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| Open AccessC/EBPβ enhances platinum resistance of ovarian cancer cells by reprogramming H3K79 methylation
In ovarian cancer, the mechanism of chemoresistance is a key question. Here, the authors demonstrate that C/EBPβ and DOT1L together increase methylation of H3K79, which upregulates expression of oncogenic genes and drives poor platinum response and poor survival in ovarian cancer.
- Dan Liu
- , Xiao-Xue Zhang
- & Qing-Lei Gao
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Article
| Open AccessPlasma cell differentiation is controlled by multiple cell division-coupled epigenetic programs
During B cell differentiation, the role of different genomic loci in transcriptional and epigenetic regulation in vivo is not well defined. Here the authors use an in vivo B cell differentiation model to map cellular division-dependent cis-regulatory element road map with ATAC-seq.
- Christopher D. Scharer
- , Benjamin G. Barwick
- & Jeremy M. Boss
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Article
| Open AccessA somatic role for the histone methyltransferase Setdb1 in endogenous retrovirus silencing
Previous studies suggest that DNA methylation is the main mechanism to silence endogenous retroviruses (ERVs) in somatic cells. Here the authors provide evidence that distinctive sets of ERVs are silenced by Setdb1 in different types of somatic cells, suggesting a general function in ERV silencing.
- Masaki Kato
- , Keiko Takemoto
- & Yoichi Shinkai
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Article
| Open AccessStructural analysis of human ARS2 as a platform for co-transcriptional RNA sorting
Arsenic resistance protein 2 (ARS2) plays an important role in nuclear RNA metabolism and interacts with the nuclear cap-binding complex (CBC). Here the authors present the human ARS2 structure and identify regions important for its interactions with binding partners supporting that mutually exclusive higher order CBC-ARS2 complexes are formed.
- Wiebke Manuela Schulze
- , Frank Stein
- & Stephen Cusack
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Article
| Open AccessTAK1 activation of alpha-TAT1 and microtubule hyperacetylation control AKT signaling and cell growth
Acetylation of microtubules (MT) confers mechanical stability necessary for numerous cellular functions but its regulation is unclear. Here the authors show that the MT acetyltransferase αTAT1 is regulated by TGF-β-activated kinase 1 implicating TGF-β signaling in MT-related functions and disease.
- Nirav Shah
- , Sanjay Kumar
- & Nam Y. Lee
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Article
| Open AccessBcl11b is essential for licensing Th2 differentiation during helminth infection and allergic asthma
Th2 cells are critical in the resolution of helminth infection and allergy. Here the authors show that Bcl11b is required to license the Th2 program of helper T cell differentiation and restrict alternate lineage gene expression using in vivo models of helminth infection and asthma.
- Kyle J. Lorentsen
- , Jonathan J. Cho
- & Dorina Avram
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Article
| Open AccessRNA-guided transcriptional silencing in vivo with S. aureus CRISPR-Cas9 repressors
Repression of gene transcription using CRISPR-Cas9 has been achieved in vitro but not for delivery into adult animal models. Here, the authors use AAV8 to deliver the transcriptional repressor dSaCas9KRAB to the cholesterol regulator Pcsk9, and show repression up to 24 weeks and reduced cholesterol levels in mice.
- Pratiksha I. Thakore
- , Jennifer B. Kwon
- & Charles A. Gersbach
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Article
| Open AccessCharacterization of the enhancer and promoter landscape of inflammatory bowel disease from human colon biopsies
Many SNPs associated with inflammatory bowel disease are located in non-coding genomic regions. Here, the authors perform CAGE-sequencing on descending colon biopsies of Crohn’s disease and ulcerative colitis patients to map transcription start sites and enhancer activity for analysis of regulatory regions.
- Mette Boyd
- , Malte Thodberg
- & Albin Sandelin
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Article
| Open AccessA SUMO-dependent feedback loop senses and controls the biogenesis of nuclear pore subunits
The nuclear pore complex is crucial for mediating nucleocytoplasmic exchanges. Here the authors use budding yeast to reveal a mechanism responsible of maintaining nucleoporin homeostasis by sensing changes in the complex integrity and further altering the metabolism of the corresponding mRNAs.
- Jérôme O. Rouvière
- , Manuel Bulfoni
- & Benoit Palancade
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Article
| Open AccessLong ncRNA A-ROD activates its target gene DKK1 at its release from chromatin
The functional role of dissociation of long ncRNAs from chromatin is poorly understood. Here, the authors provide evidence that release of the long ncRNA AROD from chromatin enhances DKK1 transcription, and suggest that this regulatory mechanism of transcription applies to a subset of long ncRNAs.
