Featured
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| Open AccessHigh-resolution targeted 3C interrogation of cis-regulatory element organization at genome-wide scale
Current 3C methods generate low-resolution interaction profiles across the genome or high-resolution profiles at a limited number of loci. Here the authors present Nuclear-Titrated Capture-C which produces high-resolution genome-wide interaction profiles.
- Damien J. Downes
- , Robert A. Beagrie
- & Jim R. Hughes
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Article
| Open AccessSAMMY-seq reveals early alteration of heterochromatin and deregulation of bivalent genes in Hutchinson-Gilford Progeria Syndrome
Hutchinson-Gilford progeria syndrome is a genetic disease where an aberrant form of Lamin A disrupts chromatin by interfering with lamina associated domains. Here, the authors present the SAMMY-seq, a method for genome-wide characterization of heterochromatin dynamics and detect early stage alterations of heterochromatin structure in progeria primary fibroblasts, accompained by Polycomb dysfunctions.
- Endre Sebestyén
- , Fabrizia Marullo
- & Chiara Lanzuolo
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Article
| Open AccessNonlinear mechanics of lamin filaments and the meshwork topology build an emergent nuclear lamina
Mechanical strength of in situ assembled nuclear lamin filaments arranged in a 3D meshwork is unclear. Here, using mechanical, structural and simulation tools, the authors report the hierarchical organization of the lamin meshwork that imparts strength and toughness to lamin filaments at par with silk and Kevlar®
- K. Tanuj Sapra
- , Zhao Qin
- & Ohad Medalia
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Article
| Open AccessCohesin depleted cells rebuild functional nuclear compartments after endomitosis
The role of cohesin in organizing a functional nuclear architecture remains poorly understood. Here the authors show that cohesin depleted cells pass through endomitosis forming a multilobulated nucleus able to proceed through S-phase with typical features of active and inactive nuclear compartments and spatio-temporal patterns of replication domains.
- Marion Cremer
- , Katharina Brandstetter
- & Thomas Cremer
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Article
| Open AccessTrans- and cis-acting effects of Firre on epigenetic features of the inactive X chromosome
Firre encodes a lncRNA involved in nuclear organization in mammals. Here, the authors find that allelic deletion of Firre on the active X chromosome (Xa) results in dose-dependent loss of histone H3K27me3 on the inactive X chromosome (Xi), along with other trans-acting effects, including disruption of the perinuclear location and minor dysregulation of gene expression.
- He Fang
- , Giancarlo Bonora
- & Christine M. Disteche
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Article
| Open AccessComputer vision for pattern detection in chromosome contact maps
Chromatin loops bridging distant loci within chromosomes can be detected by a variety of techniques such as Hi-C. Here the authors present Chromosight, an algorithm applied on mammalian, bacterial, viral and yeast genomes, able to detect various types of pattern in chromosome contact maps, including chromosomal loops.
- Cyril Matthey-Doret
- , Lyam Baudry
- & Axel Cournac
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Article
| Open AccessATR is essential for preservation of cell mechanics and nuclear integrity during interstitial migration
The nucleus is a mechanically stiff organelle of the cell and the DNA damage response protein ATR can localize to the nuclear envelope upon mechanical stress. Here, the authors show that ATR may contribute to the integrity of the nuclear envelope and may play a role in cell migration.
- Gururaj Rao Kidiyoor
- , Qingsen Li
- & Marco Foiani
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Article
| Open AccessLoss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology
Mandibuloacral dysplasias (MADs) are rare progeroid syndromes characterized by nuclear morphological and functional abnormalities. Here the authors report that loss of mitochondrial membrane protein MTX2 causes a progeroid MAD sharing clinical features with lamin-associated progeroid syndromes.
- Sahar Elouej
- , Karim Harhouri
- & Annachiara De Sandre-Giovannoli
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Article
| Open AccessNucleoporin TPR is an integral component of the TREX-2 mRNA export pathway
mRNAs export from the nucleus is thought to be regulated in part by three nucleoporins that comprise the nuclear basket, but whether and how distinct basket nucleoporins interact with the RNA export machinery is unclear. Here, the authors use rapid auxin-mediated degradation of basket nucleoporins Nup153, Nup50, and Tpr, and see that Tpr interacts with the TREX-2 mRNA export complex.
- Vasilisa Aksenova
- , Alexandra Smith
- & Mary Dasso
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Article
| Open AccessSurveillance of cohesin-supported chromosome structure controls meiotic progression
Meiosis-specific cohesins and the synaptonemal complex are essential for meiotic chromosome structure and function. Here the authors show that continued surveillance of these chromosome structures controls meiotic progression by regulating CHK-2, a master regulator of pairing and recombination.
