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Article
| Open AccessNuclear lamina dysfunction triggers a germline stem cell checkpoint
Otefin is a nuclear lamina protein required for survival of Drosophila germ stem cells. Here the authors show that nuclear lamina dysfunction resulting from loss of Otefin activates a DNA damage-independent germ stem cell-specific checkpoint, mediated by the ATR and Chk2 kinases, which ensures that healthy gametes are passed on to the next generation.
- Lacy J. Barton
- , Tingting Duan
- & Pamela K. Geyer
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Article
| Open AccessUBL3 modification influences protein sorting to small extracellular vesicles
Exosomes mediate cell-to-cell communication by transporting proteins, mRNAs, and miRNAs but the mechanisms of protein sorting to exosomes are poorly understood. Here, the authors uncover that ubiquitin-like 3 (UBL3) regulates protein sorting to exosomes by acting as a posttranslational modification.
- Hiroshi Ageta
- , Natsumi Ageta-Ishihara
- & Kunihiro Tsuchida
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Article
| Open AccessPersistent repair intermediates induce senescence
Cells with damaged DNA can permanently exit the cell cycle during the G2 phase or recover spontaneously entering mitosis. Here the authors reveal that the decision to exit from the cell cycle in G2 is dependent on the presence of repair intermediates associated with homologous recombination.
- F. M. Feringa
- , J. A. Raaijmakers
- & R. H. Medema
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Article
| Open AccessAn OB-fold complex controls the repair pathways for DNA double-strand breaks
How repair pathway selection occurs is still a matter of debate and many factors have been associated to this function. Here the authors provide insight into the role of FAM35A and C20ORF196, two REV7-interacting proteins, which are recruited at double-strand breaks to promote non-homologous end joining repair.
- Shengxian Gao
- , Sumin Feng
- & Dongyi Xu
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Article
| Open AccessLnk/Sh2b3 deficiency restores hematopoietic stem cell function and genome integrity in Fancd2 deficient Fanconi anemia
Loss of Fancd2 leads to replication stress intolerance and Fanconi Anemia, where haematopoietic stem cell (HSC) function is compromised. Here, the authors show that Lnk/Sh2b3 loss restores HSC proliferation and survival in Fancd2 knockout mice and ameliorates replication stress in a cytokine/JAK2 signaling dependent manner.
- Joanna Balcerek
- , Jing Jiang
- & Wei Tong
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Article
| Open AccessLUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L
TNF mediated inflammation is critical in autoimmune mediated pathology, however many patients are refractory to current anti-TNF therapeutics. Here the authors show induction of several death ligands, in addition to TNF is sufficient to cause fatal dermatitis in a LUBAC deficient murine model of disease.
- Lucia Taraborrelli
- , Nieves Peltzer
- & Henning Walczak
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Article
| Open AccessLoss of PRC1 induces higher-order opening of Hox loci independently of transcription during Drosophila embryogenesis
Loss of Polycomb repressive complex 1 (PRC1) proteins usually results in both chromatin unfolding and ectopic transcription. Here, the authors analyze the temporal function of two PRC1 proteins during Drosophila embryogenesis and provide evidence that PRC1 maintains gene silencing by folding chromatin domains.
- Thierry Cheutin
- & Giacomo Cavalli
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Article
| Open AccessSpatiotemporal dynamics of homologous recombination repair at single collapsed replication forks
How factors involved in homologous recombination interact and function is a matter of interest. Here the authors use super-resolution imaging to describe the spatiotemporal dynamics of proteins associated with homologous recombination DNA repair in response to replication stress.
- Donna R. Whelan
- , Wei Ting C. Lee
- & Eli Rothenberg
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Article
| Open AccessMapping of histone-binding sites in histone replacement-completed spermatozoa
While a majority of histones are replaced by protamines during spermatogenesis, a small amount is retained in mammalian spermatozoa. Here the authors develop a method to purify histones from replacement-completed sperm (HRCS), completely solubilize histones from cross-linked HRCS without MNase digestion, and map histone-binding sites in these cells.
- Keisuke Yoshida
- , Masafumi Muratani
- & Shunsuke Ishii
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Article
| Open AccessTargeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination
Targeting the glycolytic PFKFB3 enzyme is being studied as a therapeutic strategy against cancer. Here the authors identify PFKFB3 as being involved in homologous recombination (HR) repair of DNA double strand breaks (DSBs) and present a PFKFB3 inhibitor.
