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  • Specific but interdependent functions for Arabidopsis AGO4 and AGO6 in RNA‐directed DNA methylation
    1. Cheng‐Guo Duan1,,
    2. Huiming Zhang1,,
    3. Kai Tang1,,
    4. Xiaohong Zhu1,
    5. Weiqiang Qian2,
    6. Yueh‐Ju Hou1,
    7. Bangshing Wang1,
    8. Zhaobo Lang1,
    9. Yang Zhao1,2,
    10. Xingang Wang1,
    11. Pengcheng Wang1,
    12. Jianping Zhou3,
    13. Gaimei Liang4,
    14. Na Liu5,
    15. Chunguo Wang6 and
    16. Jian‐Kang Zhu*,1,2
    1. 1Department of Horticulture and Landscape Architecture, Purdue University, West Lafayette, IN, USA
    2. 2Shanghai Center for Plant Stress Biology, Shanghai Institute of Biological Sciences Chinese Academy of Sciences, Shanghai, China
    3. 3School of Life Science and Technology University of Electronic Science and Technology of China, Chengdu Sichuan, China
    4. 4Dryland Agriculture Research Center, Shanxi Academy of Agricultural Sciences, Taiyuan Shanxi, China
    5. 5Department of Horticulture, Laboratory of Genetics Resources & Functional Improvement for Horticultural Plant Zhejiang University, Hangzhou Zhejiang, China
    6. 6College of Life Sciences Nankai University, Tianjin, China
    1. *Corresponding author. Tel: +1 765 4967601; E‐mail: jkzhu{at}purdue.edu
    1. These authors contribute equally

    AGO4 and AGO6 have distinct, but cooperative functions in RNA‐directed DNA methylation in Arabidopsis and show spatially segregated interactions with RNA polymerases II and V, respectively.

    Synopsis

    AGO4 and AGO6 have distinct, but cooperative functions in RNA‐directed DNA methylation in Arabidopsis and show spatially segregated interactions with RNA polymerases II and V, respectively.

    • Genome‐wide DNA methylation analysis reveals that AGO4 and AGO6 are mutually required in the majority of AGO4‐ and AGO6‐dependent methylated loci;

    • AGO4 and AGO6 display different co‐localization patterns with DNA‐dependent RNA polymerase;

    • RNA Pol II physically interacts with AGO4 but not AGO6;

    • RNA Pol V chromatin occupancy and the accumulation of Pol V‐dependent scaffold RNAs requires AGO6 but not AGO4

    • argonautes
    • DNA methylation
    • epigenetics
    • RdDM
    • RNA polymerases
    • Received July 5, 2014.
    • Revision received November 25, 2014.
    • Accepted November 28, 2014.
    Cheng‐Guo Duan, Huiming Zhang, Kai Tang, Xiaohong Zhu, Weiqiang Qian, Yueh‐Ju Hou, Bangshing Wang, Zhaobo Lang, Yang Zhao, Xingang Wang, Pengcheng Wang, Jianping Zhou, Gaimei Liang, Na Liu, Chunguo Wang, Jian‐Kang Zhu
  • Ubiquitin Ser65 phosphorylation affects ubiquitin structure, chain assembly and hydrolysis
    1. Tobias Wauer1,,
    2. Kirby N Swatek1,,
    3. Jane L Wagstaff1,,
    4. Christina Gladkova1,
    5. Jonathan N Pruneda1,
    6. Martin A Michel1,
    7. Malte Gersch1,
    8. Christopher M Johnson1,
    9. Stefan MV Freund1 and
    10. David Komander*,1
    1. 1Medical Research Council Laboratory of Molecular Biology, Cambridge, UK
    1. *Corresponding author. Tel: +44 1223 267160; E‐mail: dk{at}mrc-lmb.cam.ac.uk
    1. These authors contributed equally to this work

    PINK1‐mediated ubiquitin phosphorylation is not only involved in Parkin activation, but has the potential to affect ubiquitin conjugation and signaling at various levels.

    Synopsis

    Ubiquitin phosphorylation by PINK1 kinase is involved in Parkin activation. Structural and biochemical work now shows that it also affects ubiquitin conformation, chain assembly and deconjugation, thus potentially affecting ubiquitin signaling more broadly.

    • PINK1 phosphorylates Ser65 both in free ubiquitin and in polyubiquitin chains.

