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| Open AccessSUMO2/3 modification of cyclin E contributes to the control of replication origin firing
The organized initiation of DNA replication at sites throughout the genome must be carefully choreographed to maintain genome stability. Bonne-Andrea and colleagues show that protein SUMOylation controls the density of origin firing, and identify cyclin E as an important substrate in this context.
- Catherine Bonne-Andrea
- , Malik Kahli
- & Olivier Coux
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A functional deficiency of TERA/VCP/p97 contributes to impaired DNA repair in multiple polyglutamine diseases
Mutations in polyglutamine proteins are implicated in neurodegenerative disorders. Okazawa and colleagues now demonstrate that mutant polyQ proteins interact directly with the ATPase TERA, resulting in reduced DNA double-strand break repair, which is a feature of neurodegenerative diseases.
- Kyota Fujita
- , Yoko Nakamura
- & Hitoshi Okazawa
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Article
| Open AccessGANP regulates recruitment of AID to immunoglobulin variable regions by modulating transcription and nucleosome occupancy
The affinity of antibodies for their targets is enhanced by somatic hypermutation, in which the cytidine deaminase AID is recruited to immunoglobulin variable region genes in B cells. Here the authors show that the nuclear protein GANP has an important role in this process by modifying chromatin structure and enhancing AID recruitment.
- Shailendra Kumar Singh
- , Kazuhiko Maeda
- & Nobuo Sakaguchi
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FTO-mediated formation of N6-hydroxymethyladenosine and N6-formyladenosine in mammalian RNA
Internal modifications in mRNA and non-coding RNA are necessary for modulating various intracellular signalling pathways. In this study, the authors report novel modifications resulting from oxidative RNA demethylation, which regulate RNA–protein interactions affecting gene expression.
- Ye Fu
- , Guifang Jia
- & Chuan He
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Ribosomal protein S1 functions as a termination factor in RNA synthesis by Qβ phage replicase
Protein S1, a subunit of the Qß phage RNA-directed RNA polymerase, was thought to only initiate copying of the phage RNA plus strand. Here, the authors show that S1 stimulates replication of any cognate template by promoting release of the newly synthesized product strand.
- Nikita N. Vasilyev
- , Zarina S. Kutlubaeva
- & Alexander B. Chetverin
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Visualization and genetic modification of resident brain microglia using lentiviral vectors regulated by microRNA-9
Microglia are specialized immune cells in the brain. Here Åkerblom and colleagues use a microRNA-9-regulated lentiviral vector for the targeted genetic modification of microglia in the rodent brain, presenting a tool that may facilitate functional studies of resident microglia.
- Malin Åkerblom
- , Rohit Sachdeva
- & Johan Jakobsson
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Article
| Open AccessmiR-155 regulates differentiation of brown and beige adipocytes via a bistable circuit
Brown fat can dissipate energy as heat and has an important role in energy homoeostasis of rodents and possibly humans. Chenet al. show that microRNA 155 regulates the differentiation of brown adipocytes as well as the 'browning' of white fat cells in mice.
- Yong Chen
- , Franziska Siegel
- & Alexander Pfeifer
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A new protein complex promoting the assembly of Rad51 filaments
RecA/Rad51 proteins catalyse the recognition and exchange between two homologous DNA strands during homologous recombination. Sasanuma et al. now demonstrate that Rad51 association with ssDNA is mediated by a complex consisting of Psy3, Csm2, Shu1 and Shu2 proteins.
- Hiroyuki Sasanuma
- , Maki S. Tawaramoto
- & Akira Shinohara
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Article
| Open AccessCSN- and CAND1-dependent remodelling of the budding yeast SCF complex
CAND1 promotes the activity of Cullin–RING ubiquitin ligases, but binds exclusively to inactive unneddylated forms of the enzyme. By identifying a simple means to reversibly activate this complex in budding yeast, Zemla et al. resolve this paradox and show that CAND1 acts as an exchange factor for substrate adaptors.
- Aleksandra Zemla
- , Yann Thomas
- & Thimo Kurz
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Impact of macromolecular crowding on DNA replication
Macromolecular crowding significantly affects interactions between macromolecules such as proteins, DNA and RNA. Akabayov and colleagues use a SAXS reconstitution assay to show that the effect of macromolecular crowding on T7 DNA replication causes structural changes of the replisome.
