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An adaptive biomolecular condensation response is conserved across environmentally divergent species
Cells must respond to environmental changes. In three fungal species adapted to different temperatures, cellular responses are conserved yet tuned to each organism’s thermal niche, including the formation of adaptive biomolecular condensates.
- Samantha Keyport Kik
- , Dana Christopher
- & D. Allan Drummond
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Regulation of meiotic telomere dynamics through membrane fluidity promoted by AdipoR2-ELOVL2
Meiosis is a specialized cell division for generating germ cells. The authors show that the lipid composition in the cellular membrane influences meiosis-specific chromosomal dynamics in mouse testis.
- Jingjing Zhang
- , Mario Ruiz
- & Hiroki Shibuya
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Article
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Protein thermal sensing regulates physiological amyloid aggregation
Cells form non-pathological amyloids to survive stressful conditions. Marijan et al. show that heat shock-induced aggregation is self-regulated by protein stability, with high-ordered motifs acting as thermo-switches that control amyloidogenesis.
- Dane Marijan
- , Evgenia A. Momchilova
- & Timothy E. Audas
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Nucleolar reorganization after cellular stress is orchestrated by SMN shuttling between nuclear compartments
DNA damage causes a major reorganization of the nucleolus. Here, the authors find that this structural restoration depends on the shuttling of the protein SMN from the Cajal bodies to the nucleolus, which requires coilin and PRMT1.
- Shaqraa Musawi
- , Lise-Marie Donnio
- & Giuseppina Giglia-Mari
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Chromatin organization drives the search mechanism of nuclear factors
Nuclear factors rapidly scan the genome for targets, but the role of nuclear organization in such search is uncharted. Here, by combining single molecule tracking of nuclear proteins with high resolution imaging of the nucleus, the authors investigate the search mechanism used by factors such as p53.
- Matteo Mazzocca
- , Alessia Loffreda
- & Davide Mazza
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SUN1/2 controls macrophage polarization via modulating nuclear size and stiffness
Stiffness and size of the nucleus may affect the function of specific cell types. Here the authors show that LPS treatment of macrophages affects the nucleus stiffness and size involving nuclear envelope proteins SUN1/2, chromatin accessibility and M1 associated gene expression.
- Shi Jiao
- , Chuanchuan Li
- & Zhaocai Zhou
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A CK2 and SUMO-dependent, PML NB-involved regulatory mechanism controlling BLM ubiquitination and G-quadruplex resolution
The Bloom syndrome helicase (BLM) unwinds a variety of complex DNA structures including G quadruplex. Here the authors report RNF111-ARKL1-dependent ubiquitination of BLM in PML NBs, which limits BLM protein levels and maintains G quadruplex abundance in the nucleus.
- Shichang Liu
- , Erin Atkinson
- & Bin Wang
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A R-loop sensing pathway mediates the relocation of transcribed genes to nuclear pore complexes
Here the authors report that DNA:RNA hybrid-containing R-loop structures are sensed by the ssDNA-binding protein RPA, triggering their relocation to nuclear pore complexes and attenuating transcription-associated genetic instability.
- Arianna Penzo
- , Marion Dubarry
- & Benoit Palancade
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Multi-feature clustering of CTCF binding creates robustness for loop extrusion blocking and Topologically Associating Domain boundaries
Most mammalian TAD boundaries, which separate functional chromosomal domains, bind the CTCF protein. Here, the authors identify multi-level clustering of CTCF binding sites at TAD boundaries and confirm their individual contribution to TAD formation.
- Li-Hsin Chang
- , Sourav Ghosh
- & Daan Noordermeer
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Cyclic AMP induces reversible EPAC1 condensates that regulate histone transcription
Spatial compartmentalization is central to nuclear function. Here, the authors demonstrate that EPAC1 can enter the nucleus and regulate the transcription of a histone cluster by forming biomolecular condensates in its proximity in response to cAMP.
- Liliana Felicia Iannucci
- , Anna Maria D’Erchia
- & Konstantinos Lefkimmiatis
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Pharmacological perturbation of the phase-separating protein SMNDC1
SMNDC1 is a splicing factor that binds arginine methylation with its Tudor domain. Here, the authors study the protein’s phase-separating behavior and develop small-molecule Tudor domain inhibitors that perturb SMNDC1 function.