- Nina M. S. Gustafsson
- , Katarina Färnegårdh
- & Thomas Helleday
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Article
| Open AccessPAXX and its paralogs synergistically direct DNA polymerase λ activity in DNA repair
PAXX functions as part of the nonhomologous end-joining pathway to repair double-strand DNA breaks. Here the authors show PAXX and its paralogs interact with polymerase lambda to promote joining of incompatible ends.
- Andrew Craxton
- , Deeksha Munnur
- & Michal Malewicz
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Article
| Open AccessA conformational sensor based on genetic code expansion reveals an autocatalytic component in EGFR activation
Upon ligand binding epidermal growth factor receptor (EGFR) dimerizes and activates its intrinsic kinase to auto-phosphorylate EGFR. Here, the authors engineer and image a FRET-based conformational EGFR indicator which reveals that activation loop phosphorylation induces a catalytically active conformation in EGFR monomers.
- Martin Baumdick
- , Márton Gelléri
- & Philippe I. H. Bastiaens
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Article
| Open AccessHierarchical and stage-specific regulation of murine cardiomyocyte maturation by serum response factor
The processes regulating cardiomyocyte (CM) maturation are unclear. Here, the authors show that serum response factor regulates CM maturation only in neonatal CMs through stage-specific chromatin occupancy that affects cell size, sarcomere and transverse-tubule organization, and mitochondria
- Yuxuan Guo
- , Blake D. Jardin
- & William T. Pu
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Article
| Open AccessA tissue-specific self-interacting chromatin domain forms independently of enhancer-promoter interactions
Self-interacting chromatin domains encompass genes and their cis-regulatory elements. Here the authors use high-resolution chromosome conformation capture and super-resolution imaging to study a 70 kb domain that includes the mouse α-globin regulatory locus and find that a tissue-specific self-interacting chromatin domain forms independently of enhancer-promoter interactions.
- Jill M. Brown
- , Nigel A. Roberts
- & Veronica J. Buckle
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Article
| Open AccessRobust single-cell DNA methylome profiling with snmC-seq2
Single-cell DNA methylome profiling allows the study of epigenomic heterogeneity in tissues but has been impeded by library quality. Here the authors demonstrate snmC-seq2 which improves mapping, throughput and library complexity.
- Chongyuan Luo
- , Angeline Rivkin
- & Joseph R. Ecker
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Article
| Open AccessFemale mice lacking Ftx lncRNA exhibit impaired X-chromosome inactivation and a microphthalmia-like phenotype
Although Ftx lncRNA has been linked to X-chromosome inactivation, its physiological roles in vivo remain unclear. Here the authors show that deletion of mouse Ftx causes eye abnormalities similar to human microphthalmia in a subset of female mice but rarely in males and provide evidence that Ftx plays a role in gene silencing on the inactive X chromosome.
- Yusuke Hosoi
- , Miki Soma
- & Shin Kobayashi
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Article
| Open AccessRoquin targets mRNAs in a 3′-UTR-specific manner by different modes of regulation
Roquin targets are known to contain two types of sequence-structure motifs, the constitutive and the alternative decay elements (CDE and ADE). Here, the authors describe a linear Roquin binding element (LBE) also involved in target recognition, and show that Roquin binding affects the translation of a subset of targeted mRNAs.
- Katharina Essig
- , Nina Kronbeck
- & Vigo Heissmeyer
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Article
| Open AccessA variant NuRD complex containing PWWP2A/B excludes MBD2/3 to regulate transcription at active genes
Transcription regulation requires recruitment of different epigenetic regulators to the chromatin. Here the authors provide evidence that an H3K36me3 reader PWWP2A forms a variant NuRD complex and plays a role in regulating transcription and histone acetylation dynamics.
- Tianyi Zhang
- , Guifeng Wei
- & Neil Brockdorff
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Article
| Open AccessThe ZZ-type zinc finger of ZZZ3 modulates the ATAC complex-mediated histone acetylation and gene activation
Histones are recognized by epigenetic readers, which play essential roles in regulation of chromatin and transcription. Here the authors provide evidence that the ZZ-type zinc finger domain of ZZZ3 functions as a reader of histone H3, which is required for the ATAC complex-mediated maintenance of histone acetylation and gene activation.
- Wenyi Mi
- , Yi Zhang
- & Xiaobing Shi
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Article
| Open AccessChromatin swelling drives neutrophil extracellular trap release
Neutrophilic granulocytes release their own DNA (NETosis) as neutrophil extracellular traps to capture pathogens. Here, the authors use time-resolved fluorescence and atomic force microscopy and reveal that NETosis is highly organized into three distinct phases with a clear point of no return defined by chromatin status.
