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Chromatin architecture is indirectly regulated by CDK7 transcriptional activity

ABSTRACT: Cyclin Dependent Kinase 7 (CDK7) is the core catalytic subunit of Cyclin Activating Kinase (CAK), a complex that has dual roles in cell cycle progression and transcription. While several CDK7 inhibitors are efficacious in preclinical models of cancer and have entered clinical trials, the mechanism(s) by which CDK7 promotes proliferation and cell viability is not well understood. Using triple negative breast cancer (TNBC) as a model, we found that inhibiting CDK7, either genomically or pharmacologically, induces mitotic dysfunction. Live and static cell imaging revealed that CDK7 inhibition prolongs mitosis and induces chromatin bridge formation, DNA double strand breaks, and abnormal nuclear features, all of which are indicative of mitotic catastrophe and chromosome instability. Transcriptome analyses revealed that CDK7 is essential for maintaining condensin complex gene expression, suggesting that CDK7 may sustain chromatin configuration, a role that extends beyond its impact on super-enhancers. Indeed, inhibiting CDK7 alters chromatin architecture consistent with condensin disruption. Confirming the importance of condensin regulation by CDK7, genetic suppression of a core subunit of this complex, structural maintenance of chromosome 2 (SMC2), phenocopies CDK7 inhibition. We report an undescribed role of CDK7 in maintaining chromatin structure and chromosome stability, as well as promoting proper mitoses, by sustaining condensin expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE223785 | GEO | 2023/05/30

REPOSITORIES: GEO

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3D topology of the SMC2/SMC4 sub-complex from chicken condensin I revealed by cross-linking and molecular modelling

Project description:SMC proteins are essential components of three protein complexes that are important for chromosome structure and function. The cohesin complex holds replicated sister chromatids together, whereas the condensin complex has an essential role in mitotic chromosome architecture. Both are involved in interphase genome organisation. SMC-containing complexes are large (>650 kDa for condensin) and contain long anti-parallel coiled-coils. They are thus difficult subjects for conventional crystallographic and electron cryomicroscopic studies. Here we have used amino acid-selective cross-linking and mass spectrometry (CLMS) combined with structure prediction to develop a full-length molecular draft 3D-structure of the SMC2/SMC4 dimeric backbone of chicken condensin. We assembled homology-based molecular models of the globular heads and hinges with the lengthy coiled-coils modelled in fragments, using numerous high-confidence cross-links and accounting for potential irregularity. Our experiments reveal that isolated condensin complexes can exist with their coiled-coil segments closely apposed to one another along their lengths and define the relative spatial alignment of the two anti-parallel coils. The centres of the coiled-coils can also approach one another closely in situ in mitotic chromosomes. In addition to revealing structural information, our cross-linking data suggest that both H2A and H4 may have roles in condensin interactions with chromatin.

2015-07-13 | PXD001835 | Pride

Plasmodium condensin core subunits (SMC2/SMC4) mediate atypical mitosis and are essential for parasite proliferation and transmission

Project description:Condensin is a multi-subunit protein complex regulating chromosome condensation and segregation during cell division. In Plasmodium spp., the causative agent of malaria, cell division is atypical and the role of condensin is unclear. Here we examine the role of SMC2 and SMC4, the core subunits of condensin, during endomitosis in schizogony and endoreduplication in male gametogenesis. During early schizogony SMC2/SMC4 localize to a distinct focus, identified as the centromeres by NDC80 fluorescence and ChIP-seq analyses, but do not form condensin I or II complexes. In mature schizonts and during male gametogenesis there is a diffuse SMC2/SMC4 distribution on chromosomes and in the nucleus, and both condensin I and II complexes form at these stages. Knockdown of smc2 and smc4 gene expression revealed essential roles in parasite proliferation and transmission. The condensin core subunits (SMC2/SMC4) form different complexes and may have distinct functions at various stages of the parasite life cycle.

2020-05-27 | PXD016833 | Pride

Fission yeast Cdk7 controls gene expression through both its CAK and CTD kinase activities

Project description:Cyclin dependent kinases activation and RNA polymerase II transcription are linked by the Cdk7 kinase that phosphorylates Cdks as a trimeric CAK complex, and serine 5 within the PolII C-terminal domain (CTD) as TFIIH bound CAK. However, the physiological importance of integrating these processes is not understood. Beside the Cdk7 ortholog Mcs6, fission yeast possesses a second CAK, Csk1. Both enzymes were proposed to act redundantly to activate Cdc2. Using an improved analogue sensitive Mcs6-as kinase, we show that Csk1 is not a relevant CAK for Cdc2. Further analyses revealed that Csk1 lacks a 20 amino acid sequence required for its budding yeast counterpart, Cak1, to bind Cdc2. Transcriptome profiling of the Mcs6-as mutant in the presence or absence of the budding yeast Cak1 kinase, in order to uncouple the CTD kinase and CAK activities of Mcs6, revealed an unanticipated role of the CAK branch in the transcriptional control of the cluster of genes implicated in ribosome biogenesis and cell growth. The analysis of a Cdc2 CAK site mutant confirmed these data. Our data show that the Cdk7 kinase modulates transcription through both its well-described RNA Polymerase II CTD kinase activity, but also through the Cdc2 activating kinase activity.

2012-02-19 | GSE27425 | GEO

RNA Pol II transcription antagonises mitotic chromosome assembly and segregation by condensin

Project description:Condensin drives mitotic chromosome assembly by folding chromatin into loops and is enriched in the vicinity of highly expressed genes, but the significance of such proximity with respect to condensin activity has remained unclear. Here, by modulating the occupancy of RNA Pol II in vivo, we show that transcription plays no role in the steady state association of condensin with DNA. Rather, transcription stalls and even displaces condensin, hindering its ability to fold chromatin and to support chromosome segregation. Our results highlight a key aspect of the integrated functioning of condensin and suggest that a tight control of transcription underlies mitotic chromosome assembly.

