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  • Long‐term therapeutic silencing of miR‐33 increases circulating triglyceride levels and hepatic lipid accumulation in mice
    1. Leigh Goedeke1,2,3,4,,
    2. Alessandro Salerno3,4,,
    3. Cristina M Ramírez1,2,3,4,
    4. Liang Guo3,4,
    5. Ryan M Allen5,
    6. Xiaoke Yin6,
    7. Sarah R Langley6,
    8. Christine Esau7,
    9. Amarylis Wanschel3,4,
    10. Edward A Fisher3,4,
    11. Yajaira Suárez1,2,3,4,
    12. Angel Baldán5,
    13. Manuel Mayr6 and
    14. Carlos Fernández‐Hernando*,1,2,3,4
    1. 1Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA
    2. 2Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine Yale University School of Medicine, New Haven, CT, USA
    3. 3Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY, USA
    4. 4Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, NY, USA
    5. 5Edward A. Doisy Department of Biochemistry and Molecular Biology, Center for Cardiovascular Research, Saint Louis University School of Medicine, Saint Louis, MO, USA
    6. 6King's British Heart Foundation Centre, King's College London, London, UK
    7. 7Regulus Therapeutics, San Diego, CA, USA
    1. *Corresponding author. Tel: +1 203 737 4615; Fax: +1 203 737 2290; E‐mail: carlos.fernandez{at}yale.edu
    1. These authors contributed equally to this work.

    Although short‐term anti‐miR‐33 therapy was reported to increase circulating HDL‐cholesterol and reduce atherosclerosis, long‐term adverse effects are here shown for the 1st time in mice fed a high‐fat‐diet to result in hypertriglyerimedia and moderate hepatic steatosis.

    Synopsis

    Although short‐term anti‐miR‐33 therapy was reported to increase circulating HDL‐cholesterol and reduce atherosclerosis, long‐term adverse effects are here shown for the first time in mice fed a high‐fat diet to result in hypertriglyceridemia and moderate hepatic steatosis.

    • The effect of long‐term inhibition of miR‐33 was determined in mice fed a chow diet and high‐fat diet.

    • Chronic therapeutic silencing of miR‐33 increased circulating triglycerides and lipid accumulation in the livers of mice fed a high‐fat diet.

    • miR‐33 inhibition raised the expression of genes involved in fatty acid synthesis and lipid metabolism.

    • Further studies are warranted to understand the complex gene regulatory network controlled by miR‐33.

    • cholesterol
    • fatty acids
    • hepatic steatosis
    • microRNA
    • Received March 8, 2014.
    • Revision received June 18, 2014.
    • Accepted June 26, 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.