- Elsa Neubert
- , Daniel Meyer
- & Sebastian Kruss
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Article
| Open AccessCharacterization and targeting of malignant stem cells in patients with advanced myelodysplastic syndromes
Myelodysplastic syndrome (MDS) arises from mutations in hematopoietic stem cells (HSCs). Here, the authors demonstrate that HSCs in higher-risk MDS express the surface marker CD123 and are characterized by activation of protein synthesis machinery and increased oxidative phosphorylation.
- Brett M. Stevens
- , Nabilah Khan
- & Craig T. Jordan
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Article
| Open AccessHistone H4K20 methylation mediated chromatin compaction threshold ensures genome integrity by limiting DNA replication licensing
Cell cycle and replication need to be tightly regulated to ensure genome stability in mammalian cells. Here the authors provide a link between chromatin structure and DNA replication regulation by showing that chromatin compaction limits replication licensing thereby promoting genome integrity.
- Muhammad Shoaib
- , David Walter
- & Claus S. Sørensen
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Article
| Open AccessThe Swr1 chromatin-remodeling complex prevents genome instability induced by replication fork progression defects
SWR-C and its substrate the histone variant Htz1 are considered important for genome maintenance. Here the authors reveal that SWR-C/Htz1 plays a critical role during replication stress caused by absence of the replication fork progression proteins Mrc1/Tof1/Csm3.
- Anjana Srivatsan
- , Bin-Zhong Li
- & Richard D. Kolodner
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Article
| Open AccessMutant FUS causes DNA ligation defects to inhibit oxidative damage repair in Amyotrophic Lateral Sclerosis
Impairment of DNA repair has been associated with neurodegeneration. Here the authors investigate the mechanisms of defects in repair caused by mutations in the RNA/DNA binding protein FUS in amyotrophic lateral sclerosis and elucidate its role in the DNA ligation during DNA single-strand break repair of oxidative breaks.
- Haibo Wang
- , Wenting Guo
- & Muralidhar L. Hegde
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Article
| Open AccessDifferent patterns of clonal evolution among different sarcoma subtypes followed for up to 25 years
Hofvander and colleagues compare the patterns of clonal evolution in different pathogenetic subgroups of sarcoma. They show that sarcomas driven by gene fusion or amplification display few additional changes over time, whereas sarcomas with complex karyotypes show a gradual increase of nucleotide- and chromosome-level mutations.
- Jakob Hofvander
- , Björn Viklund
- & Fredrik Mertens
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Article
| Open AccessER-associated ubiquitin ligase HRD1 programs liver metabolism by targeting multiple metabolic enzymes
HRD1 is an E3 ligase known to play a role in targeting degradation of misfolded proteins in the ER. Here the authors show that HRD1 interacts with metabolic enzymes and its liver specific deficiency results in lower body weight, blood glucose and plasma lipids during high fat diet in mice.
- Juncheng Wei
- , Yanzhi Yuan
- & Deyu Fang
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Article
| Open AccessDynamics of cellular states of fibro-adipogenic progenitors during myogenesis and muscular dystrophy
Fibro-adipogenic progenitors (FAPs) resident in skeletal muscle are involved in both regeneration and maladaptive processes. Here, the authors identify subpopulations of FAPs with biological activities implicated in physiological muscle repair that are altered in pathological conditions such as muscular dystrophies.
- Barbora Malecova
- , Sole Gatto
- & Pier Lorenzo Puri
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Article
| Open AccessHepatic Ago2-mediated RNA silencing controls energy metabolism linked to AMPK activation and obesity-associated pathophysiology
The RNA-induced silencing complex (RISC) represses gene expression via micro-RNA guided mRNA silencing. Here, the authors show that RISC component Argonaute 2 in the liver regulates energy metabolism by inducing microRNAs that cause metabolic disruption and by suppressing protein translation linked to AMPK activation.
- Cai Zhang
- , Joonbae Seo
- & Takahisa Nakamura
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Article
| Open AccessStaufen1 links RNA stress granules and autophagy in a model of neurodegeneration
Spinocerebellar ataxia type 2 (SCA2) is caused by polyglutamine repeats in the ATXN2 protein. Here the authors demonstrate that Staufen1, known to be an RNA-binding protein, interacts with ATXN2 and contributes to pathology in a mouse model of SCA2.
- Sharan Paul
- , Warunee Dansithong
- & Stefan M. Pulst
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Article
| Open AccessInterrogating the protein interactomes of RAS isoforms identifies PIP5K1A as a KRAS-specific vulnerability
RAS isoforms are frequently mutated in cancer but their inhibition remains challenging. By comparing the protein interactomes of the highly similar isoforms HRAS, NRAS and KRAS, the authors here identify PIP5K1A as a KRAS-specific interactor and a target to inhibit KRAS-driven cell growth.