- Lennart Enders
- , Marton Siklos
- & Stefan Kubicek
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Stepwise modifications of transcriptional hubs link pioneer factor activity to a burst of transcription
Eukaryotic transcription involves the formation of subnuclear hubs that enrich transcriptional machinery. Here the authors show that the hubs undergo stepwise modifications to fuel a burst of transcription rather than having a stable composition.
- Chun-Yi Cho
- & Patrick H. O’Farrell
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A model for organization and regulation of nuclear condensates by gene activity
Through a physics-based model framework, the authors propose a central role for the nonequilibrium processes underling gene activity in shaping morphology, dynamics, and regulation of diverse nuclear condensates.
- Halima H. Schede
- , Pradeep Natarajan
- & Krishna Shrinivas
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Engineered MED12 mutations drive leiomyoma-like transcriptional and metabolic programs by altering the 3D genome compartmentalization
There are currently a lack of genetic models to study the biology of Uterine fibroids (UFs) tumours. Here the authors precisely engineer cells with mutant MED12 Gly-44 and generate myometrial smooth muscle cells (SMCs) that recapitulate major UFs-like cellular, transcriptional, and metabolic alterations.
- Kadir Buyukcelebi
- , Xintong Chen
- & Mazhar Adli
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Nuclear lamina strain states revealed by intermolecular force biosensor
In this work, a nanobody based intermolecular strain sensor was used to follow the mechanical strain in the nuclear lamina. The results indicate that mechanical state of the nuclear lamina is not only affected by the cell contractility, but also chromatin packing.
- Brooke E. Danielsson
- , Bobin George Abraham
- & Teemu O. Ihalainen
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Chromatin alternates between A and B compartments at kilobase scale for subgenic organization
Ultra-deep mapping of genome organization uncovers precise nuclear compartments and diffuse CTCF loops. This work demonstrates that compartment domains segregate the 5′ and 3′ ends of genes and that CTCF loops create proximal structures.
- Hannah L. Harris
- , Huiya Gu
- & M. Jordan Rowley
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Autophagy receptor NDP52 alters DNA conformation to modulate RNA polymerase II transcription
An autophagy receptor, NDP52, is recruited to the nucleus where it can bind DNA. The authors show this promotes changes in chromatin accessibility which supports transcription initiation, providing a direct link between autophagy and transcription regulation.
- Ália dos Santos
- , Daniel E. Rollins
- & Christopher P. Toseland
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RNA-mediated demixing transition of low-density condensates
The cell interior is organized by diverse membrane-less condensates. Here, the authors reveal that the densities of certain condensates are surprisingly low, similar to the surrounding protoplasm and driven by cellular RNA as well as the crowded milieu.
- Taehyun Kim
- , Jaeyoon Yoo
- & Yongdae Shin
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Mena regulates nesprin-2 to control actin–nuclear lamina associations, trans-nuclear membrane signalling and gene expression
Cells transmit mechanical force to the nucleus via the cytoskeleton. Here, the authors reveal a role for the actin regulator Mena in force transmission at the nuclear envelope, where it regulates nuclear architecture, chromatin organization and gene expression.
- Frederic Li Mow Chee
- , Bruno Beernaert
- & Adam Byron
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PIP4K2B is mechanoresponsive and controls heterochromatin-driven nuclear softening through UHRF1
PIP4Ks are phosphoinositide kinases often dysregulated in cancer. Here Poli and colleagues find that PIP4K2B is downregulated on soft substrates, and its depletion leads to altered nuclear mechanical properties and defects in cell spreading and motility.
- Alessandro Poli
- , Fabrizio A. Pennacchio
- & Paolo Maiuri
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Orthodenticle homeobox 2 is transported to lysosomes by nuclear budding vesicles
Many homeodomain transcription factors are secreted and move to neighboring cells. Here, orthodenticle homeobox 2 is shown to be exported from the nucleus in a nuclear membrane, which buds off to then be degraded or secreted.
- Jun Woo Park
- , Eun Jung Lee
- & Jin Woo Kim
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Mapping nucleolus-associated chromatin interactions using nucleolus Hi-C reveals pattern of heterochromatin interactions
Here the authors developed a nucleolus Hi-C technique (nHi-C) for enriching nucleolus-associated interactions, and revealed specific heterochromatin interaction patterns within and around nucleoli in human cells at high resolution.