    Leigh Goedeke, Alessandro Salerno, Cristina M Ramírez, Liang Guo, Ryan M Allen, Xiaoke Yin, Sarah R Langley, Christine Esau, Amarylis Wanschel, Edward A Fisher, Yajaira Suárez, Angel Baldán, Manuel Mayr, Carlos Fernández‐Hernando
  • Heat shock factor 2 is a stress‐responsive mediator of neuronal migration defects in models of fetal alcohol syndrome
    1. Rachid El Fatimy1,2,3,413,
    2. Federico Miozzo1,2,3,4,,
    3. Anne Le Mouël1,2,,
    4. Ryma Abane1,2,3,4,
    5. Leslie Schwendimann5,6,
    6. Délara Sabéran‐Djoneidi1,2,
    7. Aurélie de Thonel7,8,
    8. Illiasse Massaoudi1,2,
    9. Liliana Paslaru9,
    10. Kazue Hashimoto‐Torii101415,
    11. Elisabeth Christians11,12,
    12. Pasko Rakic10,
    13. Pierre Gressens5,6 and
    14. Valérie Mezger*,1,2
    1. 1CNRS UMR7216 Épigénétique et Destin Cellulaire, Paris Cedex 13, France
    2. 2Univ Paris Diderot Sorbonne Paris Cité, Paris Cedex 13, France
    3. 3ED 387 iViv UPMC Univ Paris 06, Paris, France
    4. 4Univ Paris Diderot, Paris Cedex 13, France
    5. 5INSERM U1141, Hôpital Robert Debré, Paris, France
    6. 6Faculté de Médecine Denis Diderot, Univ Paris Diderot Sorbonne Paris Cité, Paris, France
    7. 7INSERM UMR 866, Dijon, France
    8. 8Faculty of Medicine and Pharmacy, Univ Burgundy, Dijon, France
    9. 9Carol Davila University of Medicine and Pharmacy Fundeni Hospital, Bucharest, Romania
    10. 10Department of Neurobiology and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT, USA
    11. 11Laboratoire de Biologie du Développement de Villefranche‐sur‐mer, Observatoire Océanologique, CNRS, Villefranche‐sur‐mer, France
    12. 12Sorbonne Universités UPMC Univ Paris 06, Villefranche‐sur‐mer, France
    13. 13Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School Harvard Institutes of Medicine, Boston, MA, USA
    14. 14Center for Neuroscience Research, Children's National Medical Center, Washington, DC, USA
    15. 15Department of Pediatrics, Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA
    1. *Corresponding author. Tel: +33 1 57 27 89 14; +33 6 75 77 11 98; Fax: +33 1 57 27 89 11; E‐mail: valerie.mezger{at}univ-paris-diderot.fr
    1. These authors contributed equally to the work.

    Foetal Alcohol Spectrum Disorders (FASD) is the most frequent cause of non‐genetic mental retardation induced by mothers consuming alcohol during pregnancy. HSF2‐induced activation of HSF1 and formation of alcohol‐specific HSF1/HSF2 heterotrimers leads to cortical neuronal positioning defects in the foetus brain.

    Synopsis

    Foetal Alcohol Spectrum Disorders (FASD) is the most frequent cause of non‐genetic mental retardation induced by mothers consuming alcohol during pregnancy. HSF2‐induced activation of HSF1 and formation of alcohol‐specific HSF1/HSF2 heterotrimers leads to cortical neuronal positioning defects in the foetus brain.

    • HSF2 fine‐tunes neuronal migration in control conditions.

    • Upon foetal alcohol exposure, HSF2 drives the activation of HSF1.

    • The alcohol‐induced formation of HSF1‐HSF2 heterotrimers disturbs the expression of genes controlling radial neuronal migration in the cortex (including MAP genes).

    • In the absence of HSF2, the perturbation in radial neuronal migration and in the expression of MAP genes is less severe.

    • HSF2 is a mediator of radial neuronal migration aspects of Foetal Alcohol Syndrome.

    • fetal alcohol syndrome
    • heat shock factors
    • microtubule‐associated proteins
    • radial neuronal migration
    • transcription
    • Received July 23, 2013.
    • Revision received June 1, 2014.
    • Accepted June 2, 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.

    Rachid El Fatimy, Federico Miozzo, Anne Le Mouël, Ryma Abane, Leslie Schwendimann, Délara Sabéran‐Djoneidi, Aurélie de Thonel, Illiasse Massaoudi, Liliana Paslaru, Kazue Hashimoto‐Torii, Elisabeth Christians, Pasko Rakic, Pierre Gressens, Valérie Mezger
  • Targeting macrophage Histone deacetylase 3 stabilizes atherosclerotic lesions
    1. Marten A Hoeksema1,
    2. Marion JJ Gijbels1,2,3,
    3. Jan Van den Bossche1,
    4. Saskia van der Velden1,
    5. Ayestha Sijm1,
    6. Annette E Neele1,
    7. Tom Seijkens1,
    8. J Lauran Stöger1,
    9. Svenja Meiler1,
    10. Marieke CS Boshuizen1,
    11. Geesje M Dallinga‐Thie4,
    12. Johannes HM Levels4,
    13. Louis Boon5,
    14. Shannon E Mullican6,
    15. Nathanael J Spann7,
    16. Jack P Cleutjens2,
    17. Chris K Glass7,
    18. Mitchell A Lazar6,
    19. Carlie JM de Vries1,
    20. Erik AL Biessen2,
    21. Mat JAP Daemen8,
    22. Esther Lutgens1,9 and
    23. Menno PJ de Winther*,1
    1. 1Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
    2. 2Department of Pathology, Maastricht University, Maastricht, The Netherlands
    3. 3Department of Molecular Genetics, Maastricht University, Maastricht, The Netherlands
    4. 4Department of Vascular and Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
    5. 5Bioceros BV, Utrecht, The Netherlands
    6. 6Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
    7. 7Department of Cellular and Molecular Medicine, University of California, San Diego, CA, USA
    8. 8Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
    9. 9Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian's University, Munich, Germany
    1. *Corresponding author. Tel: +31 20 5666762; E‐mail: m.dewinther{at}amc.uva.nl