- Hema Adhikari
- & Christopher M. Counter
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Article
| Open AccessMapping molecular landmarks of human skeletal ontogeny and pluripotent stem cell-derived articular chondrocytes
Human development provides a roadmap for advancing pluripotent stem cell-based regenerative therapies. Here the authors mapped human skeletogenesis using RNA sequencing on 5 cell types from a single foetal stage as well as chondrocytes at 4 stages in vivo and 2 stages during in vitro differentiation.
- Gabriel B. Ferguson
- , Ben Van Handel
- & Denis Evseenko
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Article
| Open AccessJungle Express is a versatile repressor system for tight transcriptional control
Tightly regulated promoters with strong inducibility and scalability are highly desirable for biological applications. Here the authors describe ‘Jungle Express’, a EilR repressor-based broad host system activated by cationic dyes.
- Thomas L. Ruegg
- , Jose H. Pereira
- & Michael P. Thelen
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Article
| Open AccessmicroCLIP super learning framework uncovers functional transcriptome-wide miRNA interactions
AGO-PAR-CLIP is widely used for high-throughput miRNA target characterization. Here, the authors show that the previously neglected non-T-to-C clusters denote functional miRNA binding events, and develop microCLIP, a super learning framework that accurately detects miRNA interactions.
- Maria D. Paraskevopoulou
- , Dimitra Karagkouni
- & Artemis G. Hatzigeorgiou
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Article
| Open AccessLincRNA H19 protects from dietary obesity by constraining expression of monoallelic genes in brown fat
Brown adipose tissue (BAT) thermogenesis counteracts obesity and promotes metabolic health. The role of long non-coding RNAs (lncRNAs) in the regulation of this process is not well understood. Here the authors identify a maternally expressed lncRNA, H19, that increases BAT oxidative metabolism and energy expenditure.
- Elena Schmidt
- , Ines Dhaouadi
- & Jan-Wilhelm Kornfeld
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Article
| Open AccessLocal enrichment of HP1alpha at telomeres alters their structure and regulation of telomere protection
Chromatin dynamics is thought to play an important role in the maintenance of telomeres, yet how has remained poorly understood. Here the authors locally enrich heterochromatin protein 1α (HP1α) at human telomeres to provide insights into the crosstalk between epigenetic regulations and structural dynamics at the telomeres.
- Tracy T. Chow
- , Xiaoyu Shi
- & Elizabeth H. Blackburn
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Article
| Open AccessStructural and biochemical insights into small RNA 3′ end trimming by Arabidopsis SDN1
Small RNA degrading nucleases (SDNs) can degrade short RNAs. Here the authors report the crystal structure of Arabidopsis SDN1 in complex with a single-stranded RNA, and provide new insight into 3′ end trimming mechanism of 3′ to 5′ riboexonucleases in the metabolism of various species of small RNAs.
- Jiayi Chen
- , Li Liu
- & Jinbiao Ma
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Article
| Open AccessOverexpressing lncRNA LAIR increases grain yield and regulates neighbouring gene cluster expression in rice
The effect of long noncoding RNAs (lncRNAs) on crop yield is unknown. Here, the authors show overexpression of a lncRNA, transcribed from the antisense strand of the previously discovered gene cluster LRK, can upregulate LRK genes’ expression, change histone modification status of LRK1, and increase rice grain yield.
- Ying Wang
- , Xiaojin Luo
- & Jinshui Yang
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Article
| Open AccessIn vivo phosphoproteomics reveals kinase activity profiles that predict treatment outcome in triple-negative breast cancer
Triple-negative breast cancer (TNBC) lacks prognostic and predictive markers. Here, the authors use phosphoproteomics to define kinases with distinct activity profiles in TNBC, demonstrating their prognostic value as well as their utility for simplifying TNBC classification and designing drug regimens.
- Ivana Zagorac
- , Sara Fernandez-Gaitero
- & Miguel Quintela-Fandino
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Article
| Open AccessHigh-fidelity CRISPR/Cas9- based gene-specific hydroxymethylation rescues gene expression and attenuates renal fibrosis
Suppression of gene expression due to aberrant promoter methylation contributes to organ fibrosis. Here, the authors couple a deactivated Cas9 to the TET3 catalytic domain to induce expression of four antifibrotic genes, and show that lentiviral-mediated delivery is effective in reducing kidney fibrosis in mouse models.
- Xingbo Xu
- , Xiaoying Tan
- & Michael Zeisberg
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Article
| Open AccessA molecular switch orchestrates enzyme specificity and secretory granule morphology
Regulated secretion is an essential process that requires packing and maturation of cargo proteins in membranous secretory granules. Here, authors identify a gene, pgant9, that influences the glycosylation status of the secretory cargo as well as the structure of secretory granules within the Drosophila salivary gland.
