The Self-Organizing Genome: Principles of Genome Architecture and Function

Cell, Journal Year: 2020, Volume and Issue: 183(1), P. 28 - 45

Published: Sept. 24, 2020

Language: Английский

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Integrated spatial genomics reveals global architecture of single nuclei

Nature, Journal Year: 2021, Volume and Issue: 590(7845), P. 344 - 350

Published: Jan. 27, 2021

Language: Английский

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Roles of transposable elements in the regulation of mammalian transcription

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 23(7), P. 481 - 497

Published: Feb. 28, 2022

Language: Английский

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The Mediator complex as a master regulator of transcription by RNA polymerase II

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 23(11), P. 732 - 749

Published: June 20, 2022

Language: Английский

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How subtle changes in 3D structure can create large changes in transcription

eLife, Journal Year: 2021, Volume and Issue: 10

Published: July 9, 2021

Animal genomes are organized into topologically associated domains (TADs). TADs thought to contribute gene regulation by facilitating enhancer-promoter (E-P) contacts within a TAD and preventing these across borders. However, the absolute difference in contact frequency boundaries is usually less than 2-fold, even though disruptions of borders can change expression 10-fold. Existing models fail explain this hypersensitive response. Here, we propose futile cycle model enhancer-mediated that exhibit hypersensitivity through bistability hysteresis. Consistent with recent experiments, does not strong correlation between E-P promoter activity, occurs contact. Through mathematical analysis stochastic simulation, show system create an illusion biochemical specificity importance weak boundaries. It also offers mechanism reconcile apparently contradictory results from global disruption local boundary deletion experiments. Together, analyses advance our understanding cis-regulatory controlling suggest new experimental directions.

Language: Английский

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The spatial organization of transcriptional control

Nature Reviews Genetics, Journal Year: 2022, Volume and Issue: 24(1), P. 53 - 68

Published: Sept. 14, 2022

Language: Английский

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An intrinsically disordered region-mediated confinement state contributes to the dynamics and function of transcription factors

Molecular Cell, Journal Year: 2021, Volume and Issue: 81(7), P. 1484 - 1498.e6

Published: Feb. 8, 2021

Language: Английский

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The Mediator kinase module: an interface between cell signaling and transcription

Trends in Biochemical Sciences, Journal Year: 2022, Volume and Issue: 47(4), P. 314 - 327

