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Granulocyte macrophage colony-stimulating factor is required for aortic dissection/intramural haematoma
Aortic dissection and intramural haematoma are caused by separation of the aortic wall via an unknown mechanism. Here the authors show that the inflammatory cytokine, granulocyte macrophage colony-stimulating factor, is a central regulatory molecule causative of these conditions in mice and humans.
- Bo-Kyung Son
- , Daigo Sawaki
- & Toru Suzuki
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In vivo model with targeted cAMP biosensor reveals changes in receptor–microdomain communication in cardiac disease
cAMP is a second messenger that acts in distinct intracellular locations regulating diverse cellular functions. Here the authors design a FRET-based cAMP biosensor and use it to measure in vivodynamics of cAMP concentration changes in the sarcoplasmatic reticulum of mouse cardiomyocytes in health and disease.
- Julia U. Sprenger
- , Ruwan K. Perera
- & Viacheslav O. Nikolaev
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Heparanase is a host enzyme required for herpes simplex virus-1 release from cells
Herpesviruses bind to heparan sulphate (HS) on the surface of cells before infecting them. Here, the authors show that heparanase, a host enzyme that degrades HS and is upregulated on viral infection, is required for the release of newly formed viruses from infected cells.
- Satvik R. Hadigal
- , Alex M. Agelidis
- & Deepak Shukla
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Article
| Open AccessReal-time submillisecond single-molecule FRET dynamics of freely diffusing molecules with liposome tethering
Single-molecule fluorescence resonance energy transfer is widely used to probe biomolecular dynamics, but is limited by its temporal resolution. Here, Kim et al. push the limit to submillisecond for the duration of tens of milliseconds by tethering target molecules to liposomes in buffer solutions.
- Jae-Yeol Kim
- , Cheolhee Kim
- & Nam Ki Lee
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Article
| Open AccessNkx2.1-derived astrocytes and neurons together with Slit2 are indispensable for anterior commissure formation
Guidepost cells provide guidance cues that orient growing axons in the brain but little is known about the midline guidepost cells that populate the mouse anterior commissure (AC). Here, the authors show that the transcription factor Nkx2.1 regulates the differentiation of astroglia and neurons that cooperate to guide AC axons through the expression of Slit2.
- Shilpi Minocha
- , Delphine Valloton
- & Cécile Lebrand
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Regulation of endogenous transmembrane receptors through optogenetic Cry2 clustering
Signaling through transmembrane receptors regulates diverse biological processes including cell proliferation, motility and differentiation. Here, the authors demonstrate the optogenetic control of endogenous transmembrane receptor activity through clustering using a new modular strategy.
- L. J. Bugaj
- , D. P. Spelke
- & D. V. Schaffer
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Article
| Open AccessStructural basis for the targeting of complement anaphylatoxin C5a using a mixed L-RNA/L-DNA aptamer
Spiegelmers are mirror-image oligonucleotide aptamers designed for therapeutic use. Here the authors describe the crystal structure of the mixed L-RNA/L-DNA Spiegelmer NOX-D20 bound to complement component C5a, a key mediator of the innate immune response and clinical target in acute and chronic inflammatory disorders.
- Laure Yatime
- , Christian Maasch
- & Axel Vater
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Article
| Open AccessOsmosensing and scaffolding functions of the oligomeric four-transmembrane domain osmosensor Sho1
The yeast high osmolarity glycerol pathway activates the Hog1 MAP kinase via two branches, SLN1 and SHO, but the identity of the osmosensor has only been shown for the SLN1 branch. Here the authors demonstrate that the four-TM domain protein Sho1 functions as both an osmosensor and adaptor protein necessary for Hog1 activation.
- Kazuo Tatebayashi
- , Katsuyoshi Yamamoto
- & Haruo Saito
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Article
| Open AccessDynamic caveolae exclude bulk membrane proteins and are required for sorting of excess glycosphingolipids
Recent data question the long-assumed link between caveolae and endocytosis of membrane proteins. Shvets et al. use genome editing to tag and trace endogenous caveolar proteins, providing evidence that these structures exclude membrane proteins and are instead required for proper sorting of excess membrane lipids.
- Elena Shvets
- , Vassilis Bitsikas
- & Benjamin J. Nichols
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Article
| Open AccessTonic endocannabinoid-mediated modulation of GABA release is independent of the CB1 content of axon terminals
A simple model for receptor number–function relationships dictates a positive correlation between receptor content and ligand effect. Here, the authors demonstrate that the degree of type-1 cannabinoid receptor (CB1)-modulated GABA release cannot be predicted from CB1content of axon terminals.