- Evgenia Ntini
- , Annita Louloupi
- & Ulf Andersson Vang Ørom
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Article
| Open AccessMethylated DNMT1 and E2F1 are targeted for proteolysis by L3MBTL3 and CRL4DCAF5 ubiquitin ligase
Lysine methylation is increasingly being implicated in the modification of non-histone proteins. Here the authors find that the methylation of DNMT1 and E2F1 are recognized by the protein L3MBTL3 and the ubiquitin E3 ligase CRL4DCAF5, which cooperatively target these methylated proteins for ubiquitin-dependent proteolysis.
- Feng Leng
- , Jiekai Yu
- & Hui Zhang
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Article
| Open AccessChromatin conformation regulates the coordination between DNA replication and transcription
The maintenance of chromatin integrity during replication is critical for cell viability. Here the authors study how dividing cells respond to alterations in chromatin structure and find that these elicit a range of responses in the dynamics of DNA replication and consequences on replicative stress.
- Ricardo Almeida
- , José Miguel Fernández-Justel
- & María Gómez
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Article
| Open AccessSelf-replication of DNA by its encoded proteins in liposome-based synthetic cells
Replicating DNA and converting genetic information to protein is a feature of cellular life. Here the authors implement a coupled DNA replication and gene expression system inside vesicles.
- Pauline van Nies
- , Ilja Westerlaken
- & Christophe Danelon
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Article
| Open AccessA proteomics landscape of circadian clock in mouse liver
As a circadian organ, liver functions are regulated by circadian clock. Here, the authors present a comprehensive proteomics landscape of the mouse liver, including transcription factor binding profiles, phosphorylation and ubiquitylation patterns, nuclear and whole proteome, and the transcriptome.
- Yunzhi Wang
- , Lei Song
- & Chen Ding
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Article
| Open AccessGlobal H3.3 dynamic deposition defines its bimodal role in cell fate transition
Histone variant H3.3 is incorporated at transcriptionally active genes and is associated with active marks. Here, the authors investigate H3.3 deposition during reprogramming and find that initially H3.3 helps maintain parental cell fate and is later required for establishment of the cell lineages.
- Hai-Tong Fang
- , Chadi A. EL Farran
- & Yuin-Han Loh
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Article
| Open AccessHistone H2AX deficiency causes neurobehavioral deficits and impaired redox homeostasis
H2AX is a histone variant with an essential function in DNA double-strand break repair and genome stability. Here, Weyemi and colleagues show that loss of neuronal H2AX leads to locomotor dysfunction and alteration in oxidative stress response.
- Urbain Weyemi
- , Bindu D. Paul
- & Solomon H. Snyder
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Article
| Open AccessTERRA recruitment of polycomb to telomeres is essential for histone trymethylation marks at telomeric heterochromatin
Long non-coding RNA TERRAs are essential for telomere protection and telomere length maintenance. Here the authors report a role for TERRAs in telomeric heterochromatin formation by recruiting Polycomb Repressive Complex 2 to telomeres.
- Juan J. Montero
- , Isabel López-Silanes
- & Maria A. Blasco
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Article
| Open AccessViral proteins as a potential driver of histone depletion in dinoflagellates
Dinoflagellates are known to use dinoflagellate-viral-nucleoproteins (DVNPs) in place of histones, yet this evolutionary transition is not well understood. Here, Irwin et al. use yeast expressing DVNP to show that DVNP displaces histones and that histone reduction allows cells to cope with DVNP.
- Nicholas A. T. Irwin
- , Benjamin J. E. Martin
- & LeAnn J. Howe
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Article
| Open AccessGenome-wide excision repair in Arabidopsis is coupled to transcription and reflects circadian gene expression patterns
Plants use nucleotide excision repair to maintain genome integrity in response to damage caused by stresses such as UV radiation. Here Oztas et al. use genome-wide profiling to show that excision repair in Arabidopsis is strongly coupled to transcription and reflects circadian patterns of gene expression.