- Maikel Castellano-Pozo
- , Sarai Pacheco
- & Enrique Martinez-Perez
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Article
| Open Access3D genome organization contributes to genome instability at fragile sites
Common fragile sites are regions susceptible to replication stress and are prone to chromosomal instability. Here, the authors, by analyzing the contribution of 3D chromatin organization, identify and characterize a fragility signature and precisely map these fragility regions.
- Dan Sarni
- , Takayo Sasaki
- & Batsheva Kerem
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Article
| Open AccessDynamics of the 4D genome during in vivo lineage specification and differentiation
The relationship between regulatory elements, chromatin interactions and gene expression during development remains poorly understood. Here the authors present Tiled-C, a low-input 3C approach to study genome architecture at high resolution, and apply it to mouse erythroid differentiation in vivo, finding that enhancer-promoter interactions are formed gradually during differentiation, concomitant with progressive upregulation of gene activity.
- A. Marieke Oudelaar
- , Robert A. Beagrie
- & Jim R. Hughes
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Article
| Open AccessNucleoporin 153 links nuclear pore complex to chromatin architecture by mediating CTCF and cohesin binding
The nuclear pore complex components, nucleoporins, have been proposed to mediate spatial and temporal organization of chromatin. Here, the authors show that Nucleoporin 153 interacts with CTCF and cohesin, and mediates their binding across cis-regulatory elements and TAD boundaries in mouse embryonic stem cells.
- Shinichi Kadota
- , Jianhong Ou
- & Eda Yildirim
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Article
| Open AccessRole of the nuclear membrane protein Emerin in front-rear polarity of the nucleus
During cell migration, cells are polarized with distinct front vs. rear regions but whether and how polarity is transmitted to the nucleus is unclear. Here the authors show that frontally-biased endoplasmic reticulum and the nuclear membrane protein Emerin contribute to front-rear nuclear cell polarity.
- Paulina Nastały
- , Divya Purushothaman
- & Paolo Maiuri
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Article
| Open AccessUltrastructural visualization of 3D chromatin folding using volume electron microscopy and DNA in situ hybridization
The genome is folded in 3-dimensions, though the lack of robust ultra-resolution imaging makes this difficult to visualise. Here, the authors present 3D-EMISH that combines serial block-face scanning electron microscopy with in situ hybridization.
- Paweł Trzaskoma
- , Błażej Ruszczycki
- & Grzegorz M. Wilczyński
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Article
| Open AccessIncreasing ambient temperature progressively disassembles Arabidopsis phytochrome B from individual photobodies with distinct thermostabilities
Temperature modulates plant development and environmental responses. Here, the authors show that increasing ambient temperature reduces the number of sub-nuclear photobodies in Arabidopsis by promoting selective disassembly of thermo-unstable photobodies in a manner dependent on phytochrome B’s photosensory module.
- Joseph Hahm
- , Keunhwa Kim
- & Meng Chen
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Article
| Open AccessDual functions of Aire CARD multimerization in the transcriptional regulation of T cell tolerance
The transcription factor Aire mediates tissue-specific antigen expression in the thymus for T cell central tolerance induction. Here the authors show that Aire, via its CARD domain, forms multimers that can misdirect Aire to PML bodies leading to the loss of Aire transcriptional activity and induction of autoimmunity.
- Yu-San Huoh
- , Bin Wu
- & Sun Hur
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Article
| Open AccessDNA repair by Rad52 liquid droplets
Genome dynamics allow cells to repair DNA double-strand breaks (DSBs), which are highly toxic DNA lesions. Here the authors reveal that in S. cerevisiae, Rad52 DNA repair proteins assemble in liquid droplets that work with dynamic nuclear microtubules to relocalize lesions to the nuclear periphery for repair.
- Roxanne Oshidari
- , Richard Huang
- & Karim Mekhail
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Article
| Open AccessIdentification of distinct maturation steps involved in human 40S ribosomal subunit biosynthesis
Ribosome synthesis is a complex multi-step process. Here the authors present a method that allows the efficient isolation and characterization of the preribosomal complexes formed along the entire ribosome synthesis pathway in human cells.
- Blanca Nieto
- , Sonia G. Gaspar
- & Mercedes Dosil
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Article
| Open AccessTreacle controls the nucleolar response to rDNA breaks via TOPBP1 recruitment and ATR activation
DNA double-strand breaks in ribosomal DNA repeats is associated with repression of ribosomal RNA synthesis. Here the authors reveal a cooperation between TOPBP1 and Treacle in the signaling cascade that triggers transcriptional inhibition and nucleolar segregation in response to rDNA breaks.