    • Parkin is activated by phospho‐ubiquitin only in the presence of unphosphorylated ubiquitin.

    • Ser65 phospho‐ubiquitin interconverts between a major, canonical ubiquitin conformation and a previously unknown minor conformation.

    • Due to beta‐strand slippage, the ubiquitin C‐terminal tail is retracted in the minor conformation.

    • Ser65 phospho‐ubiquitin is charged onto E2 enzymes, but discharging with and without E3 can be inhibited.

    • Ser65 phospho‐ubiquitin‐incorporating polyubiquitin chains are less well hydrolyzed by all classes of DUB enzymes.

    • deubiquitinase
    • Parkin
    • phosphorylation
    • PINK1
    • ubiquitin
    • Received August 18, 2014.
    • Revision received November 20, 2014.
    • Accepted November 21, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Tobias Wauer, Kirby N Swatek, Jane L Wagstaff, Christina Gladkova, Jonathan N Pruneda, Martin A Michel, Malte Gersch, Christopher M Johnson, Stefan MV Freund, David Komander
  • Tox: a multifunctional transcription factor and novel regulator of mammalian corticogenesis
    1. Benedetta Artegiani1,
    2. Antonio M de Jesus Domingues2,
    3. Sara Bragado Alonso1,
    4. Elisabeth Brandl1,
    5. Simone Massalini1,
    6. Andreas Dahl2 and
    7. Federico Calegari*,1
    1. 1DFG‐Research Center for Regenerative Therapies, Cluster of Excellence, TU‐Dresden, Dresden, Germany
    2. 2Deep Sequencing Group–SFB655, Biotechnology Center, TU‐Dresden, Dresden, Germany
    1. *Corresponding author. Tel.: +49 351 45882204; Fax: +49 351 45882348; E‐mail: federico.calegari{at}crt-dresden.de

    A novel neuronal transcription factor promotes renewal in neural stem cells and neurite outgrowth in newborn neurons, but is transiently downregulated while neural stem cells switch to neurogenic divisions.

    Synopsis

    Calcineurin signalling triggers the nuclear transport of Nfat4 in neural stem cells and neurons leading to the activation of the transcription factor Tox. Tox regulates the expression of a number of cell‐specific downstream targets to promote stem and progenitor cell self‐renewal and to regulate neurite outgrowth and specification of newborn neurons.

    • Tox is a HMG‐box transcription factor expressed during mammalian brain development. Tox is expressed in neural stem cells, downregulated in neurogenic progenitors and reinduced in newborn neurons.

    • Tox expression is controlled by the calcineurin/Nfat4 signalling.

    • DamID‐Seq identified a GC‐rich Tox binding motif and a number of downstream targets that are involved in brain development and neurite outgrowth.

    • In vivo manipulation of Tox expression during embryonic development inhibited neurogenesis, induced the expansion of neural progenitors and altered neurite outgrowth and specification of postmitotic neurons.

    • Tox is a novel regulator of corticogenesis with multiple and diverse roles at the level of progenitors and neurons.

    • brain development
    • DamID sequencing
    • HMG‐box transcription factors
    • neural stem cells
    • Tox
    • Received September 15, 2014.
    • Revision received December 2, 2014.
    • Accepted December 3, 2014.
    Benedetta Artegiani, Antonio M de Jesus Domingues, Sara Bragado Alonso, Elisabeth Brandl, Simone Massalini, Andreas Dahl, Federico Calegari
  • Functional screen reveals essential roles of miR‐27a/24 in differentiation of embryonic stem cells
    1. Yanni Ma1,2,,
    2. Nan Yao1,3,,
    3. Guang Liu1,3,,
    4. Lei Dong1,2,
    5. Yufang Liu1,3,
    6. Meili Zhang1,3,
    7. Fang Wang1,2,
    8. Bin Wang1,2,
    9. Xueju Wei1,2,
    10. He Dong1,2,
    11. Lanlan Wang1,2,
    12. Shaowei Ji1,3,
    13. Junwu Zhang1,2,
    14. Yangming Wang4,
    15. Yue Huang*,1,3 and
    16. Jia Yu*,1,2
    1. 1State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
    2. 2Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
    3. 3Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
    4. 4Peking‐Tsinghua Joint Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing, China
    1. * Corresponding author. Tel: +86 10 69156462; E‐mail: huangyue{at}pumc.edu.cn

      Corresponding author. Tel: +86 10 69156423; E‐mail: j-yu{at}ibms.pumc.edu.cn

    1. These authors contributed equally to this work

    A focused screen, followed by CRISPR/Cas9 functional genome editing establishes the miR‐23~27~24 cluster as essential regulator of self‐renewal and ESC‐differentiation.