- Ting Peng
- , Yingping Hou
- & Cheng Li
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PQBP5/NOL10 maintains and anchors the nucleolus under physiological and osmotic stress conditions
The nucleolus is a liquid-liquid phase separation droplet that dynamically changes under stress. Here, the authors report PQBP5/NOL10 is a critical component of the nucleolus, maintaining its structure and position in the nucleus during osmotic stress.
- Xiaocen Jin
- , Hikari Tanaka
- & Hitoshi Okazawa
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The 3D enhancer network of the developing T cell genome is shaped by SATB1
Here the authors analyze the 3D genome structure of murine thymocytes and show that SATB1, a predominantly T-cell specific protein, helps to establish a regulatory, finer-scale organizational layer built upon a pre-existing chromatin scaffold mediated by other architectural proteins, such as CTCF.
- Tomas Zelenka
- , Antonios Klonizakis
- & Charalampos Spilianakis
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FRET-FISH probes chromatin compaction at individual genomic loci in single cells
Chromatin compaction affects many nuclear processes yet compaction levels at individual genomic loci have been notoriously difficult to assess. Here, Ana Mota and co-authors from the Bienko-Crosetto Lab present FRET-FISH for probing chromatin compaction at selected loci in single cells.
- Ana Mota
- , Szymon Berezicki
- & Magda Bienko
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Lamin A/C-dependent chromatin architecture safeguards naïve pluripotency to prevent aberrant cardiovascular cell fate and function
LMNA mutations cause severe heart dysfunction. Here the authors show that Lamin A/C plays a key role in 3D chromatin architecture in naïve pluripotent stem cells, which ensures proper cardiovascular cell fate and function, and shed light on the mechanisms involved in LMNA cardiomyopathies.
- Yinuo Wang
- , Adel Elsherbiny
- & Gergana Dobreva
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RG/RGG repeats in the C. elegans homologs of Nucleolin and GAR1 contribute to sub-nucleolar phase separation
Spaulding et al. survey RG/RGG repeats in C. elegans and identify the homologs of Nucleolin (NUCL-1) and GAR1 (GARR-1). RG/RGG repeats are dispensable for nucleolar accumulation but critical for sub-nucleolar phase separation.
- Emily L. Spaulding
- , Alexis M. Feidler
- & Dustin L. Updike
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Exploration of nuclear body-enhanced sumoylation reveals that PML represses 2-cell features of embryonic stem cells
Here the authors identify novel PML-partners and demonstrate that PML NBs control their sumoylation and that PML-controlled sumoylation of transcriptional regulators maintains the embryonic stem cell transcriptome and transposable element silencing.
- Sarah Tessier
- , Omar Ferhi
- & Valérie Lallemand-Breitenbach
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Isoform-specific and ubiquitination dependent recruitment of Tet1 to replicating heterochromatin modulates methylcytosine oxidation
A short isoform of the Tet1 enzyme (Tet1s) that oxidizes the DNA 5-methylcytosine (5mC) mark is overexpressed in tumors. Here the authors show Tet1s, but not full length Tet1, changes localization over the cell cycle upon ubiquitination and Uhrf1 interaction and is targeted to heterochromatin during S-phase. This leads to 5mC oxidation and loss of DNA methylation in heterochromatin.
- María Arroyo
- , Florian D. Hastert
- & M. Cristina Cardoso
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Cytoplasmic forces functionally reorganize nuclear condensates in oocytes
Cytoskeletal activity generates mechanical forces known to agitate and displace membrane-bound organelles in the cytoplasm. In oocytes, Al Jord et al. discover that these cytoplasmic forces functionally remodel nuclear RNA-processing condensates across scales for developmental success.
- Adel Al Jord
- , Gaëlle Letort
- & Marie-Hélène Verlhac
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Cohesin couples transcriptional bursting probabilities of inducible enhancers and promoters
Here the authors show inducible genes and enhancers are regulated mainly by transcriptional burst frequency and that this is coordinated in single cells and individual alleles. Cohesin, which is important for inducible gene expression, is largely dispensable for regulating enhancer burst frequencies; however, it is required for coupling burst frequencies of inducible enhancers and promoters.