- Onur Oztas
- , Christopher P. Selby
- & Ogun Adebali
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Article
| Open AccessHOXA9 inhibits HIF-1α-mediated glycolysis through interacting with CRIP2 to repress cutaneous squamous cell carcinoma development
Hypoxia-inducible transcription factor HIF-1α promotes glycolysis allowing cell survival under stress. Here the authors show, using both cell lines and animal models, that in cutaneous squamous cell carcinoma HOXA9 acts as a tumor suppressor and inhibits glycolysis by associating with CRIP2 to repress HIF-1α binding to target genes.
- Liang Zhou
- , Yinghui Wang
- & Zhenhua Ding
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Article
| Open AccessPausing controls branching between productive and non-productive pathways during initial transcription in bacteria
RNA synthesis by bacterial RNA polymerase is interrupted by pauses but their role in RNA synthesis is poorly understood. Here the authors use single-molecule FRET and biochemical analysis to show that pausing regulates branching between the abortive and productive outcomes of initial transcription.
- David Dulin
- , David L. V. Bauer
- & Achillefs N. Kapanidis
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Article
| Open AccessA switch point in the molecular chaperone Hsp90 responding to client interaction
The heat shock protein 90 (Hsp90) chaperone undergoes large conformational changes during its functional cycle. Here the authors combine in vivo, biochemical, biophysical and computational approaches and provide insights into the allosteric regulation of Hsp90 by identifying and characterizing a switch point in the Hsp90 middle domain.
- Daniel Andreas Rutz
- , Qi Luo
- & Johannes Buchner
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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
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Article
| Open AccessIncorporation of bridged nucleic acids into CRISPR RNAs improves Cas9 endonuclease specificity
Minimizing off-target effects is an important concern for therapeutic applications of CRISPR-Cas9. Here, the authors show that incorporating bridged or locked nucleic acids into crRNA improves editing kinetics and reduces off-target cleavage.
- Christopher R. Cromwell
- , Keewon Sung
- & Basil P. Hubbard
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Article
| Open AccessSomatic genome editing with the RCAS-TVA-CRISPR-Cas9 system for precision tumor modeling
Accurate recapitulation of human disease in animal models requires generation of complex and heterogeneous genetic variation. Here the authors combine RCAS-TVA with CRISPR-Cas9 to generate mouse models of cancer.
- Barbara Oldrini
- , Álvaro Curiel-García
- & Massimo Squatrito
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Article
| Open AccessOrientation-dependent Dxz4 contacts shape the 3D structure of the inactive X chromosome
The inactive X chromosome condenses into a bipartite structure. Here the authors use cells with allelic deletions or inversions to show that the Dxz4 locus is necessary to maintain the bipartite structure and that Dxz4 orientation controls the distribution of contacts on the inactive X chromosome.
- G. Bonora
- , X. Deng
- & C. M. Disteche
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Article
| Open AccessGFI1 facilitates efficient DNA repair by regulating PRMT1 dependent methylation of MRE11 and 53BP1
The transcription factor GFI1 mediates the DNA damage response (DDR) of T cells through a yet unknown mechanism. Here the authors show that GFI1 can adopt non-transcriptional roles during DDR, enabling PRMT1 to bind and methylate the DNA repair proteins MRE11 and 53BP1.
- Charles Vadnais
- , Riyan Chen
- & Tarik Möröy
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Article
| Open AccessEpigenetic control of IL-23 expression in keratinocytes is important for chronic skin inflammation
Although IL-23 is expressed by psoriatic keratinocytes as well as immune cells, only the immune cell derived IL-23 is thought to be important for the development of psoriasis. Here the authors provide evidence that keratinocyte-produced IL-23 is sufficient to cause a chronic skin inflammation.
- Hui Li
- , Qi Yao
- & Cord Brakebusch
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Article
| Open AccessDistinct molecular pathways mediate Mycn and Myc-regulated miR-17-92 microRNA action in Feingold syndrome mouse models
Feingold syndrome is a skeletal dysplasia caused by mutations in MYCN or MIR17HG, but it is not clear if these mutations lead to pathology via a common molecular mechanism. Here, the authors show that mutations in MIR17HG lead to upregulated TGF-β signaling in limb mesenchymal cells, while mutations in MYCN downregulate PI3K signaling.
- Fatemeh Mirzamohammadi
- , Anastasia Kozlova
- & Tatsuya Kobayashi
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Article
| Open AccessRecurrent acquisition of cytosine methyltransferases into eukaryotic retrotransposons
Cytosine methyltransferases (DNMTs) often silence transposons in eukaryotic genomes. Here the authors describe the recurrent acquisition of DNMTs by transposons from two distantly-related eukaryotes and suggest that methylation of CG dinucleotides by transposon DNMTs could modify the host epigenome in dinoflagellates.