    Synopsis

    A focused screen, followed by CRISPR/Cas9 functional genome editing establishes the miR‐23~27~24 cluster as essential regulator of self‐renewal and ESC‐differentiation.

    • A functional screen annotates 14 miRNAs as new regulators of ESC differentiation.

    • miR‐27a and miR‐24 operate as suppressors of ESC self‐renewal.

    • The inhibition of miR‐27a and miR‐24 promotes somatic cell reprogramming.

    • The miR‐23~27~24 cluster is shown to be essential for mesoderm differentiation.

    • c‐Myc
    • differentiation
    • embryonic stem cells
    • iPSC generation
    • microRNA
    • Received September 1, 2014.
    • Revision received October 28, 2014.
    • Accepted October 29, 2014.
    Yanni Ma, Nan Yao, Guang Liu, Lei Dong, Yufang Liu, Meili Zhang, Fang Wang, Bin Wang, Xueju Wei, He Dong, Lanlan Wang, Shaowei Ji, Junwu Zhang, Yangming Wang, Yue Huang, Jia Yu
  • The Sm protein methyltransferase PRMT5 is not required for primordial germ cell specification in mice
    1. Ziwei Li1,2,
    2. Juehua Yu3,
    3. Linzi Hosohama1,
    4. Kevin Nee1,2,
    5. Sofia Gkountela1,2,
    6. Sonal Chaudhari1,
    7. Ashley A Cass4,5,6,
    8. Xinshu Xiao4,5,6 and
    9. Amander T Clark*,1,2,5,7
    1. 1Department of Molecular Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA
    2. 2Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA
    3. 3David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
    4. 4Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, CA, USA
    5. 5Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA
    6. 6Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, USA
    7. 7Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA
    1. *Corresponding author. Tel: +1 310 794 4201; E‐mail: clarka{at}ucla.edu

    Conditional deletion of Prmt5 in the mouse germline rules out anticipated roles in germline specification. Instead, Prmt5 controls ground state pluripotency in primordial cells by virtue of RNA splicing.

    Synopsis

    Conditional deletion of Prmt5 in the mouse germline rules out anticipated roles in germline specification. Instead, Prmt5 controls ground state pluripotency in primordial cells by virtue of RNA splicing.

    • PRMT5 is required for survival and proliferation of primordial germ cells and ground state pluripotent stem cells.

    • PRMT5 does not have a major role in primordial germ cell specification.

    • PRMT5 is required for RNA identity in primordial germ cells and ground state pluripotent stem cells by regulating RNA splicing.

    • conditional knockout
    • germline absence
    • PGC specification
    • PRMT5
    • splicing
    • Received June 18, 2014.
    • Revision received December 1, 2014.
    • Accepted December 2, 2014.
    Ziwei Li, Juehua Yu, Linzi Hosohama, Kevin Nee, Sofia Gkountela, Sonal Chaudhari, Ashley A Cass, Xinshu Xiao, Amander T Clark
  • Spontaneous development of hepatocellular carcinoma with cancer stem cell properties in PR‐SET7‐deficient livers
    1. Kostas C Nikolaou1,
    2. Panagiotis Moulos1,
    3. George Chalepakis2,
    4. Pantelis Hatzis1,
    5. Hisanobu Oda3,4,
    6. Danny Reinberg5 and
    7. Iannis Talianidis*,1
    1. 1Biomedical Sciences Research Center Al. Fleming, Vari, Greece
    2. 2Department of Biology University of Crete, Herakleion, Greece
    3. 3Medical Institute of Bioregulation Kyusyu University, Fukuoka, Japan
    4. 4Gastrointestinal and Oncology Division, National Kyusyu Cancer Center, Fukuoka, Japan
    5. 5HHMI, Department of Biochemistry, New York University School of Medicine, New York, NY USA
    1. *Corresponding author. Tel: +30 210 9653773; E‐mail: talianidis{at}fleming.gr

    DNA damage, necrosis and inflammation caused by loss of the histone methyltransferase PR‐SET7 in adult mouse hepatocytes triggers compensatory activation of resident ductal progenitor cells, culminating in hepatocellular carcinoma.