- Irene Robles-Rebollo
- , Sergi Cuartero
- & Matthias Merkenschlager
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Extensive co-binding and rapid redistribution of NANOG and GATA6 during emergence of divergent lineages
The authors show that the transcription factors NANOG and GATA6 co-bind the same enhancers in common progenitors before divergent epiblast and primitive endoderm lineages emerge. This may help maintain plasticity at early stages and facilitate bifurcation into distinct lineages
- Joyce J. Thompson
- , Daniel J. Lee
- & Pedro P. Rocha
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Polycomb-lamina antagonism partitions heterochromatin at the nuclear periphery
Here the authors developed ‘Lamina-Inducible Methylation and Hi-C’ (LIMe-Hi-C) to simultaneously measure chromosome conformation, DNA methylation, and nuclear lamina positioning. Application of the method revealed dynamic changes upon PRC2 inhibition and an essential function of H3K27me3 in regulating sub-compartments and lamina association.
- Allison P. Siegenfeld
- , Shelby A. Roseman
- & Brian B. Liau
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Lsm7 phase-separated condensates trigger stress granule formation
Stress granules are non-membranous organelles connected to stress responses and age-related disease. Here, the authors identify a conserved yeast protein, Lsm7, that facilitates stress granule formation through dynamic liquid-liquid phase separation condensates upon 2-deoxy-D-glucose-induced stress.
- Michelle Lindström
- , Lihua Chen
- & Beidong Liu
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Anopheles mosquitoes reveal new principles of 3D genome organization in insects
Anopheles mosquitoes are vectors of human malaria, and better understanding of them has implications for public health. Here, the authors apply Hi-C, FISH, RNA-seq, and ChIP-seq techniques to comprehensively characterize chromatin architecture and its evolutionary dynamics in five Anopheles species.
- Varvara Lukyanchikova
- , Miroslav Nuriddinov
- & Veniamin Fishman
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CRISPR-mediated multiplexed live cell imaging of nonrepetitive genomic loci with one guide RNA per locus
Three-dimensional (3D) structures of the genome are dynamic, heterogeneous and functionally important. Here the authors present a CRISPR-based approach for labeling the genome at multiple nonrepetitive loci in living cells and to image chromatin loops in the presence and absence of cohesin.
- Patricia A. Clow
- , Menghan Du
- & Albert W. Cheng
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Article
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Genome-wide maps of nucleolus interactions reveal distinct layers of repressive chromatin domains
Mapping nucleolar-associated domains (NADs) is challenging as the nucleolus is membrane-less. Here the authors adapted the DNA adenine methyltransferase identification (DamID) method by engineering a “nucleolar histone” that can mark genomic contacts with the nucleolus through DNA methylation (m6A) and characterized NADs in mouse embryonic stem cells (ESCs) and derived neural progenitors (NPCs).
- Cristiana Bersaglieri
- , Jelena Kresoja-Rakic
- & Raffaella Santoro
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Myosin VI regulates the spatial organisation of mammalian transcription initiation
The actin-based molecular motors, myosins, have also been linked to transcription, but their precise role has remained elusive. Here the authors show RNA polymerase II (RNAPII) is lost from chromatin upon myosin perturbation and that myosin acts as a molecular anchor to maintain RNAPII spatial organisation.
- Yukti Hari-Gupta
- , Natalia Fili
- & Christopher P. Toseland
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Article
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Nuclear export of the pre-60S ribosomal subunit through single nuclear pores observed in real time
Ribosomal biogenesis is known to require nuclear to cytoplasmic export, but the precise kinetics remain unclear. Here, the authors use super-resolution confocal microscopy and single molecule tracking to visualize export of single pre-60S particles through nuclear pore complexes.
- Jan Andreas Ruland
- , Annika Marie Krüger
- & Ulrich Kubitscheck
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Nucleolar release of rDNA repeats for repair involves SUMO-mediated untethering by the Cdc48/p97 segregase
rDNA repeats residing in the nucleolus must be released to the nucleoplasm to allow repair by homologous recombination. Here the authors reveal insights into the molecular mechanism proposing that phosphorylation and SUMOylation of the rDNA-tethering complex facilitate the nucleolar release of damaged repeats to maintain genome integrity.
