Rules of engagement for cohesin and condensin complexes during mitotic chromosome formation
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ABSTRACT:
SUBMITTER: William C Earnshaw
PROVIDER: EMPIAR-11919 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:Chromosome folding is modulated as cells progress through the cell cycle. During mitosis, condensins fold chromosomes into helical loop arrays. In interphase, the cohesin complex generates loops and topologically associating domains (TADs), while a separate process of compartmentalization drives segregation of active and inactive chromatin. We used synchronized cell cultures to determine how the mitotic chromosome conformation transforms into the interphase state. Using high-throughput chromosome conformation capture (Hi-C) analysis, chromatin binding assays and immunofluorescence, we show that, by telophase, condensin-mediated loops are lost and a transient folding intermediate is formed that is devoid of most loops. By cytokinesis, cohesin-mediated CTCF-CTCF loops and the positions of TADs emerge. Compartment boundaries are also established early, but long-range compartmentalization is a slow process and proceeds for hours after cells enter G1. Our results reveal the kinetics and order of events by which the interphase chromosome state is formed and identify telophase as a critical transition between condensin- and cohesin-driven chromosome folding.
| S-EPMC6858582 | biostudies-literature
Project description:In mitosis, the pericentromere is organized into a spring composed of cohesin, condensin, and a rosette of intramolecular chromatin loops. Cohesin and condensin are enriched in the pericentromere, with spatially distinct patterns of localization. Using model convolution of computer simulations, we deduce the mechanistic consequences of their spatial segregation. Condensin lies proximal to the spindle axis, whereas cohesin is radially displaced from condensin and the interpolar microtubules. The histone deacetylase Sir2 is responsible for the axial position of condensin, while the radial displacement of chromatin loops dictates the position of cohesin. The heterogeneity in distribution of condensin is most accurately modeled by clusters along the spindle axis. In contrast, cohesin is evenly distributed (barrel of 500-nm width × 550-nm length). Models of cohesin gradients that decay from the centromere or sister cohesin axis, as previously suggested, do not match experimental images. The fine structures of cohesin and condensin deduced with subpixel localization accuracy reveal critical features of how these complexes mold pericentric chromatin into a functional spring.
| S-EPMC3861086 | biostudies-literature
Project description:Cohesion between sister chromatids in mitotic and meiotic cells is promoted by a ring-shaped protein structure, the cohesin complex. The cohesin core complex is composed of four subunits, including two structural maintenance of chromosome (SMC) proteins, one ?-kleisin protein, and one SA protein. Meiotic cells express both mitotic and meiosis-specific cohesin core subunits, generating cohesin complexes with different subunit composition and possibly separate meiotic functions. Here, we have analyzed the in vivo function of STAG3, a vertebrate meiosis-specific SA protein. Mice with a hypomorphic allele of Stag3, which display a severely reduced level of STAG3, are viable but infertile. We show that meiocytes in homozygous mutant Stag3 mice display chromosome axis compaction, aberrant synapsis, impaired recombination and developmental arrest. We find that the three different ?-kleisins present in meiotic cells show different dosage-dependent requirements for STAG3 and that STAG3-REC8 cohesin complexes have a critical role in supporting meiotic chromosome structure and functions.
| S-EPMC4198027 | biostudies-literature
Project description:The chromokinesin KIF4A has been implicated in shaping mitotic chromosomes, but its functional relationship to condensin complexes remains controversial. Here, we found that, in mitosis, KIF4A associates with condensin I but not with condensin II. Mutational analyses indicated that the enrichment of condensin I to chromosomal axes depends on its association with KIF4A in a way that likely involves its motor activity. Remarkably, this interaction is required for condensin I to confer physiological properties to chromosomes. These observations provide an insight into how condensin I is enriched at chromosomal axes and underscore the significance of axial structure in organizing mitotic chromosomes.
| S-EPMC5066236 | biostudies-literature
Project description:Research on the formation of mitotic chromosomes from interphase chromatin domains, ongoing for several decades, made significant progress in recent years. It was stimulated by the development of advanced microscopic techniques and implementation of chromatin conformation capture methods that provide new insights into chromosome ultrastructure. This review aims to summarize and compare several models of chromatin fiber folding to form mitotic chromosomes and discusses them in the light of the novel findings. Functional genomics studies in several organisms confirmed condensins and cohesins as the major players in chromosome condensation. Here we compare available data on the role of these proteins across lower and higher eukaryotes and point to differences indicating evolutionary different pathways to shape mitotic chromosomes. Moreover, we discuss a controversial phenomenon of the mitotic chromosome ultrastructure - chromosome cavities - and using our super-resolution microscopy data, we contribute to its elucidation.