    Synopsis

    Loss of the histone H4 lysine 20 mono‐methyltransferase PR‐SET7 in adult mouse hepatocytes causes DNA damage and necrotic cell death followed by tissue inflammation, fibrosis and ROS accumulation. Subsequent aberrant compensatory proliferation of resident progenitor cells with ductal markers elicits the development of hepatocellular carcinoma, providing insights into the controversial origin of hepatic cancer stem cells.

    • Proliferating PR‐SET7‐deficient adult mouse hepatocytes die via necrosis.

    • PR‐SET7‐deficient livers develop hepatocellular carcinoma.

    • The tumors are composed of cells with cancer stem cell (CSC) features.

    • Hepatic CSCs express ductal progenitor markers and re‐express hepatic oncofetal genes (factors that are usually expressed during fetal liver development).

    • ductal progenitors
    • hepatocellular carcinoma
    • histone methylase
    • Received June 16, 2014.
    • Revision received November 5, 2014.
    • Accepted November 11, 2014.

    This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs 4.0 License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

    Kostas C Nikolaou, Panagiotis Moulos, George Chalepakis, Pantelis Hatzis, Hisanobu Oda, Danny Reinberg, Iannis Talianidis
  • microRNA‐379 couples glucocorticoid hormones to dysfunctional lipid homeostasis
    1. Roldan M de Guia1,
    2. Adam J Rose1,
    3. Anke Sommerfeld1,
    4. Oksana Seibert1,
    5. Daniela Strzoda1,
    6. Annika Zota1,
    7. Yvonne Feuchter1,
    8. Anja Krones‐Herzig1,
    9. Tjeerd Sijmonsma1,
    10. Milen Kirilov1,
    11. Carsten Sticht2,
    12. Norbert Gretz2,
    13. Geesje Dallinga‐Thie3,
    14. Sven Diederichs4,5,
    15. Nora Klöting6,
    16. Matthias Blüher6,
    17. Mauricio Berriel Diaz1 and
    18. Stephan Herzig*,1
    1. 1Joint Division Molecular Metabolic Control, DKFZ‐ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany
    2. 2Medical Research Center, Klinikum Mannheim, Mannheim, Germany
    3. 3Department of Vascular Medicine, AMC Amsterdam, Amsterdam, The Netherlands
    4. 4Helmholtz‐University‐Group Molecular RNA Biology and Cancer DKFZ, Heidelberg, Germany
    5. 5Institute of Pathology Heidelberg University, Heidelberg, Germany
    6. 6Department of Medicine, University of Leipzig, Leipzig, Germany
    1. *Corresponding author. Tel: +49 6221 42 3594; E‐mail: s.herzig{at}dkfz.de

    The discovery of miR‐379 as a direct glucocorticoid receptor target in the liver integrates miRNAs in the physiological control of lipid homeostasis.

    Synopsis

    The discovery of miR‐379 as a direct glucocorticoid receptor target in the liver integrates miRNAs in the physiological control of lipid homeostasis.

    • The conserved microRNA (miR)‐379/410 genomic cluster is a direct GR target.

    • Silencing of miR‐379 ameliorates obesity‐related hypertriglyceridemia.

    • miR‐379 acts through LSR‐ and LDLR‐mediated hepatic lipid uptake.

    • miR‐379 levels correlate with serum cortisol and triglycerides in human obese patients.

    • glucocorticoid signalling
    • LDLR
    • LSR
    • miRNA‐379
    • VLDL triglyceride
    • Received November 4, 2014.
    • Revision received November 19, 2014.
    • Accepted November 21, 2014.
    Roldan M de Guia, Adam J Rose, Anke Sommerfeld, Oksana Seibert, Daniela Strzoda, Annika Zota, Yvonne Feuchter, Anja Krones‐Herzig, Tjeerd Sijmonsma, Milen Kirilov, Carsten Sticht, Norbert Gretz, Geesje Dallinga‐Thie, Sven Diederichs, Nora Klöting, Matthias Blüher, Mauricio Berriel Diaz, Stephan Herzig