- Nora Lenkey
- , Tekla Kirizs
- & Zoltan Nusser
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Article
| Open AccessRadixin regulates synaptic GABAA receptor density and is essential for reversal learning and short-term memory
Lateral diffusion of receptors between synaptic and extrasynaptic sites is known to mediate plasticity. Hausrat et al. show that diffusion of α5-containing GABAAreceptors is controlled by phosphorylation of the extrasynaptic anchoring protein Radixin, and reveal a role for Radixin in learning and memory.
- Torben J. Hausrat
- , Mary Muhia
- & Matthias Kneussel
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Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex
Tuberous sclerosis complex (TSC) arises from mutations in an activator of the small GTPase Rheb. Here the authors show that syntenin binds to GDP-bound Rheb, and loss of this interaction in TSC leads to increased syntenin expression and downstream signalling defects leading to aberrant spine synapse morphogenesis.
- Hiroko Sugiura
- , Shin Yasuda
- & Kanato Yamagata
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High-throughput and quantitative assessment of enhancer activity in mammals by CapStarr-seq
Characterizing mammalian gene expression regulation by enhancer elements is complicated by the size and complexity of the genome. Here Vanhille et al.demonstrate CapStarr-Seq, a novel high-throughput method for assessing potential enhancers and deciphering the mechanisms regulating transcription
- Laurent Vanhille
- , Aurélien Griffon
- & Salvatore Spicuglia
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Article
| Open AccessLRH-1 mediates anti-inflammatory and antifungal phenotype of IL-13-activated macrophages through the PPARγ ligand synthesis
Macrophages activate gene expression of alternative activation program in response to IL-13. Here the authors show that Liver Receptor Homologue-1 regulates synthesis of lipid metabolites stimulating antifungal and repressing proinflammatory genes in macrophages exposed to IL-13 through PPAR activation.
- Lise Lefèvre
- , Hélène Authier
- & Agnès Coste
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Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3
The chemical honokiol is found in the bark of magnolia trees, which are used for traditional medicine in Asian countries. Here, Pillai et al, show honokiol protects the heart from hypertrophic remodelling in mice, and even reverses established cardiac hypertrophy, by activating the deacetylase Sirt3.
- Vinodkumar B. Pillai
- , Sadhana Samant
- & Mahesh P. Gupta
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Article
| Open AccessFoxp1-mediated programming of limb-innervating motor neurons from mouse and human embryonic stem cells
The differentiation of spinal motor neurons (MNs) from mouse and human embryonic stem cells provides opportunities to model MN development and disease, but most protocols produce only a subset of the MN subtypes found in vivo. Here the authors show that limb projecting lateral motor column MNs can be efficiently generated though the expression of Foxp1.
- Katrina L. Adams
- , David L. Rousso
- & Bennett G. Novitch
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Article
| Open AccessAnalgesia and unwanted benzodiazepine effects in point-mutated mice expressing only one benzodiazepine-sensitive GABAA receptor subtype
Benzodiazepines (BDZs) target GABAA receptors to alleviate pain but these also cause side effects. Here the authors use mice in which only one GABAA receptor is BDZ-sensitive at a time to identify α2GABAAas the receptor that provides maximal analgesic activity but minimal side-effects in response to BDZs.
- William T. Ralvenius
- , Dietmar Benke
- & Hanns Ulrich Zeilhofer
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Article
| Open AccessCDK1 structures reveal conserved and unique features of the essential cell cycle CDK
Cyclin-dependent kinases are the principal drivers of cell cycle progression. Here the authors present several crystal structures of Cdk1 in complex with cyclin B and/or the assembly factors Cks1/2 and a small molecule inhibitor to reveal key features of this essential mitotic kinase.
- Nicholas R. Brown
- , Svitlana Korolchuk
- & Jane A. Endicott
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Article
| Open AccessPontin functions as an essential coactivator for Oct4-dependent lincRNA expression in mouse embryonic stem cells
Long non-coding RNAs or lincRNAs identified in embryonic stem (ES) cells have been shown to regulate ES cell states; however, how these lincRNAs are regulated remains unclear. Here the authors show that the transcriptional coactivator Pontin regulates the expression of lincRNAs involved in ES cell maintenance in an Oct4-dependent manner.