- Barak Akabayov
- , Sabine R. Akabayov
- & Charles C. Richardson
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Article
| Open Accessβ-lactam antibiotics promote bacterial mutagenesis via an RpoS-mediated reduction in replication fidelity
Sub-lethal concentrations of antibiotics are known to promote mutagenesis of bacterial DNA. Here the authors show that β-lactam antibiotics trigger mutagenesis by upregulating the stress-response protein RpoS, which downregulates mismatch-repair activity.
- A. Gutierrez
- , L. Laureti
- & I. Matic
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Structure of the full-length HCV IRES in solution
The hepatitis C virus RNA genome is translated via an internal ribosome entry site. Pérard et al. present an atomic model of this site, and using molecular dynamics simulations, identify conformational flexibility that may underlie its function during translation initiation.
- Julien Pérard
- , Cédric Leyrat
- & Marc Jamin
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A novel metatranscriptomic approach to identify gene expression dynamics during extracellular electron transfer
Extracellular electron transfer is a ubiquitous process that occurs in natural microbial communities. Here, Ishii et al.identify specific microbial strains and genes involved in extracellular electron transfer in a biofilm community that is associated with a microbial fuel cell.
- Shun’ichi Ishii
- , Shino Suzuki
- & Orianna Bretschger
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Article
| Open AccessTopoisomerase IIα promotes activation of RNA polymerase I transcription by facilitating pre-initiation complex formation
Topoisomerases facilitate the progress of elongating polymerases during transcription. Zomerdijk and colleagues now demonstrate an additional role for this enzyme; their data suggest that Top2 can cleave DNA inducing topological changes at the ribosomal DNA promoter, which assists de novoassembly of the RNA polymerase I pre-initiation complex.
- Swagat Ray
- , Tatiana Panova
- & Joost C. B. M. Zomerdijk
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The role and assembly mechanism of nucleoprotein in influenza A virus ribonucleoprotein complexes
The nucleoprotein of negative-strand RNA viruses forms a part of the ribonucleoprotein complex. Here Turrell et al.show that nucleoprotein does not regulate the initiation and termination of transcription and replication by the viral RNA polymerase, suggesting that nucleoprotein instead is an elongation factor.
- Lauren Turrell
- , Jon W. Lyall
- & Frank T. Vreede
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Two sequential cleavage reactions on cruciform DNA structures cause palindrome-mediated chromosomal translocations
Palindromic DNA sequences in the genome can cause gross chromosomal rearrangements. Inagaki et al.demonstrate how the pathways of Holliday-junction resolution and antigen-receptor gene rearrangement interact to process cruciform conformation of palindrome DNA into chromosomal translocations in human embryonic kidney cells.
- Hidehito Inagaki
- , Tamae Ohye
- & Hiroki Kurahashi
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MacroH2A histone variants act as a barrier upon reprogramming towards pluripotency
Chromatin templates can act as barriers against cellular reprogramming. Gaspar-Maia and colleagues use mouse models deficient in the histone variants macroH2A1 and macroH2A2, and find that macroH2A functions as an epigenetic barrier against induced pluripotency by silencing Utx target genes.
- Alexandre Gaspar-Maia
- , Zulekha A. Qadeer
- & Emily Bernstein
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UHRF1 targets DNMT1 for DNA methylation through cooperative binding of hemi-methylated DNA and methylated H3K9
Epigenetic inheritance of DNA methylation requires the recruitment of DNA methyltransferase activity to the replication fork by UHRF1. Liu et al. show that optimal association of UHRF1 with the replication fork and resulting DNA methylation requires two domains that bind hemi-methylated DNA and methylated histones, respectively.
- Xiaoli Liu
- , Qinqin Gao
- & Jiemin Wong
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Article
| Open AccessSir2a regulates rDNA transcription and multiplication rate in the human malaria parasite Plasmodium falciparum
The factors that modulate growth rate of the human malaria parasite Plasmodium falciparum remain poorly understood. Here Scherf and collaborators demonstrate that the Plasmodiumsirtuin PfSir2a regulates the transcription of ribosomal DNA, thereby modulating parasite proliferation rate and virulence.
- Liliana Mancio-Silva
- , Jose Juan Lopez-Rubio
- & Artur Scherf
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Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1–PP2A protein complex
Expansion of CAG repeats in messenger RNAs is a common feature of various neurodegenerative disorders, including Huntington’s disease. Krauß et al.show that messenger RNAs with expanded CAG repeats bind to a protein complex that regulates translation and promotes overproduction of such aberrant proteins.