2024-02-03 | GSE236395 | GEO

Condensin-mediated remodeling of the mitotic chromatin landscape in fission yeast

Project description:Chromatin fibres dynamically change their organisation during cell cycle. In interphase nucleus, chromatin fibres are evenly distributed whereas their spatial occupancy are reorganised to form condensed chromosomes in mitosis. This process called chromosome condensation is necessary for an accomplishment of faithful chromosome segregation. One of the Structural Maintenance of Chromosomes complexes, Condensin, is indispensable for chromosome condensation. It remains, however, unknown how Condensin plays its role in shaping mitotic chromosome. Here we show that chromatin fibres change their interacting partners; short-range contacts in interphase nucleus are converted into long-range interactions to shape condensed chromosomes. This conversion of interactions among chromatin fibres results in the formation of larger domains within mitotic chromosomes. Condensin is solely in charge of the conversion and large domain formation in fission yeast mitosis. Our results show how fission yeast Condensin is involved in shaping mitotic chromosomes.

2017-07-13 | GSE94474 | GEO

Condensin-mediated remodeling of the mitotic chromatin landscape in fission yeast

2017-07-13 | GSE94475 | GEO

Mitotic chromatin proteomics - Proteomics analysis with a nano Random Forest approach reveals novel functional interactions regulated by SMC complexes on mitotic chromosomes

Project description:we used stable isotope labeling with amino acids in cell culture (SILAC) to compare the proteomes of mitotic chromosomes isolated from cell lines harboring conditional knockouts of members of the condensin (SMC2, CAP-H, CAP-D3), cohesin (Scc1/Rad21), and SMC5/6 (SMC5) complexes.

2016-05-31 | PXD003427 | Pride

Identification of a novel Bromodomain / Casein Kinase II / TAF-containing complex as a regulator of mitotic condensin function

Project description:ABSTRACT: Condensin is a central regulator of mitotic genome structure, with mutants showing poorly condensed chromosomes and profound segregation defects. Here we identify the fission yeast NCT complex, comprising the Nrc1 BET-family tandem bromodomain protein (SPAC631.02), Casein Kinase II (CKII) and several TAFs, as a novel regulator of condensin function (where NCT mutants restore the formation of segregation-competent chromosomes in cells containing defective condensin). Synchronous ChIP-seq shows that NCT and condensin bind similar genomic regions, but only briefly co-localize during the periods of chromosome condensation and decondensation. These results are consistent with a model where NCT targets CKII to chromatin in a cell cycle-directed manner to modulate the activity of condensin during chromosome condensation and decondensation. DATA: Study includes ChIP-seq of fission yeast H3-K4Me3, H3-K36Me3, TBP, Taf7, Nrc1, Cka1 from aynchronous cells; Nrc1 and Cut3 (representing condensin) from four synchronized cell-cycle stages estimated as G2/M, Metaphase, Anaphase and G1/S.

2014-01-10 | E-GEOD-53955 | biostudies-arrayexpress

Transcription-dependent positioning of Structural Maintenance of Chromosome complexes across the genome: RNA-Seq

Project description:The Structural Maintenance of Chromosomes (SMC) complexes regulate the chromosome structures essential for proper genome regulation and cell viability. In mammals, the coordinated actions of the SMC complexes condensin I, condensin II and cohesin regulate dynamic chromosome structures throughout the cell cycle, but it is not clear how these complexes are positioned across the genome. We report here that condensin I, condensin II and cohesin occupy active euchromatic regions of the embryonic stem cell genome, but not heterochromatic regions. Like cohesin, we find that condensin II is deposited at active genes by the SMC loading factor Nipbl. The recruitment of Condensin II to active genes is dependent on their transcriptional activation. Subsequent transcriptional elongation by RNA polymerase II distributes condensin II across gene bodies. During mitosis, condensin I occupies the same set of active genes occupied by condensin II during interphase. Thus, SMC complexes are positioned in the genome by transcription-dependent processes, indicating that condensin-dependent condensation mechanisms are preferentially utilized in euchromatic regions. RNA-seq in mES cells after known-down of Smc1, CapH2 or Smc2.

2013-10-28 | E-GEOD-46316 | biostudies-arrayexpress

Genome-wide analysis of condensin binding sites in vertebrate genome

Project description:The condensin complex is well known to be essential for correct packaging and segregation of chromosomes during mitosis and meiosis in all eukaryotes. To date, the genome wide location and the nature of condensin binding sites has remained elusive in vertebrate systems. A detailed knowledge of condensin binding sites is essential to understand the as-yet enigmatic function of this complex and to define its greater role in chromosome architecture. To address this, we have used next generation sequencing to map condensin I in chicken DT40 cells. Unexpectedly, we found condensin I binds predominately to promoter sequences in mitotic cells. We also found a striking enrichment at both centromeres and telomeres, highlighting the importance of the complex in chromosome segregation. Taken together, the results show condensin I is largely absent from heterochromatic regions. These results reveal for the first time the condensin I binding sites in the vertebrate genome, and demonstrate the importance of the complex in genome segregation and suggest a novel function in gene regulation. Condensin associated DNA from chicken DT40 cells were affinity purified using streptavidin and deep sequenced by Illumina Hiseq2000

2013-10-03 | E-GEOD-45552 | biostudies-arrayexpress

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