- Alex de Mendoza
- , Amandine Bonnet
- & Ryan Lister
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Article
| Open AccessStructural rearrangements of the histone octamer translocate DNA
Nucleosomes are dynamic and can move along DNA in an uncatalyzed manner but little is known about the mechanisms of histone octamer translocation. Here the authors present cryo-EM structures of nucleosomes in differently organized histone octamer and DNA states and show how histone octamers translocate DNA.
- Silvija Bilokapic
- , Mike Strauss
- & Mario Halic
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Article
| Open AccessDe novo reconstruction of human adipose transcriptome reveals conserved lncRNAs as regulators of brown adipogenesis
Long non-coding RNAs are known to regulate mouse white adipose tissue development and brown adipose tissue program expression. Here, the authors construct a roadmap for human long non-coding RNAs expressed in fetal brown adipose tissue, adult omental and subcutaneous white adipose tissues.
- Chunming Ding
- , Yen Ching Lim
- & Lei Sun
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Article
| Open AccessCryptic glucocorticoid receptor-binding sites pervade genomic NF-κB response elements
Glucocorticoid receptor (GR) regulates immunity and inflammation but the mechanisms by which GR represses proinflammatory genes are still being debated. Here the authors use a multidisciplinary approach and show that GR binds to a cryptic site within genome-wide NFκB DNA response elements to repress pro-inflammatory genes.
- William H. Hudson
- , Ian Mitchelle S. de Vera
- & Eric A. Ortlund
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Article
| Open AccessHelraiser intermediates provide insight into the mechanism of eukaryotic replicative transposition
Helitrons are eukaryotic DNA transposons that have profoundly affected genome variation due to their ability to capture and mobilize host genomic fragments. Here the authors provide insight into the mechanism of action of these transposons both in cells and in vitro.
- Ivana Grabundzija
- , Alison B. Hickman
- & Fred Dyda
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Article
| Open AccessRING tetramerization is required for nuclear body biogenesis and PML sumoylation
Promyelocytic leukemia protein (PML) is a scaffolding protein that organizes PML nuclear bodies. Here the authors present the tetrameric crystal structure of the PML RING domain and show that RING tetramerization is functionally important for nuclear body formation and PML sumoylation.
- Pengran Wang
- , Shirine Benhenda
- & Guoyu Meng
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Article
| Open AccessZeb1-Hdac2-eNOS circuitry identifies early cardiovascular precursors in naive mouse embryonic stem cells
The production of nitric oxide (NO) is required for early stage embryo implantation into the uterus. Here the authors show that during differentiation of naive mouse ESCs, early production of endogenous NO leads to a mesendoderm differentiation commitment pathway by inhibiting the action of the transcriptional repressor Zeb1.
- Chiara Cencioni
- , Francesco Spallotta
- & Carlo Gaetano
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Article
| Open AccessUSP52 acts as a deubiquitinase and promotes histone chaperone ASF1A stabilization
Histone chaperone ASF1A is often dysregulated in cancers, however the regulation of its abundance is unclear. Here, the authors show that USP52 promotes ASF1A stability through deubiquitination while impairment of this stability reduces breast tumorigenesis and confers sensitivity to DNA damage.
- Shangda Yang
- , Ling Liu
- & Lei Shi
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Article
| Open AccessA licensing step links AID to transcription elongation for mutagenesis in B cells
Activation-induced deaminase (AID) is important for inducing desirable mutations at the B cell receptor genes for effective antibody responses. Here the authors show that three key arginine residues of AID link AID-chromatin association with transcription elongation to license AID for specific mutagenesis in B cells.
- Stephen P. Methot
- , Ludivine C. Litzler
- & Javier M. Di Noia
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Article
| Open AccessKlf4 glutamylation is required for cell reprogramming and early embryonic development in mice
Embryonic stem cell pluripotency depends upon precise regulation by a core transcription network. Here the authors show that polyglutamylation mediated stabilization of the transcription factor Klf4 by TTLL1 and TTLL4 promotes reprogramming, pluripotency and preimplantation embryonic development.
- Buqing Ye
- , Benyu Liu
- & Zusen Fan
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Article
| Open AccessDownregulation of cytoplasmic DNases is implicated in cytoplasmic DNA accumulation and SASP in senescent cells
Activation of DNA damage response induces the acquisition of senescence-associated secretory phenotype (SASP) in senescent cells, but precise mechanisms remain unclear. Here, the authors show that the cytoplasmic accumulation of nuclear DNA activated cytoplasmic DNA sensors to provoke SASP.