- Sybille Krauß
- , Nadine Griesche
- & Susann Schweiger
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DNA replication timing and higher-order nuclear organization determine single-nucleotide substitution patterns in cancer genomes
Human cancer genomes often contain large amounts of single-nucleotide substitutions (SNS). Liu et al. catalogued SNS signatures across various cancer and normal genomes, demonstrating coordinative effects between replication timing and nuclear architecture on SNS patterns in cancer genomes.
- Lin Liu
- , Subhajyoti De
- & Franziska Michor
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A subset of Drosophila Myc sites remain associated with mitotic chromosomes colocalized with insulator proteins
Myc is a transcription factor present at gene promoters that activates expression of genes involved in pluripotency and cancer. Yang et al. report that Myc is also present at enhancers of Drosophilagenes during interphase and colocalizes with insulator proteins in mitosis.
- Jingping Yang
- , Elizabeth Sung
- & Victor G. Corces
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Strong bias in the bacterial CRISPR elements that confer immunity to phage
Bacterial CRISPR–Cas systems provide adaptive immunity against phage by transcribing interfering RNA from phage DNA inserted into the bacterial genome. Using deep-sequencing, the authors detect a bias in the phage genome locations sampled, suggestive of selection.
- David Paez-Espino
- , Wesley Morovic
- & Jillian F. Banfield
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FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress
DNA replication stress promotes genome instability and cell death. Here Fugger et al.describe how FBH1, via its helicase activity, is required to eliminate cells with excessive DNA replication stress, through the generation of MUS81-induced DNA double-strand breaks.
- Kasper Fugger
- , Wai Kit Chu
- & Claus Storgaard Sørensen
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Plant tumour biocontrol agent employs a tRNA-dependent mechanism to inhibit leucyl-tRNA synthetase
Agrobacterium radiobacter strain K84 generates an antibiotic targeting pathogenic strains of Agrobacterium tumefaciens, enabling its use as a biocontrol to prevent infection of crops. Here the authors show that this antibiotic inhibits leucyl-tRNA synthetases via an unusual mechanism that depends on binding of tRNALeu.
- Shaileja Chopra
- , Andrés Palencia
- & John S. Reader
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Evolution of the protein stoichiometry in the L12 stalk of bacterial and organellar ribosomes
The ribosomal stalk L12 is the only multi-copy protein in the ribosome and is essential for translation. Here Davydov et al.use a bioinformatics and mass spectrometry approach to study the evolution of L12 in bacterial ribosomes and predict its stoichiometry in a wide range of species.
- Iakov I. Davydov
- , Ingo Wohlgemuth
- & Marina V. Rodnina
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MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11
The role of microRNAs in chemotherapy resistance remains to be elucidated. Bockhorn et al.report that microRNA-30c, a human breast tumour prognostic marker, has a key role by targeting the epithelial-to-mesenchymal transition promoter twinfilin 1 and downstream interleukin-11 expression.
- Jessica Bockhorn
- , Rachel Dalton
- & Huiping Liu
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Article
| Open AccessStructural insights into protein-only RNase P complexed with tRNA
RNase P is a key enzyme implicated in transfer RNA maturation that removes the 5′-leader sequences from transfer RNA precursors. In this study, a biophysical characterization of a novel protein-only variant of RNase P, known as PRORP (PROteinaceous RNase P), reveals that transfer RNA recognition by PRORP is similar to that by ribonucleoprotein RNase P.
- Anthony Gobert
- , Franziska Pinker
- & Philippe Giegé
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A structural basis for streptomycin-induced misreading of the genetic code
The antibiotic streptomycin increases errors in protein translation, but it is unclear how streptomycin exerts its effect on the ribosome. Demirci et al. present X-ray crystal structures that reveal conformational changes induced by streptomycin, which may inspire future efforts in antibiotics design.
- Hasan Demirci
- , Frank Murphy IV
- & Gerwald Jogl
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Splicing factor SRSF3 is crucial for hepatocyte differentiation and metabolic function
Splicing factors, such as the protein SRSF3, regulate mRNA metabolism but are hard to study in vivobecause genetic kockouts are usually lethal. Here, Sen and colleagues create mice with a hepatocyte-specific knockout of Srsf3 and demonstrate its role in hepatocyte differentiation and liver function.