- Kyungjin Boo
- , Jinhyuk Bhin
- & Sung Hee Baek
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Article
| Open AccessRegulation of autophagy and the ubiquitin–proteasome system by the FoxO transcriptional network during muscle atrophy
FoxO transcription factors promote muscle atrophy in response to stresses such as low nutrient availability. By generating muscle-specific FoxO triple-knockout mice, Milan et al.identify mechanisms by which the FoxO transcriptional network coordinates autophagic and proteasomal protein degradation.
- Giulia Milan
- , Vanina Romanello
- & Marco Sandri
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Article
| Open AccessMaking water-soluble integral membrane proteins in vivo using an amphipathic protein fusion strategy
The study of integral membrane proteins (IMPs) is hampered by yields and the difficulty in retaining activity once they have been solubilized. Here Mizrachi et al. develop a strategy for in vivoexpression and solubilization of IMPs in functionally relevant states by fusing them to truncated apolipoprotein A-I.
- Dario Mizrachi
- , Yujie Chen
- & Matthew P. DeLisa
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Article
| Open AccessHsp90 regulates the dynamics of its cochaperone Sti1 and the transfer of Hsp70 between modules
The chaperones Hsp70 and Hsp90 are physically linked via the cochaperone Sti1/Hop, that has two binding sites for Hsp70. Here, Röhl et al.show that binding of Hsp90 changes the conformation of Sti1/Hop and determines to which site Hsp70 binds, perhaps facilitating transfer of client proteins from Hsp70 to Hsp90.
- Alina Röhl
- , Daniela Wengler
- & Johannes Buchner
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Article
| Open AccessSystematic functional profiling of transcription factor networks in Cryptococcus neoformans
Cryptococcus neoformans is a fungal pathogen that causes meningoencephalitis. Here the authors describe the production of a gene-deletion mutant collection representing most C. neoformansnon-essential transcription factors, providing insight into the signalling networks that govern the biology and pathogenicity of this fungus.
- Kwang-Woo Jung
- , Dong-Hoon Yang
- & Yong-Sun Bahn
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Article
| Open AccessQuantitative analysis of the TNF-α-induced phosphoproteome reveals AEG-1/MTDH/LYRIC as an IKKβ substrate
Inflammatory cytokines such as TNF-α influence inflammation, apoptosis and tumour development through regulation of the kinase IKKβ. Krishnan and Nolte et al.apply quantitative proteomics to identify potential IKKβ targets, and reveal phosphorylation of AEG-1 by IKKβ as a mechanism controlling NF-κB signalling.
- Ramesh K. Krishnan
- , Hendrik Nolte
- & Jakub M. Swiercz
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Article |
The Parkinson’s-associated protein DJ-1 regulates the 20S proteasome
Mutations in the gene encoding DJ-1 are associated with early-onset familial forms of Parkinson’s disease, and several different molecular functions have been attributed to this protein. Moscovitz et al.show that DJ-1 physically binds the 20S proteasome and inhibits its degradation activity.
- Oren Moscovitz
- , Gili Ben-Nissan
- & Michal Sharon
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Sox2 antagonizes the Hippo pathway to maintain stemness in cancer cells
Transcriptional regulators Sox2 and YAP maintain expression of stemness genes in normal and cancerous cells. Here the authors show that, in osteosarcomas, Sox2 activates YAP by directly repressing transcription of its upstream negative regulators Nf2 and WWC1, promoting cancer cell stemness.
- Upal Basu-Roy
- , N. Sumru Bayin
- & Claudio Basilico
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Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome
Dietary fibre is metabolized into short-chain fatty acids by gut bacteria. Here the authors show that these metabolites activate the NLRP3 inflammasome in gut epithelial cells and protect mice from injury-induced colitis, suggesting a mechanism for the benefits of a high-fibre diet.
- Laurence Macia
- , Jian Tan
- & Charles R. Mackay
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The nuclear translocation of ERK1/2 as an anticancer target
The extracellular signal-regulated kinase 1/2 (ERK1/2) cascade is involved in the induction and maintenance of cancers. Here the authors design an ERK-derived peptide that blocks ERK nuclear import, thus proposing a novel approach to treat tumours with mutational activation of the ERK pathway.
- Alexander Plotnikov
- , Karen Flores
- & Rony Seger
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EphrinB2 controls vessel pruning through STAT1-JNK3 signalling
Pruning of newly formed blood vessels is an important and yet poorly understood aspect of angiogenesis. Here the authors show that endothelial phosphotyrosine-dependent EphrinB2 signalling represses JNK3 function via STAT1, and identify JNK3 as an effector of endothelial cell death and vessel pruning in mice.