| S-EPMC7305364 | biostudies-literature
Project description:BackgroundCondensin complexes organize chromosome structure and facilitate chromosome segregation. Higher eukaryotes have two complexes, condensin I and condensin II, each essential for chromosome segregation. The nematode Caenorhabditis elegans was considered an exception, because it has a mitotic condensin II complex but appeared to lack mitotic condensin I. Instead, its condensin I-like complex (here called condensin I(DC)) dampens gene expression along hermaphrodite X chromosomes during dosage compensation.ResultsHere we report the discovery of a third condensin complex, condensin I, in C. elegans. We identify new condensin subunits and show that each complex has a conserved five-subunit composition. Condensin I differs from condensin I(DC) by only a single subunit. Yet condensin I binds to autosomes and X chromosomes in both sexes to promote chromosome segregation, whereas condensin I(DC) binds specifically to X chromosomes in hermaphrodites to regulate transcript levels. Both condensin I and II promote chromosome segregation, but associate with different chromosomal regions during mitosis and meiosis. Unexpectedly, condensin I also localizes to regions of cohesion between meiotic chromosomes before their segregation.ConclusionsWe demonstrate that condensin subunits in C. elegans form three complexes, one that functions in dosage compensation and two that function in mitosis and meiosis. These results highlight how the duplication and divergence of condensin subunits during evolution may facilitate their adaptation to specialized chromosomal roles and illustrate the versatility of condensins to function in both gene regulation and chromosome segregation.
| S-EPMC2682549 | biostudies-literature
Project description:The assembly of a functional mitotic spindle is essential for cell reproduction and requires a precise coordination between the nuclear cycle and the centrosome. This coordination is particularly prominent in organisms that undergo closed mitosis where centrosomes must not only respond to temporal signals, but also to spatial considerations, e.g. switching from the production of cytoplasmic microtubule arrays to the generation of dynamic intra-nuclear microtubules required for spindle assembly. We utilize a gene knockout of Kif9, a Dictyostelium discoideum Kin-I kinesin, to destabilize the physical association between centrosomes and the nuclear envelope. This approach presents a unique opportunity to reveal temporal and spatial components in the regulation of centrosomal activities in a closed-mitosis organism. Here we report that centrosome-nuclear engagement is not required for the entry into mitosis. Although detached centrosomes can duplicate in the cytoplasm, neither they nor nuclei alone can produce spindle-like microtubule arrays. However, the physical association of centrosomes and the nuclear envelope is required to progress through mitosis beyond prometaphase.
| S-EPMC3507195 | biostudies-literature
Project description:Mitotic chromosome condensation, sister chromatid cohesion, and higher order folding of interphase chromatin are mediated by condensin and cohesin, eukaryotic members of the SMC (structural maintenance of chromosomes)-kleisin protein family. Other members facilitate chromosome segregation in bacteria [1]. A hallmark of these complexes is the binding of the two ends of a kleisin subunit to the apices of V-shaped Smc dimers, creating a tripartite ring capable of entrapping DNA (Figure 1A). In addition to creating rings, kleisins recruit regulatory subunits. One family of regulators, namely Kite dimers (Kleisin interacting winged-helix tandem elements), interact with Smc-kleisin rings from bacteria, archaea and the eukaryotic Smc5-6 complex, but not with either condensin or cohesin [2]. These instead possess proteins containing HEAT (Huntingtin/EF3/PP2A/Tor1) repeat domains whose origin and distribution have not yet been characterized. Using a combination of profile Hidden Markov Model (HMM)-based homology searches, network analysis and structural alignments, we identify a common origin for these regulators, for which we propose the name Hawks, i.e. HEAT proteins associated with kleisins.
| S-EPMC5228436 | biostudies-literature
Project description:Meiosis is a specialized cell division essential for sexual reproduction. During meiosis the chromosomes are highly organized, and correct chromosome architecture is required for faithful segregation of chromosomes at anaphase I and II. Condensin is involved in chromosome organization during meiotic and mitotic cell divisions. Three condensin subunits, AtSMC4 and the condensin I and II specific subunits AtCAP-D2 and AtCAP-D3, respectively, have been studied for their role in meiosis. This has revealed that both the condensin I and condensin II complexes are required to maintain normal structural integrity of the meiotic chromosomes during the two nuclear divisions. Their roles appear functionally distinct in that condensin I is required to maintain normal compaction of the centromeric repeats and 45S rDNA, whereas loss of condensin II was associated with extensive interchromosome connections at metaphase I. Depletion of condensin is also associated with a slight reduction in crossover formation, suggesting a role during meiotic prophase I.
| S-EPMC4552968 | biostudies-literature
Project description:During cell division, chromosomes must be folded into their compact mitotic form to ensure their segregation. This process is thought to be largely controlled by the action of condensin SMC protein complexes on chromatin fibers. However, how condensins organize metaphase chromosomes is not understood. We have combined micromanipulation of single human mitotic chromosomes, sub-nanonewton force measurement, siRNA interference of condensin subunit expression, and fluorescence microscopy, to analyze the role of condensin in large-scale chromosome organization. Condensin depletion leads to a dramatic (~?10-fold) reduction in chromosome elastic stiffness relative to the native, non-depleted case. We also find that prolonged metaphase stalling of cells leads to overloading of chromosomes with condensin, with abnormally high chromosome stiffness. These results demonstrate that condensin is a main element controlling the stiffness of mitotic chromosomes. Isolated, slightly stretched chromosomes display a discontinuous condensing staining pattern, suggesting that condensins organize mitotic chromosomes by forming isolated compaction centers that do not form a continuous scaffold.
| S-EPMC6370136 | biostudies-literature