- Supriya Sen
- , Hassan Jumaa
- & Nicholas J. G. Webster
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PPARγ is an E3 ligase that induces the degradation of NFκB/p65
NFκB/p65 and PPARγ are both transcription factors that perform distinct but overlapping roles in cellular regulation. Hou et al. report that PPARγ acts as an E3 ubiquitin ligase and promotes Lys48-linked ubiquitination and degradation of p65, terminating NFκB-mediated inflammation and tumorigenesis.
- Yongzhong Hou
- , France Moreau
- & Kris Chadee
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Elevated oncofoetal miR-17-5p expression regulates colorectal cancer progression by repressing its target gene P130
Tumorigenesis has been likened to a form of cellular reversion to the embryonic state. Ma et al.identify a foetal miRNA as an oncogenic activator of the Wnt/β-catenin pathway in colorectal cancer, whose expression is negatively correlated with survival but is positively correlated with response to adjuvant chemotherapy.
- Yanlei Ma
- , Peng Zhang
- & Huanlong Qin
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Article
| Open AccessAn RNA architectural locus control region involved in Dscam mutually exclusive splicing
Alternative splicing at the Drosophila Down syndrome cell adhesion molecule gene generates 38,016 isoforms, and underlies self-avoidance of growing neurons. Wang et al. identify a structure in the DSCAM mRNA that ensures mutually exclusive splicing and observe expansion of the structure with increasing number of exons during arthropod evolution.
- Xuebin Wang
- , Guoli Li
- & Yongfeng Jin
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Article
| Open AccessEvolution of the human-specific microRNA miR-941
miRNAs simultaneously regulate a range of genes, making them potential master players in evolution. Huet al.identify a human-specific miRNA called miR-941, whose copy number remains polymorphic in modern humans, and show that miR-941 is expressed in the brain and could regulate important signalling pathways.
- Hai Yang Hu
- , Liu He
- & Philipp Khaitovich
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Article
| Open AccessWidespread impact of horizontal gene transfer on plant colonization of land
Although horizontal gene transfer is prevalent in microorganisms, such sharing of genetic information is thought to be rare in land plants. Focusing on the sequenced moss species,Physcomitrella patens, these authors report genes acquired from microorganisms, which might have facilitated early evolution of land plants.
- Jipei Yue
- , Xiangyang Hu
- & Jinling Huang
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Annotation of microsporidian genomes using transcriptional signals
Microsporidia are widespread human parasites, but limited genome annotation has hampered efforts to understand their biology. Peyretailladeet al. use sequence motifs upstream of start codons to annotate or re-annotate microsporidian genomes and find new genes potentially involved in interactions with the host.
- Eric Peyretaillade
- , Nicolas Parisot
- & Pierre Peyret
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Article
| Open AccessThe miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy
Heart failure is often a consequence of pathological growth of cardiomyocytes or cardiac hypertrophy. Here Ucar and colleagues report that the microRNAs miR-132 and miR-212 promote cardiac hypertrophy and inhibit autophagy in cardiomyocytes by downregulating the transcription factor FoxO3.
- Ahmet Ucar
- , Shashi K. Gupta
- & Thomas Thum
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Article
| Open AccessEscherichia coli noncoding RNAs can affect gene expression and physiology of Caenorhabditis elegans
It is known that differences in the bacterial food ofCaenorhabditis elegans can alter their behaviour. In this study, bacteria expressing two different noncoding RNAs alter the chemosensory and longevity of C. elegans, suggesting a role in modulating C. elegansphysiology.
- Huijie Liu
- , Xueren Wang
- & Ge Shan
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Article
| Open AccessEnhanced HSP70 lysine methylation promotes proliferation of cancer cells through activation of Aurora kinase B
HSP70 is a molecular chaperone that aids protein folding. In this study, HSP70 is shown to be methylated and this post-translationally modified protein is elevated in expression in human cancers and promotes the activity of Aurora kinase B.
- Hyun-Soo Cho
- , Tadahiro Shimazu
- & Ryuji Hamamoto
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Article
| Open AccessHigh-fat or ethinyl-oestradiol intake during pregnancy increases mammary cancer risk in several generations of offspring
Environmental factors can influence one's susceptibility to cancer, but it is not clear whether such an influence extends beyond the directly exposed generations. Here, feeding pregnant rats with a high-fat diet or a hormone derivative, the authors observe increased breast cancer risk in up to three subsequent generations.