- Suena Ji
- , Nadine L. Samara
- & Kelly G. Ten Hagen
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Article
| Open AccessLysine benzoylation is a histone mark regulated by SIRT2
Histone marks regulate chromatin structure and function. Here the authors identify and characterize lysine benzoylation, a histone mark that can be modulated by sodium benzoate, a widely used chemical food preservative, associated with specific regulation of gene expression.
- He Huang
- , Di Zhang
- & Yingming Zhao
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Article
| Open AccessCFP1 coordinates histone H3 lysine-4 trimethylation and meiotic cell cycle progression in mouse oocytes
The transcription-independent function of trimethylation of histone H3 (H3K4me) in cell division is unclear. Here, Heng-Yu Fan and colleagues report that CFP1, a subunit of the H3K4 methyltransferase, is required for oocyte meiosis, being phosphorylated and degraded during cell cycle transition.
- Qian-Qian Sha
- , Xing-Xing Dai
- & Heng-Yu Fan
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Article
| Open AccessReplication of bacterial plasmids in the nucleus of the red alga Porphyridium purpureum
Genetic tools for research on red algae (rhodophytes) are lacking. Here, Li and Bock present an efficient genetic transformation system for a model rhodophyte, and show that the transgenic DNA can be maintained as an extrachromosomal multi-copy plasmid in the algal nucleus.
- Zhichao Li
- & Ralph Bock
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Article
| Open AccessSIRT6 haploinsufficiency induces BRAFV600E melanoma cell resistance to MAPK inhibitors via IGF signalling
The epigenetic mechanisms of melanoma drug resistance are poorly understood. Here, the authors develop a CRISPR-Cas9 screen targeting epigenetic regulators and discover that SIRT6 haploinsufficiency induces BRAFV600E melanoma cell resistance to MAPK inhibitors via IGF signalling.
- Thomas Strub
- , Flavia G. Ghiraldini
- & Emily Bernstein
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Article
| Open AccessLoss of the E3 ubiquitin ligase MKRN1 represses diet-induced metabolic syndrome through AMPK activation
AMPK activation has been suggested as treatment for obesity and its complications. Here the authors show that the ubiquitin ligase MKRN1 binds to AMPK and mediates its ubiquitination and degradation. Loss of MKRN1 leads to AMPK activation, increased glucose consumption and decreased lipid accumulation.
- Min-Sik Lee
- , Hyun-Ji Han
- & Jaewhan Song
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Article
| Open AccessJunB defines functional and structural integrity of the epidermo-pilosebaceous unit in the skin
Epidermal homeostasis is maintained by the activity of stem cells. Here, the authors show that deficiency of the transcription factor JunB leads to altered Notch signaling in stem cells, resulting in a cell fate switch and de novo formation of aberrant sebaceous glands, altered epidermal differentiation and impaired barrier function.
- Karmveer Singh
- , Emanuela Camera
- & Karin Scharffetter-Kochanek
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Article
| Open AccessNF-κB inhibition rescues cardiac function by remodeling calcium genes in a Duchenne muscular dystrophy model
The molecular mechanisms leading to heart failure in patients with Duchenne muscular dystrophy are unclear. Here the authors show that NF-κB is activated in the heart of dystrophin-deficient mice and that its ablation rescues cardiac function through chromatin remodeling and activation of gene expression.
- Jennifer M. Peterson
- , David J. Wang
- & Denis C. Guttridge
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Article
| Open AccessCTD-dependent and -independent mechanisms govern co-transcriptional capping of Pol II transcripts
The co-transcriptional capping of transcripts synthesized by RNA Pol II is substantially more efficient than capping of free RNA, a process that has been shown to depend on CTD phosphorylation. Here the authors demonstrate that a CTD-independent mechanism functions in parallel with CTD-dependent processes to ensure efficient capping.
- Melvin Noe Gonzalez
- , Shigeo Sato
- & Ronald C. Conaway
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Article
| Open AccessPolycomb complexes associate with enhancers and promote oncogenic transcriptional programs in cancer through multiple mechanisms
The role of Polycomb Repressive Complex 1 (PRC1) is well described in development. Here, the authors investigate canonical PRC1’s regulation of transcriptional programs in breast cancer where, in addition to its repressive function, it is also recruited to oncogenic active enhancers to regulate enhancer activity and chromatin accessibility.
- Ho Lam Chan
- , Felipe Beckedorff
- & Lluis Morey
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