    Hdac3 is shown to be an important modulator of the fibrotic phenotype of macrophages in atherosclerosis and, in humans, the expression of Hdac3 is linked to plaque vulnerability to rupture.

    Synopsis

    Hdac3 is shown to be an important modulator of the fibrotic phenotype of macrophages in atherosclerosis and, in humans, the expression of Hdac3 is linked to plaque vulnerability to rupture.

    • Myeloid Hdac3 deficiency promotes collagen deposition in atherosclerosis

    • Macrophage Hdac3 deletion enhances TGF‐β secretion thereby increasing collagen production by vascular smooth muscle cells and results in improved lipid handling by de‐repression of PPARγ and LXR responses

    • In humans, Hdac3 is upregulated in ruptured atherosclerotic lesions and is associated with inflammatory macrophages

    • Fine‐tuning of the macrophage phenotype by altering the epigenetic landscape can be applied to affect atherosclerotic disease outcome

    • atherosclerosis
    • epigenetics
    • fibrosis
    • lipids
    • macrophages
    • Received April 14, 2014.
    • Revision received June 6, 2014.
    • Accepted June 10, 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.

    Marten A Hoeksema, Marion JJ Gijbels, Jan Van den Bossche, Saskia van der Velden, Ayestha Sijm, Annette E Neele, Tom Seijkens, J Lauran Stöger, Svenja Meiler, Marieke CS Boshuizen, Geesje M Dallinga‐Thie, Johannes HM Levels, Louis Boon, Shannon E Mullican, Nathanael J Spann, Jack P Cleutjens, Chris K Glass, Mitchell A Lazar, Carlie JM de Vries, Erik AL Biessen, Mat JAP Daemen, Esther Lutgens, Menno PJ de Winther
  • Molecular pathogenesis of Spondylocheirodysplastic Ehlers‐Danlos syndrome caused by mutant ZIP13 proteins
    1. Bum‐Ho Bin1,2,,
    2. Shintaro Hojyo3,4,,
    3. Toshiaki Hosaka5,6,
    4. Jinhyuk Bhin7,
    5. Hiroki Kano8,
    6. Tomohiro Miyai9,10,
    7. Mariko Ikeda5,6,
    8. Tomomi Kimura‐Someya5,6,
    9. Mikako Shirouzu5,6,
    10. Eun‐Gyung Cho1,
    11. Kazuhisa Fukue11,
    12. Taiho Kambe11,
    13. Wakana Ohashi3,
    14. Kyu‐Han Kim1,
    15. Juyeon Seo1,
    16. Dong‐Hwa Choi12,
    17. Yeon‐Ju Nam12,
    18. Daehee Hwang13,
    19. Ayako Fukunaka14,
    20. Yoshio Fujitani14,
    21. Shigeyuki Yokoyama5,15,
    22. Andrea Superti‐Furga16,
    23. Shiro Ikegawa8,
    24. Tae Ryong Lee*,1 and
    25. Toshiyuki Fukada*,2,3
    1. 1Bioscience Research Institute, Amorepacific Corporation R&D Center, Yongin, Republic of Korea
    2. 2Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry Showa University, Shinagawa, Japan
    3. 3Laboratory for Homeostatic Network, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
    4. 4Deutsches Rheuma‐Forschungszentrum, Berlin, Osteoimmunology, Berlin, Germany
    5. 5RIKEN Systems and Structural Biology Center, Yokohama, Japan
    6. 6Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, Yokohama, Japan
    7. 7Department of Chemical Engineering, POSTECH, Pohang, Republic of Korea
    8. 8Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan
    9. 9Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan
    10. 10Laboratory for Immune Regeneration, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
    11. 11Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
    12. 12Gyeonggi Bio Center, Gyeonggi Institute of Science & Technology Promotion, Suwon, Republic of Korea
    13. 13Center for Systems Biology of Plant Senescence and Life History, Institute for Basic Science, Daegu, Republic of Korea
    14. 14Center for Beta‐Cell Biology and Regeneration, Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
    15. 15RIKEN Structural Biology Laboratory, Yokohama, Japan
    16. 16Department of Pediatrics, Centre Hospitalier Universitaire Vaudois University of Lausanne, Lausanne, Switzerland
    1. * Corresponding author. Tel: +82 31 280 5850; Fax: +82 31 899 2595; E‐mail: trlee{at}amorepacific.com