- Ombretta Salvucci
- , Hidetaka Ohnuki
- & Giovanna Tosato
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The transcription factor Foxc1 is necessary for Ihh–Gli2-regulated endochondral ossification
Skeletal development relies on endochondral ossification. Here the authors show that transcription factors Foxc1 and Gli2 interact to modulate expression of Ihh target genes that control endochondral ossification, and that disruption of this interaction partly underlies skeletal disorders in the Axenfeld–Rieger syndrome.
- Michiko Yoshida
- , Kenji Hata
- & Toshiyuki Yoneda
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Article
| Open AccessMitochondrial protein import receptors in Kinetoplastids reveal convergent evolution over large phylogenetic distances
Protein translocation into the mitochondrion is a conserved process in all eukaryotes. Here, Mani et al. describe a non-conventional translocase complex in Trypanosoma bruceiand propose that protein import receptors were recruited to the core complex after the divergence of the major eukaryotic supergroups.
- Jan Mani
- , Silvia Desy
- & André Schneider
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Transformation of the intestinal epithelium by the MSI2 RNA-binding protein
In mammals there are two Musashi proteins, MSI1 and MSI2, orthologues of the Drosophila protein, with roles in asymmetric stem cell division and cell fate determination. Here the authors report new functions for MSI2 in colorectal cancer using in vitro loss of function and in vivoectopic overexpression.
- Shan Wang
- , Ning Li
- & Christopher J. Lengner
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Vimentin regulates activation of the NLRP3 inflammasome
The mechanism of NLRP3 activation remains incompletely characterized. Here the authors show that it is dependent on vimentin, and that NLRP3-mediated lung injury and fibrosis induced by endotoxin, asbestos or bleomycin are reduced in vimentin-deficient mice.
- Gimena dos Santos
- , Micah R. Rogel
- & Karen M. Ridge
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Article
| Open AccessArtificial human Met agonists based on macrocycle scaffolds
Activation of the Met receptor by hepatocyte growth factor requires Met receptor dimerization. Here, the authors identify Met-binding peptide macrocycles that, in a dimeric form as a result of chemical crosslinking, induce Met receptor dimerization and activation in cultured human cells.
- Kenichiro Ito
- , Katsuya Sakai
- & Hiroaki Suga
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Integrin β1 controls VE-cadherin localization and blood vessel stability
The role of integrin β1 in angiogenesis is poorly understood. Here, the authors show that integrin β1 regulates murine angiogenesis and adherens junction integrity by controlling VE-cadherin localization, myosin light chain phosphorylation and the function of the Rap1/MRCK and Rho/Rho-kinase pathways.
- Hiroyuki Yamamoto
- , Manuel Ehling
- & Ralf H. Adams
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Article
| Open AccessTriggering HIV polyprotein processing by light using rapid photodegradation of a tight-binding protease inhibitor
The study of HIV proteolysis during maturation and replication can be difficult since different steps in these processes occur simultaneously. Here, the authors present a photolabile HIV protease inhibitor which can be deactivated by light irradiation, allowing synchronized induction of viral maturation.
- Jiří Schimer
- , Marcela Pávová
- & Jan Konvalinka
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Article
| Open AccessChromatin organization at the nuclear pore favours HIV replication
Retroviruses such as HIV integrate into the host genome as an essential step prior to their replication. Here Lelek et al. identify nuclear pore complex proteins that are essential for HIV nuclear import and productive integration, and show that the intranuclear protein Tpr influences integration into transcriptionally active chromatin.
- Mickaël Lelek
- , Nicoletta Casartelli
- & Francesca Di Nunzio
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Article |
Cerebrospinal fluid-derived Semaphorin3B orients neuroepithelial cell divisions in the apicobasal axis
The spatial orientation of cell divisions is fundamental for tissue architecture and homeostasis but the extracellular cues regulating this process are largely unknown. Here, the authors show that Semaphorin3B released from the floor plate and the nascent choroid plexus controls progenitor division orientation in the developing mouse spinal cord.
- Elise Arbeille
- , Florie Reynaud
- & Valérie Castellani
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Article |
Pre-B cell receptor binding to galectin-1 modifies galectin-1/carbohydrate affinity to modulate specific galectin-1/glycan lattice interactions
Galectin-1 (GAL1) is a secreted protein that binds to glycans and to the pre-B-cell receptor (pre-BCR). Here Bonzi et al. show that pre-BCR binding to GAL1 causes a conformational change in the GAL1 carbohydrate-binding site to inhibit binding to selected glycans.