Published: Feb. 19, 2022

The Mediator kinase module transforms function through physical interaction and its activity.The regulates transcription by altering factor at enhancers promoters.Rapid, stimulus-specific transcriptional responses are enabled the module.By controlling (TF) polymerase II (pol II) activity, helps convert signaling inputs to outputs. complex controls RNA activity coordinating assembly of pol regulatory factors start sites mediating interactions between enhancer-bound (TFs) enzyme. structure is completely altered upon binding module, a multi-subunit that contains CDK8 or vertebrate-specific paralog CDK19. Here, we review mechanisms which transcription, emphasizing impact on TF elongation, enhancer function, chromatin architecture. We also highlight how integrates pathways with enable rapid, responses, as well links human disease. (see Glossary) genome-wide regulator transcription; consequently, itself targeted an array regulate function. For example, sequence-specific, DNA-binding TFs bind control recruitment specific genomic loci. Also, reversibly associates (forming what here call CDK-Mediator) in several ways. Conserved from yeast humans, consists four subunits: kinase, CCNC, MED12, MED13. However, vertebrates evolved subunit paralogs, called CDK19, MED12L, MED13L (Box 1), expand functional diversity ways remain poorly defined. Not surprisingly, subunits required for mammalian embryogenesis [1.Li N. et al.Cyclin C haploinsufficient tumour suppressor.Nat. Cell Biol. 2014; 16: 1080-1091Google Scholar, 2.Miao Y.L. al.Mediator component MED13 zygotic genome activation postimplantation development mouse.Biol. Reprod. 2018; 98: 449-464Google 3.Westerling T. al.Cdk8 essential preimplantation mouse development.Mol. Cell. 2007; 27: 6177-6182Google 4.Rocha P.P. al.Med12 early canonical Wnt Wnt/PCP signaling.Development. 2010; 137: 2723-2731Google Scholar] linked myriad diseases 2).Box 1Vertebrate-specific paralogs subunitsThe conserved among eukaryotes, but CDK8, emerged (Figure I). Each expressed different chromosomes appears be mutually exclusive within [52.Galbraith M.D. al.HIF1A employs CDK8-Mediator stimulate RNAPII elongation response hypoxia.Cell. 2013; 153: 1327-13239Google Scholar]. Comparatively little known about these connections disease have been discovered (Table S1 supplemental information online).CDK8 CDK19 highest sequence identity inhibitors invariably block both proteins. show evidence redundant [109.Sooraj D. al.MED12 BRD4 cooperate sustain cancer growth loss mediator kinase.Mol. 2022; 82: 123-139Google nonredundant functions each has shown kinase-dependent -independent [25.Steinparzer I. al.Transcriptional IFN-gamma require pause release mechanistically distinct functions.Mol. 2019; 76: 485-499Google Scholar,87.Audetat K.A. al.A kinase-independent role cyclin-dependent 19 p53 response.Mol. 2017; 37e00626-16Google Scholar,109.Sooraj Scholar,117.Menzl BCR-ABL1(+) leukemia.Nat. Commun. 10: 4741Google Scholar].The MED12 protein implicated numerous X-linked online) X chromosome, whereas MED12L gene resides chromosome 3. Interestingly, Xist repression (CDK19 no effect) mice [118.Postlmayr A. establishment H3K27me3 development.Development. 2020; 147dev175141Google shows more restricted expression across tissues compared MED12. Whereas necessary [8.Park M.J. al.Oncogenic exon 2 mutations disrupt allosteric cyclin C-CDK8/19.J. Chem. 293: 4870-4882Google Scholar,81.Knuesel M.T. al.The subcomplex histone requires Med12 can independently Mediator.Mol. 2009; 29: 650-661Google Scholar], it unknown whether activates CDK8/19 similarity N-terminal helix I) suggests similar activation.One basic link [10.Knuesel molecular switch co-activator function.Genes Dev. 23: 439-451Google Scholar,11.Tsai K.L. Mediator-CDK8 association Mediator-RNA interaction.Nat. Struct. Mol. 20: 611-619Google Notably, proteomics data suggest modules containing (instead MED13) maintain [39.Ebmeier C.C. Taatjes D.J. Activator-Mediator Mediator-cofactor interactions.Proc. Natl. Acad. Sci. U. S. 107: 11283-11288Google Scholar,119.Sato set consensus identified multidimensional identification technology.Mol. 2004; 14: 685-691Google Moreover, ubiquitylated FBW7, initiates dissociation degradation [110.Davis M.A. SCF-Fbw7 ubiquitin ligase degrades Mediator.Genes 151-156Google Clinical similar, not identical, biological roles online).Box 2Mediator diseaseMutations cause disability online), broadly grouped into two categories: neurological/developmental disorders (reviewed [7.Srivastava Kulshreshtha R. Insights clinical relevance subunit, diseases.J. Physiol. 2021; 236: 3163-3177Google Scholar]). In addition, wide range cancers subunits, summarized recent reviews [121.Dannappel M.V. al.Molecular vivo modules.Front. 6: 171Google Scholar,122.Roninson I.B. al.Identifying impacted CDK8/19.Cells. 8: 821Google Scholar].Three medically related intellectual/developmental syndromes MED12: Opitz-Kaveggia, Lujan, Ohdo syndrome. Furthermore, domains associated intellectual exhibit comparable phenotypes individuals online). introduction could compensate deletion Drosophila, mutant neurological not, resulting seizures reduced fitness surviving flies [123.Chung H.L. al.De novo variants syndrome involving epileptic encephalopathy.Am. J. Hum. Genet. 106: 717-725Google Likewise, induced pathogenic mutants resulted developmental defects [124.Tian al.Somatic de germline MEDs neural tube defects.Front. 9641831Google These results disease-associated CDK19.Mutations nonmalignant uterine leiomyoma most well-studied changes enhancer-promoter looping architecture [79.Moyo M.B. al.Altered landscape engagement underlie dysregulation leiomyomas.Nat. 11: 1019Google negatively Scholar,9.Turunen M. al.Uterine leiomyoma-linked mediator-associated CDK activity.Cell Rep. 7: 654-660Google Such consistent regulation super-enhancer [67.Kuuluvainen E. al.Depletion represses superenhancer-associated genes colon cells.Mol. 38e00573-17Google Scholar,74.Pelish H.E. inhibition further super-enhancer-associated AML.Nature. 2015; 526: 273-276Google Scholar,75.Lynch C.J. al.Global hyperactivation stabilizes naive pluripotency kinases.Nat. 22: 1223-1238Google Scholar].Targeting therapeutic benefit remains work progress, novel strategies continue emerge. Firestein lab showed bromodomain extraterminal domain (BET) (e.g., JQ1) may complement + certain compensatory increases occupancy BET were observed double knockout cells (HCT116 DLD1), suggesting cooperativity agreement other studies [51.Donner A.J. al.CDK8 positive serum network.Nat. 17: 194-201Google Scholar,125.Bhagwat A.S. al.BET releases select cis-regulatory elements.Cell 2016; 15: 519-530Google activation. One Mutations Three Targeting Although current structural only CDK8-CCNC dimer [5.Schneider E.V. CDK8/CycC implicates specificity CDK/cyclin family reveals deep pocket binder.J. 2011; 412: 251-266Google cryogenic electron microscopy (cryoEM) (Saccharomyces cerevisiae) was recently determined Tsai [6.Li Y.C. al.Structure noncanonical Cdk8 mechanism Argonaute-containing module.Sci. Adv. 7eabd4484Google This provided first high-resolution large Med13 subunits. key module. N terminus interacts Cdk8–Ccnc 1). mutated variety clustering around residues 36–44 Structural coworkers occupy complex. otherwise disordered loop, allows substrate access active site Additionally, prior Boyer oncogenic model Med12-dependent likely humans. While details available, Cramer completed crosslinking-mass spectrometry analysis (S. CDK-Mediator [12.Osman II.J. 296100734Google extensive Mediator, including and/or Med19 Med10, Med10 reside hook [13.Zhao H. Tail core.Nat. 12: 1355Google represents interface TFIIH-associated later). this review, some considering past context results. enables cell cascades help 'reprogram' patterns changing conditions. then discuss module-dependent stages (initiation, pausing, elongation) new clarified expanded biochemical cell-based experiments. Finally, represent powerful elements coordinate type- programs outline contribute looping. Throughout, areas understanding limited conclude open questions future research. genome-wide, remodelers, way, serve 'master regulators' pre-initiation (PIC) Activation causes phosphorylation nuclear localization 2). As examples: (i) interferon-induced STAT triggers their allow target activation, (ii) ELK1 phosphorylated during MAPK pathway enhances ELK1-dependent [14.Balamotis al.Complexity domain-Mediator interface.Sci. Signal. 2: ra20Google representative examples, endpoints cascades. Importantly, common targets kinases later), yielding direct signaling. Coordination evident ancient metabolism. Signaling metabolic integrated interdependent, such will trigger adaptation, vice versa 2) [15.Zhu Thompson C.B. Metabolic proliferation.Nat. Rev. 436-450Google flux directly enzymes phosphorylation), they modulate well. organisms cerevisiae, coordinates nutrients [16.Khakhina al.Med13p prevents mitochondrial fission programmed death retention C.Mol. 25: 2807-2816Google 17.Lindsay A.K. al.Analysis Candida albicans defective reveal metabolism biofilm formation.PLoS 10e1004567Google 18.Mousley sterol-binding endosomal lipid TOR nitrogen sensing.Cell. 2012; 148: 702-715Google via [19.Hirst al.GAL4 regulated holoenzyme-associated SRB10/CDK8.Mol. 1999; 3: 673-678Google Scholar,20.Nelson C. al.Srb10/Cdk8 filamentous phosphorylating Ste12.Nature. 2003; 421: 187-190Google Similarly, indirectly metazoans modification TFs. cells, phosphorylates major regulators metabolism, SREBP [21.Zhao X. al.Regulation lipogenesis 8-mediated SREBP-1.J. Clin. Invest. 122: 2417-2427Google Notch ICD Scholar,22.Fryer al.Mastermind recruits CycC:Cdk8 phosphorylate notch turnover.Mol. 509-520Google SMAD1/3 [23.Alarcon al.Nuclear CDKs drive Smad turnover BMP TGF-b pathways.Cell. 139: 757-769Google STAT1/3/5a [24.Bancerek STAT1 selectively interferon response.Immunity. 38: 250-262Google insulin, WNT/β-catenin, TGFβ, cascades, respectively. CDK8-dependent stability co