- Sonia de Assis
- , Anni Warri
- & Leena Hilakivi-Clarke
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Lysine methylation of VCP by a member of a novel human protein methyltransferase family
Methyltransferases modify cellular proteins in addition to DNA and histones. These authors identify a new family of lysine-specific methyltransferases and show that a member of this family, which is associated with tumour metastasis, methylates the ATP-dependent protein chaperone VCP/p97.
- Stefan Kernstock
- , Erna Davydova
- & Pål Ø. Falnes
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Protein sliding and DNA denaturation are essential for DNA organization by human mitochondrial transcription factor A
The mitochondrial transcription factor A (TFAM) mediates both mitochondrial transcription and DNA compaction, but how it achieves these two functions is unknown. In this study, TFAM is shown to slide along DNA and cause local melting, suggesting a mechanism for how TFAM modulates both transcription and compaction.
- Géraldine Farge
- , Niels Laurens
- & Gijs J.L. Wuite
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Structures of Pup ligase PafA and depupylase Dop from the prokaryotic ubiquitin-like modification pathway
Pupylation is a bacterial posttranslational modification pathway with functional analogies to ubiquitination. Here, Özceliket al.report the structures of the Pup Ligase, PafA and the Depupylase, Dop. Mutational analysis revealed residues required for catalysis and for the interaction with Pup.
- Dennis Özcelik
- , Jonas Barandun
- & Eilika Weber-Ban
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Article
| Open AccessPINK1 autophosphorylation upon membrane potential dissipation is essential for Parkin recruitment to damaged mitochondria
The kinase PINK1 is mutated in Parkinson's disease and accumulates in defective mitochondria, where it recruits Parkin. Here, PINK1 is shown to be autophosphorylated and this is required for the localization of PINK1 to mitochondria with a reduced membrane potential, and for the recruitment of Parkin.
- Kei Okatsu
- , Toshihiko Oka
- & Noriyuki Matsuda
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TREX exposes the RNA-binding domain of Nxf1 to enable mRNA export
The TREX complex and Nxf1 are involved in the export of mRNA from the nucleus but the precise molecular function of TREX is unclear. Here, the TREX components Aly and Thoc5 are shown to bind to Nxf1 resulting in a change in Nxf1 conformation that permits binding to mRNA and nuclear export.
- Nicolas Viphakone
- , Guillaume M. Hautbergue
- & Stuart A. Wilson
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DNA replication timing and selection shape the landscape of nucleotide variation in cancer genomes
Cancer cells form by somatic mutations and natural selection, but how these factors affect tumorigenesis is not clear. Here, somatic mutations are characterized in human cancer genomes, revealing that DNA replication timing influences the frequency of single-nucleotide variants in different genomic regions.
- Yong H Woo
- & Wen-Hsiung Li
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FOXO3 signalling links ATM to the p53 apoptotic pathway following DNA damage
The protein ataxia-telangiectasia mutated (ATM) detects DNA damage and can trigger cellular apoptosis, but how this process is regulated at the molecular level is unclear. Here, Chunget al. show that the transcription factor FOXO3 controls the formation of ATM-containing signalling complexes at sites of DNA damage that trigger apoptosis.
- Young Min Chung
- , See-Hyoung Park
- & Mickey C.-T. Hu
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Dynamic histone marks in the hippocampus and cortex facilitate memory consolidation
Changes in gene expression in the hippocampus and the cortex are pivotal for memory consolidation. Gräff and colleagues use a recognition task in mice to show that epigenetic post-translational modifications are rapidly activated in the hippocampus after learning, but induced with a delay in the cortex.
- Johannes Gräff
- , Bisrat T. Woldemichael
- & Isabelle M. Mansuy
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Post-transcriptional spliceosomes are retained in nuclear speckles until splicing completion
It is unclear where in the nucleus splicing takes place and how much occurs post-transcriptionally. Using antibodies raised against a phosphorylated splicing factor, Girardet al. show that the majority of splicing occurs co-transcriptionally and that post-transcriptional splicing occurs in nuclear speckles.
- Cyrille Girard
- , Cindy L. Will
- & Reinhard Lührmann
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