- Clémence Mooser
- , Ioanna-Eleni Symeonidou
- & Manuel Stucki
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Article
| Open AccessInvolvement of condensin in cellular senescence through gene regulation and compartmental reorganization
Cell senescence involves stable arrest of cell proliferation and changes in gene expression and 3D genome reorganization. Here, the authors show that human condensin II complex participates in reorganization of the chromatin compartments, primarily through switching from heterochromatic B to euchromatic A compartments.
- Osamu Iwasaki
- , Hideki Tanizawa
- & Ken-ichi Noma
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Article
| Open AccessA revised model for promoter competition based on multi-way chromatin interactions at the α-globin locus
The coordination of interactions between multiple regulatory elements and genes within a chromatin domain remains poorly understood. Here, the authors use a method to detect multi-way chromatin interactions in a mouse model in which the α-globin domain is extended to include several additional genes, finding that the promoters do not form mutually exclusive interactions with the enhancers, but all interact simultaneously in a single complex.
- A. Marieke Oudelaar
- , Caroline L. Harrold
- & Jim R. Hughes
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Article
| Open AccessThe ubiquitin-like modifier FAT10 interferes with SUMO activation
FAT10 is an ubiquitin-like modifier that targets proteins to proteasomal degradation. Here, the authors show that FAT10 also regulates SUMO activation in vitro and in cells, providing evidence for functional crosstalk between two ubiquitin-like modifiers.
- Annette Aichem
- , Carolin Sailer
- & Marcus Groettrup
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Article
| Open AccessNuclear decoupling is part of a rapid protein-level cellular response to high-intensity mechanical loading
Cells must be robust to the mechanical demands of their environments. Here, Gilbert et al. expose cells to high-intensity strain cycling and use proteomics to identify a protein, SUN2, that behaves as a strain-induced breakpoint that can decouple the nucleoskeleton from the cytoskeleton.
- Hamish T. J. Gilbert
- , Venkatesh Mallikarjun
- & Joe Swift
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Article
| Open AccessSpatially clustered loci with multiple enhancers are frequent targets of HIV-1 integration
HIV-1 usually targets active genes and integrates near the nuclear pore compartment. Here the authors show that recurrently targeted genes are proximal to super-enhancer genomic elements, which cluster in specific spatial compartments of the T cell nucleus, suggesting a role for nuclear organisation in viral infection.
- Bojana Lucic
- , Heng-Chang Chen
- & Marina Lusic
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Article
| Open AccessB1 oligomerization regulates PML nuclear body biogenesis and leukemogenesis
Promyelocytic leukemia protein (PML) is the scaffolding protein that organizes PML nuclear bodies. Here the authors determine the crystal structure of a PML B1-box multimer and characterise the oligomerisation behaviour of the PML RBCC construct and show that disrupting B1-B1 interactions precludes promyelocytic leukemia leukemogenesis in transgenic mice.
- Yuwen Li
- , Xiaodan Ma
- & Guoyu Meng
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Article
| Open AccessStructural basis for lamin assembly at the molecular level
Lamins are intermediate filaments and the major component of the nuclear lamina. Here the authors determine the crystal structure of a construct comprising the N-terminal half of human lamin A/C and use their structure and cross-linking and biochemical experiments to discuss lamin assembly.
- Jinsook Ahn
- , Inseong Jo
- & Nam-Chul Ha
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Article
| Open AccessArkadia/RNF111 is a SUMO-targeted ubiquitin ligase with preference for substrates marked with SUMO1-capped SUMO2/3 chain
The cellular functions of poly-SUMO chains of different compositions are not fully understood. Here, the authors characterize Arkadia/RNF111 as a SUMO-targeted ubiquitin ligase that recognizes proteins with hybrid SUMO1-capped SUMO2/3 chains and targets them for proteasomal degradation.
- Annie M. Sriramachandran
- , Katrin Meyer-Teschendorf
- & R. Jürgen Dohmen
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Article
| Open AccessThe prion-like protein kinase Sky1 is required for efficient stress granule disassembly
The factors regulating stress granule dissolution are not fully understood. Here, the authors identify Sky1 as a stress granule component in yeast, and show that Sky1 kinase activity is required for timely stress granule disassembly during stress recovery.
- Jenifer E. Shattuck
- , Kacy R. Paul
- & Eric D. Ross
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Article
| Open AccessThe AAA + ATPase TorsinA polymerizes into hollow helical tubes with 8.5 subunits per turn
Torsins are unusual AAA + ATPases of unknown function that reside in the endoplasmic reticulum of all animals. Here the authors report that TorsinA forms tubular helical filaments with an unusual periodicity and that filamentous TorsinA directly interacts with membranes to form tubular protrusions.