Language: Английский

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Loop-extrusion and polymer phase-separation can co-exist at the single-molecule level to shape chromatin folding

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: July 13, 2022

Loop-extrusion and phase-separation have been proposed as mechanisms that shape chromosome spatial organization. It is unclear, however, how they perform relative to each other in explaining chromatin architecture data whether compete or co-exist at the single-molecule level. Here, we compare models of polymer physics based on loop-extrusion phase-separation, well where both act simultaneously a single molecule, against multiplexed FISH available human loci IMR90 HCT116 cells. We find different recapitulate bulk Hi-C average microscopy data. Single-molecule conformations are also captured, especially by better reflect experimentally reported segregation globules considered genomic their cell-to-cell structural variability. Such variability consistent with two main concurrent causes: single-cell epigenetic heterogeneity an intrinsic thermodynamic conformational degeneracy folding. Overall, model combining provides very good description data, particularly higher-order contacts, showing can shaping

Language: Английский

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In diverse conditions, intrinsic chromatin condensates have liquid-like material properties

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(18)

Published: April 24, 2023

Nuclear DNA in eukaryotes is wrapped around histone proteins to form nucleosomes on a chromatin fiber. Dynamic folding of the fiber into loops and variations degree compaction regulate essential processes such as transcription, recombination, mitotic chromosome segregation. Our understanding physical properties that allow be dynamically remodeled even highly compacted states limited. Previously, we reported has an intrinsic capacity phase separate dynamic liquid-like condensates, which can regulated by cellular factors [B. A. Gibson et al. , Cell 179 470–484.e421 (2019)]. Recent contradictory reports claim specific set solution conditions required for fluidity condensates would otherwise solid [J. C. Hansen, K. Maeshima, M. J. Hendzel, Epigenetics Chromatin 14 50 (2021); H. Strickfaden 183 1772–1784.e1713 (2020)]. We sought resolve these discrepancies, our ability translate with confidence biophysical observations cells requires their precise characterization. Moreover, whether assemblies are or static affects how loop extrusion, remodeling will engage them inside cells. Here, show diverse without buffering components fragments separated fluids vitro. also explore sample preparation imaging affect experimental observation condensate dynamics. Last, describe vitro behaviors locally but globally constrained movement observed

Language: Английский

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