- Matías Capella
- , Imke K. Mandemaker
- & Sigurd Braun
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Subcellular localization of biomolecules and drug distribution by high-definition ion beam imaging
Multiplexed ion beam imaging can provide subcellular localisation information but with limited resolution. Here the authors report an ion beam imaging method with nanoscale resolution which they use to assess the subcellular distribution of cisplatin.
- Xavier Rovira-Clavé
- , Sizun Jiang
- & Garry P. Nolan
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Article
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VCP maintains nuclear size by regulating the DNA damage-associated MDC1–p53–autophagy axis in Drosophila
Cells maintain a constant cytoplasm to nucleus volume ratio, although the role of DNA damage is not well explored. Here, the authors use Drosophila to connect TER94, the fly homolog of VCP, to disruption of DNA damage repair, leading to ubiquitinated Mu2 protein accumulation and enlarged nuclei.
- Ya-Chu Chang
- , Yu-Xiang Peng
- & Tzu-Kang Sang
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M1BP cooperates with CP190 to activate transcription at TAD borders and promote chromatin insulator activity
Transcriptional state plays a role in genome organization, however factors that link these processes are not well known. Here, the authors show Drosophila transcription factor Motif 1-binding protein (M1BP) interacts with the insulator protein CP190 to promote insulator function and activate Motif 1-dependent transcription at topologically associating domain (TAD) borders.
- Indira Bag
- , Shue Chen
- & Elissa P. Lei
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Deep learning connects DNA traces to transcription to reveal predictive features beyond enhancer–promoter contact
Recent advances in super-resolution microscopy have made it possible to measure chromatin 3D structure and transcription in thousands of single cells. Here, authors present a deep learning-based approach to characterise how chromatin structure relates to transcriptional state of individual cells and determine which structural features of chromatin regulation are important for gene expression state.
- Aparna R. Rajpurkar
- , Leslie J. Mateo
- & Alistair N. Boettiger
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Article
| Open Access
Impact of DNA methylation on 3D genome structure
Multi-layered epigenetic regulation in higher eukaryotes makes it challenging to disentangle the individual effects of modifications on chromatin structure and function. Here, the authors expressed mammalian DNA methyltransferases in yeast, which have no DNA methylation, to show that methylation has intrinsic effects on chromatin structure.
- Diana Buitrago
- , Mireia Labrador
- & Modesto Orozco
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Nuclear organisation and replication timing are coupled through RIF1–PP1 interaction
How nuclear architecture overall affects the replication-timing programme is not yet clear. Here the authors reveal RIF1’s dual role as a chromatin-interaction scaffold and regulator of replication timing that allows the coordination of these two aspects of nuclear function.
- Stefano Gnan
- , Ilya M. Flyamer
- & Sara C. B. Buonomo
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Apico-basal cell compression regulates Lamin A/C levels in epithelial tissues
The nuclear lamina bridges mechanical forces from the cytoskeleton to the nucleus, and while Lamin A/C is known to be crucial for this process, its regulation remains unclear. Here the authors show that levels of Lamin A/C scale with apico-basal compression of cells independently of tissue stiffness using Drosophila epithelial tissues and mammalian cells.
- K. Venkatesan Iyer
- , Anna Taubenberger
- & Frank Jülicher
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Nanoscopic subcellular imaging enabled by ion beam tomography
Secondary ion beam mass spectrometry (SIMS) is a method to obtain a chemical snapshot of biological tissue, but the spatial resolution is low. Here, the authors develop a computational and technology pipeline to localise a chemical signal in SIMS in 3D and sub-25 nm accuracy, called Ion Beam Tomography
- Ahmet F. Coskun
- , Guojun Han
- & Garry P. Nolan
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The nuclear envelope protein Net39 is essential for muscle nuclear integrity and chromatin organization
The nuclear envelope tethers chromatin to the nuclear periphery to control genome architecture. Here, the authors show that Net39 preserves the integrity and gene expression of muscle nuclei in mice, and it may contribute to the pathogenesis of Emery–Dreifuss muscular dystrophy.
- Andres Ramirez-Martinez
- , Yichi Zhang
- & Eric N. Olson
Dynamics of DNA damage-induced nuclear inclusions are regulated by SUMOylation of Btn2