- Jeremy Bonzi
- , Olivier Bornet
- & Latifa Elantak
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Article |
Developmental enhancers revealed by extensive DNA methylome maps of zebrafish early embryos
DNA methylation undergoes dynamic changes during development and cell differentiation. Here, by comparing DNA methylomes from different stages of embryonic development of the zebrafish, the authors suggest that developmental enhancers are a major target of DNA methylation changes during embryogenesis.
- Hyung Joo Lee
- , Rebecca F. Lowdon
- & Ting Wang
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Article
| Open AccessA highly potent human antibody neutralizes dengue virus serotype 3 by binding across three surface proteins
There is no licensed vaccine or therapeutic for dengue virus (DENV) infection. Here, the authors show that a highly potent human monoclonal antibody binds to DENV particles in an unusual and very effective way by interacting with three viral envelope proteins.
- Guntur Fibriansah
- , Joanne L. Tan
- & Shee-Mei Lok
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Article
| Open AccessRoquin binds microRNA-146a and Argonaute2 to regulate microRNA homeostasis
Roquin is an RNA-binding protein that promotes the degradation of specific mRNAs and is crucial for the maintenance of peripheral immune tolerance. Here the authors show that, in addition to its target mRNAs, Roquin can bind miR-146a and the RISC component Ago2 to control homeostasis of both RNA species.
- Monika Srivastava
- , Guowen Duan
- & Carola G. Vinuesa
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Article
| Open AccessDeltex1 antagonizes HIF-1α and sustains the stability of regulatory T cells in vivo
Foxp3, a key transcription factor of regulatory T cells, is targeted to degradation by HIF-1α. Here the authors show that Deltex1 promotes degradation of HIF-1α, thus stabilizing Foxp3 levels and function of regulatory T cells in vivo.
- Huey-Wen Hsiao
- , Tzu-Sheng Hsu
- & Ming-Zong Lai
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Article
| Open AccessA balance between membrane elasticity and polymerization energy sets the shape of spherical clathrin coats
A relationship between membrane tension and clathrin polymerization during endocytosis has not been experimentally established. Here, the authors show using an in vitroreconstituted system and theoretical modelling that membrane tension regulates clathrin polymerization into spherical cages by varying the membrane budding energy.
- Mohammed Saleem
- , Sandrine Morlot
- & Aurélien Roux
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Mutation within the hinge region of the transcription factor Nr2f2 attenuates salt-sensitive hypertension
Transcription factor Nr2f2 is linked to high blood pressure in humans and animals. Using hypertensive rats that have been genetically modified to express a mutant Nr2f2 that binds stronger to transcription factor Fog2, the authors show that the interaction between these two proteins is critical for blood pressure regulation.
- Sivarajan Kumarasamy
- , Harshal Waghulde
- & Bina Joe
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Article |
Histone demethylase KDM5A is regulated by its reader domain through a positive-feedback mechanism
Histone lysine methylation plays crucial roles in controlling gene expression. Here the authors demonstrate that the activity of the histone lysine demethylase KDM5A is regulated through a feedback mechanism involving communication between the histone tail-binding and catalytic domains.
- Idelisse Ortiz Torres
- , Kristopher M. Kuchenbecker
- & Danica Galonić Fujimori
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Article |
The transcriptional regulator BBX24 impairs DELLA activity to promote shade avoidance in Arabidopsis thaliana
Plants respond to shade by elongating their stems to grow toward the light. Here, Crocco et al. show that the BBX24 transcriptional regulator promotes the shade avoidance response by activating gibberellin signalling and the PIF4 transcription factor under low light conditions.
- Carlos D. Crocco
- , Antonella Locascio
- & Javier F. Botto
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ZNF143 provides sequence specificity to secure chromatin interactions at gene promoters
Chromatin interactions can connect distal regulatory elements to promoters via protein factors, but few such factors have been identified. Here, the authors show that zinc-finger protein ZNF143 is a sequence-specific chromatin-looping factor that connects promoters with distal regulatory elements.
- Swneke D. Bailey
- , Xiaoyang Zhang
- & Mathieu Lupien
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Complete architecture of the archaeal RNA polymerase open complex from single-molecule FRET and NPS
The archaeal RNA transcription machinery does not have a dedicated helicase factor. Here, the authors report the three-dimensional architecture of the open complex of DNA, RNA polymerase and its associated factors from M. jannaschii, providing a possible mechanism for promoter DNA melting.
- Julia Nagy
- , Dina Grohmann
- & Jens Michaelis
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