      Corresponding author. Tel: +81 45 503 9273; Fax: +81 45 503 9271; E‐mail: fukada{at}rcai.riken.jp

    1. These authors contributed equally to this work.

    The Spondylocheirodysplastic Ehlers‐Danlos syndrome pathogenic ZIP13 mutants are degraded by the ubiquitin‐proteasome pathway. Inhibition of this pathway restores ZIP13 levels with consequent improvement of intracellular Zn homeostasis.

    Synopsis

    The Spondylocheirodysplastic Ehlers‐Danlos syndrome pathogenic ZIP13 mutants are degraded by the ubiquitin‐proteasome pathway. Inhibition of this pathway restores ZIP13 levels with consequent improvement of intracellular Zn homeostasis.

    • The Spondylocheirodysplastic Ehlers‐Danlos syndrome pathogenic ZIP13 mutant proteins: ZIP13G64D and ZIP13ΔFLA, are degraded by the ubiquitin‐proteasome pathway.

    • Valosin‐containing protein (VCP) is involved in the degradation of the pathogenic mutant ZIP13 proteins.

    • The reduced expression levels of the ZIP13 mutant proteins are rescued by inhibition of the degradation pathways, resulting in improved intracellular zinc homeostasis.

    • Proteasome
    • SCD‐EDS
    • VCP
    • zinc transporter
    • ZIP13
    • Received December 29, 2013.
    • Revision received May 26, 2014.
    • Accepted May 27, 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.

    Bum‐Ho Bin, Shintaro Hojyo, Toshiaki Hosaka, Jinhyuk Bhin, Hiroki Kano, Tomohiro Miyai, Mariko Ikeda, Tomomi Kimura‐Someya, Mikako Shirouzu, Eun‐Gyung Cho, Kazuhisa Fukue, Taiho Kambe, Wakana Ohashi, Kyu‐Han Kim, Juyeon Seo, Dong‐Hwa Choi, Yeon‐Ju Nam, Daehee Hwang, Ayako Fukunaka, Yoshio Fujitani, Shigeyuki Yokoyama, Andrea Superti‐Furga, Shiro Ikegawa, Tae Ryong Lee, Toshiyuki Fukada
  • DOT1L‐HES6 fusion drives androgen independent growth in prostate cancer
    1. Matti Annala1,2,,
    2. Kati Kivinummi1,,
    3. Katri Leinonen1,
    4. Joonas Tuominen1,
    5. Wei Zhang3,
    6. Tapio Visakorpi (tapio.visakorpi{at}uta.fi) 1, and
    7. Matti Nykter (matti.nykter{at}uta.fi) 1,
    1. 1Institute of Biosciences and Medical Technology, Tampere, Finland
    2. 2Department of Signal Processing, Tampere University of Technology, Tampere, Finland
    3. 3Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
    1. Equally contributing authors

    2. Co‐corresponding authors

    Evidence is presented for a case of androgen receptor‐negative prostate cancer driven by a DOT1LHES6 fusion gene which directly induces overexpression and pathological activation of HES6.