- Akiko Takahashi
- , Tze Mun Loo
- & Eiji Hara
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Article
| Open AccessTRIM11 activates the proteasome and promotes overall protein degradation by regulating USP14
The proteasome-bound ubiquitinase USP14 plays an important role in determining proteasome activity and substrate specificity. Here the authors show that TRIM11, a member of the mammalian tripartite motif family, regulates USP14 and is an important activator of the proteasome.
- Liang Chen
- , Guixin Zhu
- & Xiaolu Yang
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Article
| Open AccessThe RNA-binding protein ARPP21 controls dendritic branching by functionally opposing the miRNA it hosts
Many microRNA encoding regions are within introns of other coding genes, and yet the molecular or functional interaction between the two is unclear. This study shows that miR-128′s function is opposed by its host gene ARPP21, and they have complementary effects on neuronal development.
- Frederick Rehfeld
- , Daniel Maticzka
- & F. Gregory Wulczyn
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Article
| Open AccessMice lacking the mitochondrial exonuclease MGME1 accumulate mtDNA deletions without developing progeria
It has been debated whether premature ageing in mitochondrial DNA mutator mice is driven by point mutations or deletions of mtDNA. Matic et al generate Mgme1 knockout mice and show here that these mice have tissue-specific replication stalling and accumulate deleted mtDNA, without developing progeria.
- Stanka Matic
- , Min Jiang
- & Dusanka Milenkovic
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Article
| Open AccessDop1 enhances conspecific olfactory attraction by inhibiting miR-9a maturation in locusts
Migratory locusts shift between aggregating together during gregarious phases and living individually during solitary phases. Here, the authors find that the D1-like dopamine receptor regulates the olfactory attraction underlying this behavioral switch via microRNA-9a and adenylyl cyclase.
- Xiaojiao Guo
- , Zongyuan Ma
- & Le Kang
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Article
| Open AccessStructure of Schlafen13 reveals a new class of tRNA/rRNA- targeting RNase engaged in translational control
Translation inhibition is a strategy for organisms to overcome various environmental stresses including viral infections. Here the authors show that a tRNA/rRNA-targeting RNase Schlafen13 inhibits protein synthesis by directly digesting cytoplasmic tRNA and rRNA with the ability to restrict viral propagation.
- Jin-Yu Yang
- , Xiang-Yu Deng
- & Song Gao
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Article
| Open Accessnc886 is induced by TGF-β and suppresses the microRNA pathway in ovarian cancer
Ovarian cancers often display elevated TGF-β signaling but repressed miRNA expression. Here the authors identify that non-coding RNA nc886 expression is induced by TGF-β, which then binds to DICER and impairs miRNA maturation.
- Ji-Hye Ahn
- , Hyun-Sung Lee
- & Yong Sun Lee
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Article
| Open AccessA spliced latency-associated VZV transcript maps antisense to the viral transactivator gene 61
Varicella-zoster virus (VZV) establishes lifelong infection in the majority of the population, but mechanisms underlying latency remain unclear. Here, the authors use ultra-deep RNA sequencing, enriched for viral RNAs, of latently infected human trigeminal ganglia and identify a spliced, latency-associated VZV mRNA.
- Daniel P. Depledge
- , Werner J. D. Ouwendijk
- & Judith Breuer
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Article
| Open AccessZFR coordinates crosstalk between RNA decay and transcription in innate immunity
Type I interferon signaling is critical for the control of infection. Here the authors show that zinc finger RNA-binding protein (ZFR) can control type I interferon responses, and that this control is itself regulated by distinct ZFR truncation patterns that differ between monocytes and macrophages.
- Nazmul Haque
- , Ryota Ouda
- & J. Robert Hogg
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Article
| Open AccessArchitecture of the Saccharomyces cerevisiae NuA4/TIP60 complex
The NuA4 histone acetyltransferase complex is important for gene regulation, DNA repair processes and cell cycle progression. Here the authors give molecular insights into the NuA4 complex by presenting the cryo-EM structures of the NuA4 TEEAA (Tra1, Eaf1, Eaf5, actin, and Arp4) and TEEAA-piccolo NuA4 assemblies.
- Xuejuan Wang
- , Salar Ahmad
- & Gang Cai
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