- F. Esra Demircioglu
- , Weili Zheng
- & Thomas U. Schwartz
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Article
| Open AccessLamin A molecular compression and sliding as mechanisms behind nucleoskeleton elasticity
Lamin A is critical for nuclear architecture but its structure and assembly are not fully understood. Here, the authors use quantitative cross-linking mass spectrometry to map intra- and intermolecular interactions within lamin homomers, providing insights into the molecular basis for lamin’s mechanical properties.
- Alex A. Makarov
- , Juan Zou
- & Eric C. Schirmer
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Article
| Open AccessEnhancer accessibility and CTCF occupancy underlie asymmetric TAD architecture and cell type specific genome topology
Eukaryotic genomes fold into topologically associated domains (TAD). Here the authors characterise a TAD regulatory architecture underlying lineage-specific gene regulation, finding that stripe TADs are associated with poised and active chromatin landscapes and linked to the cells functional state.
- Christopher Barrington
- , Dimitra Georgopoulou
- & Suzana Hadjur
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Article
| Open AccessRif1 S-acylation mediates DNA double-strand break repair at the inner nuclear membrane
Rif1 is involved in different processes such as telomere homeostasis, DNA replication timing, and DNA double strand break (DSB) repair pathway choice. Here, the authors reveal that Rif1 S-acylation facilitates the accumulation of Rif1 at DSBs, attenuation of DNA end-resection, and DSB repair by non-homologous end-joining.
- Gabriele A. Fontana
- , Daniel Hess
- & Ulrich Rass
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Article
| Open AccessStructural basis for reversible amyloids of hnRNPA1 elucidates their role in stress granule assembly
Low complexity (LC) domains can drive the formation of both amyloid fibrils and protein droplets. Here, the authors identify reversible amyloid cores from the LC of hnRNPA1, based on which they elucidate the structural basis of reversible fibrillation and its interplay with hnRNPA1 droplet formation.
- Xinrui Gui
- , Feng Luo
- & Dan Li
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Article
| Open AccessNuclear membrane protein Lem2 regulates nuclear size through membrane flow
Nuclear size scales with cell size, but the underlying mechanisms are unclear. Here, the authors report in fission yeast that the inner nuclear membrane protein Lem2 and the ER membrane protein Lnp1 are barriers to membrane flow and propose that they maintain nuclear size in proportion to cell membrane content.
- Kazunori Kume
- , Helena Cantwell
- & Paul Nurse
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Article
| Open AccessThe maternal to zygotic transition regulates genome-wide heterochromatin establishment in the zebrafish embryo
Eukaryotic genomes are segregated into euchromatin and heterochromatin. Here the authors show that heterochromatin establishment during zebrafish embryo development is controlled by zygotic transcription of miR-430 and subsequent degradation of maternal transcripts encoding the chromatin remodeling protein Smarca2.
- Kathrin Laue
- , Srivarsha Rajshekar
- & Mary G. Goll
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Article
| Open AccessDynamics of genome reorganization during human cardiogenesis reveal an RBM20-dependent splicing factory
The spatial organization of the genome plays an important but unclearly defined role in gene regulation. Here, the authors integrate Hi-C, RNA-seq and ATAC-seq data to map cardiogenesis from pluripotent stem cells and describe an RBM20-dependent splicing factory assembling the TTN locus with other RBM20 targets.
- Alessandro Bertero
- , Paul A. Fields
- & Charles E. Murry
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Article
| Open AccessNuclear lamina integrity is required for proper spatial organization of chromatin in Drosophila
The role of the nuclear lamina (NL) in chromatin architecture is still poorly understood. Here, the authors provide evidence that disruption of the NL in Drosophila cells leads to overall chromatin compaction and repositioning from the nuclear envelope, whereas lamina-associated regions become less compacted and transcription within them is increased.
- Sergey V. Ulianov
- , Semen A. Doronin
- & Yuri Y. Shevelyov
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Article
| Open AccessA cell cycle-coordinated Polymerase II transcription compartment encompasses gene expression before global genome activation
Transcription is globally repressed in early stage of embryo development, but a set of genes including pri-miR-430 and zinc finger genes is known to escape the repression. Here the authors image the very first transcriptional activities in the living zebra fish embryo, demonstrating a cell cycle-coordinated polymerase II transcription compartment.