    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.

    Matti Annala, Kati Kivinummi, Katri Leinonen, Joonas Tuominen, Wei Zhang, Tapio Visakorpi, Matti Nykter
  • Disruption of Mbd5 in mice causes neuronal functional deficits and neurobehavioral abnormalities consistent with 2q23.1 microdeletion syndrome
    1. Vladimir Camarena1,
    2. Lei Cao1,
    3. Clemer Abad2,
    4. Alexander Abrams1,
    5. Yaima Toledo1,
    6. Kimi Araki3,
    7. Masatake Araki3,
    8. Katherina Walz1,2 and
    9. Juan I Young*,1,2
    1. 1Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA
    2. 2John P. Hussman Institute for Human Genomics, Miller School of Medicine University of Miami, Miami, FL, USA
    3. 3Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan
    1. *Corresponding author. Tel: +1 305 243 1027; Fax: +1 305 243 2703; E‐mail: jyoung3{at}med.miami.edu

    2q23.1 microdeletion syndrome is a rare genetic disease that causes serious neurological deficits. In humans, haplo‐insufficiency of MBD5 was thought to be responsible. This study provides the 1st mouse model of the syndrome and confirms the causal role of MBD5.

    Synopsis

    2q23.1 microdeletion syndrome is a rare genetic disease that causes serious neurological deficits. In humans, haplo‐insufficiency of MBD5 was thought to be responsible. This study provides the 1st mouse model of the syndrome and confirms the causal role of MBD5.

    • A mouse model carrying a gene trap insertion in the Mbd5 gene was generated and characterized.

    • This mouse model recapitulates the phenotype observed in 2q23.1 microdeletion patients that includes abnormal social behavior, cognitive impairment, motor deficit and craniofacial abnormalities.

    • Mbd5 is highly expressed in neurons. Reduced Mbd5 expression results in a deficiency of neurite outgrowth in neuronal primary cultures.

    • This new mouse model confirms the causal role of MBD5 in the 2q23.1 microdeletion syndrome and suggests that neuronal dysfunction is responsible for the observed phenotype.

    • autistic disorder
    • intellectual disability
    • MBD5
    • mouse model
    • Received March 11, 2014.
    • Revision received May 28, 2014.
    • Accepted June 2, 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.

    Vladimir Camarena, Lei Cao, Clemer Abad, Alexander Abrams, Yaima Toledo, Kimi Araki, Masatake Araki, Katherina Walz, Juan I Young
  • Trapping MBD5 to understand 2q23.1 microdeletion syndrome
    1. Deborah Y Kwon1 and
    2. Zhaolan Zhou (zhaolan{at}mail.med.upenn.edu) 1
    1. 1Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Despite genetic evidence implicating MBD5 as the only overlapping gene between various 2q23.1 microdeletions, the function of MBD5 and its causality to 2q23.1 microdeletion syndrome, a disorder characterized by developmental delay and autistic features, has yet to be determined. In this issue of EMBO Molecular Medicine, Camarena et al generate an Mbd5 gene‐trap mouse model and show for the first time that mice with reduced MBD5 expression develop behavioral abnormalities with neuronal function deficits, mimicking symptoms in 2q23.1 microdeletion syndrome, thus supporting a causal role for MBD5 haploinsufficiency in the disorder.

    See also: Camarena V et al

    A novel mouse model reveals that reduced MBD5 expression mimicks symptoms observed in the human 2q23.1 microdeletion syndrome, thus supporting a causal role for MBD5 haploinsufficiency in this disorder.

    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.

    Deborah Y Kwon, Zhaolan Zhou