... (Review)
Review
The processes underlying the large-scale reorganisation of chromatin in mitosis that form compact mitotic chromosomes and ensure the fidelity of chromosome segregation during cell division still remain obscure. The chromosomal condensin complex is a major molecular effector of chromosome condensation and segregation in diverse organisms ranging from bacteria to humans. Condensin is a large, evolutionarily conserved, multisubunit protein assembly composed of dimers of the structural maintenance of chromosomes (SMC) family of ATPases, clasped into topologically closed rings by accessory subunits. Condensin binds to DNA dynamically, in a poorly understood cycle of ATP-modulated conformational changes, and exhibits the ability to positively supercoil DNA. During mitosis, condensin is phosphorylated by the cyclin-dependent kinase (CDK), Polo and Aurora B kinases in a manner that correlates with changes in its localisation, dynamics and supercoiling activity. Here we review the reported architecture, biochemical activities and regulators of condensin. We compare models of bacterial and eukaryotic condensins in order to uncover conserved mechanistic principles of condensin action and to propose a model for mitotic chromosome condensation.
Topics: Adenosine Triphosphatases; Animals; Cell Cycle; Chromatin; Chromosomes; DNA-Binding Proteins; Humans; Models, Biological; Molecular Structure; Multiprotein Complexes
PubMed: 23218009
DOI: 10.1016/j.cub.2012.10.023 -
The Journal of Cell Biology Jul 2018Condensins are key players in mitotic chromosome condensation. Using an elegant combination of state-of-the-art imaging techniques, Walther et al. (2018....
Condensins are key players in mitotic chromosome condensation. Using an elegant combination of state-of-the-art imaging techniques, Walther et al. (2018. https://doi.org/10.1083/jcb.201801048) counted the number of Condensins, examined their behaviors on human mitotic chromosomes, and integrated the quantitative data to propose a new mechanistic model for chromosome condensation.
Topics: Adenosine Triphosphatases; Cell Cycle Proteins; Chromosome Segregation; Chromosomes; DNA-Binding Proteins; Humans; Mitosis; Multiprotein Complexes
PubMed: 29712733
DOI: 10.1083/jcb.201804078 -
Cold Spring Harbor Protocols Feb 2019Chromosome structure in both interphase and M-phase cells is strongly influenced by the action of the cohesin and condensin protein complexes. The cohesin complex...
Chromosome structure in both interphase and M-phase cells is strongly influenced by the action of the cohesin and condensin protein complexes. The cohesin complex tethers the identical copies of each chromosome, called sister chromatids, together following DNA replication and promotes normal interphase chromosome structure and gene expression. In contrast, condensin is active largely in M phase and promotes the compaction of individual chromosomes. The egg extract system is uniquely suited to analyze the functions of both complexes. Egg extracts, in which the cell cycle state can be manipulated, contain stockpiles of nuclear proteins (including condensin and cohesin) sufficient for the assembly of thousands of nuclei per microliter. Extract prepared from unfertilized eggs is arrested by the presence of cytostatic factor (CSF) in a state with high levels of M-phase kinase activity, but can be stimulated to enter interphase, in which DNA replication occurs spontaneously. For cohesion assays, demembranated sperm nuclei are incubated in interphase extract, where they undergo rapid and synchronous DNA replication and cohesion establishment through the recruitment of proteins and other factors (e.g., nucleotides) from the extract. Sister chromatid cohesion is assessed by then driving the extract into M phase by the addition of fresh CSF-arrested extract. In contrast, because chromosome condensation occurs spontaneously in M-phase extracts, sperm nuclei are added directly to CSF extracts to assay condensation.
Topics: Adenosine Triphosphatases; Animals; Cell Cycle Proteins; Cell Division; Chromosomal Proteins, Non-Histone; Chromosomes; Complex Mixtures; DNA-Binding Proteins; Multiprotein Complexes; Xenopus; Zygote; Cohesins
PubMed: 29475994
DOI: 10.1101/pdb.prot097121