- Yavor Hadzhiev
- , Haseeb K. Qureshi
- & Ferenc Müller
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Article
| Open AccessCombined loss of LAP1B and LAP1C results in an early onset multisystemic nuclear envelopathy
Nuclear envelopathies are a group of diseases caused by genetic mutations in essential nuclear envelope genes. Here, the authors report a nuclear envelopathy with a homozygous nonsense variant in TOR1AIP1 which leads to changes in the nuclear morphology including large nuclear-spanning channels in patients’ fibroblasts.
- Boris Fichtman
- , Fadia Zagairy
- & Ronen Spiegel
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Article
| Open AccessNuclear lipid droplets derive from a lipoprotein precursor and regulate phosphatidylcholine synthesis
The origin and physiological significance of lipid droplets (LDs) in the nucleus is not clear. Here authors show that nucleoplasmic LDs in hepatocytes are derived from apolipoprotein B (ApoB)-free lumenal LDs and constitute a feedback mechanism to regulate PC synthesis in accordance with ER stress.
- Kamil Sołtysik
- , Yuki Ohsaki
- & Toyoshi Fujimoto
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Article
| Open AccessEfficient labeling and imaging of protein-coding genes in living cells using CRISPR-Tag
Difficulties in imaging non-repetitive genes impair our ability to explore their dynamics. Here the authors present CRISPR-Tag, which marks genes of interest with small repeat sequences to recruit dCas9-GFP.
- Baohui Chen
- , Wei Zou
- & Bo Huang
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Article
| Open AccessA tissue-specific self-interacting chromatin domain forms independently of enhancer-promoter interactions
Self-interacting chromatin domains encompass genes and their cis-regulatory elements. Here the authors use high-resolution chromosome conformation capture and super-resolution imaging to study a 70 kb domain that includes the mouse α-globin regulatory locus and find that a tissue-specific self-interacting chromatin domain forms independently of enhancer-promoter interactions.
- Jill M. Brown
- , Nigel A. Roberts
- & Veronica J. Buckle
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Article
| Open AccessLamin B1 mapping reveals the existence of dynamic and functional euchromatin lamin B1 domains
Lamina-associated domains (LADs) contact lamins in the nuclear lamina, and lamin B1 was thought to bind heterochromatic regions at the nuclear envelope. Here, the authors show lamin B1 associates with actively expressed euchromatin regions, creating dynamic euchromatin lamina-associated domains (eLADs) during epithelial-to-mesenchymal transition.
- Laura Pascual-Reguant
- , Enrique Blanco
- & Sandra Peiró
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Article
| Open AccessViral regulation of host cell biology by hijacking of the nucleolar DNA-damage response
Many RNA viruses that replicate in the cytoplasm express proteins that localize to nucleoli, but the nucleolar functions remain largely unknown. Here, the authors show that the Henipavirus matrix protein mimics an endogenous Treacle partner of the DNA-damage response, resulting in suppression of rRNA biogenesis.
- Stephen M. Rawlinson
- , Tianyue Zhao
- & Gregory W. Moseley
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Article
| Open AccessNuclear microtubule filaments mediate non-linear directional motion of chromatin and promote DNA repair
Following DNA damage, different processes come to action to aid repair. The authors here find that microtubule filaments within the cell nucleus capture and non-randomly mobilize damaged chromatin to mediate DNA repair.
- Roxanne Oshidari
- , Jonathan Strecker
- & Karim Mekhail
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Article
| Open AccessSTEF/TIAM2-mediated Rac1 activity at the nuclear envelope regulates the perinuclear actin cap
The perinuclear actin cap determines nuclear morphology but its regulation is currently poorly understood. Here, the authors find that an activator of the Rac1 GTPase, STEF/TIAM2, localises to the nuclear envelope and contributes to perinuclear actin and myosin tension, which in turn regulates the actin cap.
- Anna Woroniuk
- , Andrew Porter
- & Angeliki Malliri
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Article
| Open AccessChanges in genome organization of parasite-specific gene families during the Plasmodium transmission stages
The development of malaria parasites is controlled by coordinated changes in gene expression. Here, the authors show that the three-dimensional genome structure of human malaria parasites is strongly connected with transcriptional activity of specific gene families throughout the life cycles of Plasmodium falciparum and Plasmodium vivax parasites.
- Evelien M. Bunnik
- , Kate B. Cook
- & Karine G. Le Roch
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Article
| Open AccessA TAD boundary is preserved upon deletion of the CTCF-rich Firre locus
Although CTCF binding has been implicated in the formation of topologically associated domains (TADs) the mechanisms folding the genome into TADs are not fully understood. Here the authors investigate the TAD boundary on lncRNA locus Firre, which has ~ 15 CTCF binding sites, and its organization.
- A. Rasim Barutcu
- , Philipp G. Maass
- & John L. Rinn