DOCSLIB.ORG

Lysine-Specific Histone Demethylases Contribute to Cellular

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Lysine-Specific Histone Demethylases Contribute to Cellular epigenomes Review Lysine-Specific Histone Demethylases Contribute to Cellular Differentiation and Carcinogenesis Gaetano Verde 1,*, Jessica Querol-Paños 2, Joan Pau Cebrià-Costa 2, Laura Pascual-Reguant 2, Gemma Serra-Bardenys 1, Ane Iturbide 3 and Sandra Peiró 2,* 1 Programa de Recerca en Càncer, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain; [email protected] 2 Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain; [email protected] (J.Q.-P.); [email protected] (J.P.C.-C.); [email protected] (L.P.-R.) 3 Institute of Epigenetics and Stem Cells, Helmholtz Zentrum München, D-81377 München, Germany; [email protected] * Correspondence: [email protected] (G.V.); [email protected] (S.P.) Academic Editor: Muller Fabbri Received: 9 February 2017; Accepted: 24 March 2017; Published: 30 March 2017 Abstract: Histone modifications regulate chromatin structure, gene transcription, and other nuclear processes. Among the histone modifications, methylation has been considered to be a stable, irreversible process due to the slow turnover of methyl groups in chromatin. However, the discovery of three different classes of lysine-specific demethylases—KDM1, Jumonji domain-containing demethylases, and lysyl oxidase-like 2 protein—has drastically changed this view, suggesting a role for dynamic histone methylation in different biological process. In this review, we describe the different mechanisms that these enzymes use to remove lysine histone methylation and discuss their role during physiological (cell differentiation) and pathological (carcinogenesis) processes. Keywords: epigenetics; histone demethylases; cellular differentiation; cancer 1. Introduction Histone N-terminal tails can be post-translationally modified with different chemical groups, including methylation. Histone modifications play key roles in chromatin structure and can influence different DNA processes, such as gene transcription, DNA repair, replication, and recombination. Histones can be methylated on both lysine (K) and arginine (R) residues; however, methylation is most frequently observed on lysine residues of the H3 and H4 histone tails [1]. In contrast to other histone modifications, how histone lysine methylation affects gene transcription is strongly dependent upon which amino acid of the peptide is modified. Thus, methylation of lysine 27 (H3K27) or lysine 9 (H3K9) on histone H3, or of lysine 20 on histone 4 (H4K20), is associated with silenced chromatin [2,3]. In contrast, methylation of lysine 4 on histone 4 (H3K4) is primarily associated with gene activation [4], and methylation of lysine 36 on histone H3 (H3K36) generally regulates transcriptional elongation [5]. Moreover, so-called bivalent promoters contain both active (H3K4me3) and repressive (H3K27me3) histone methylation [5]. Genes controlled by bivalent promoters, like the Hox genes, are in a poised intermediate state in stem cells. They can be activated or repressed during stem cell differentiation by removing H3K27me3 or H3K4me3, respectively [5]. It was long believed that methylation is an irreversible modification, since the half-lives of histones and the methyl-lysine residues within them are the same [6,7]—in other words, if it is an irreversible modification, the methyl group would be “removed” by natural histone turnover or by dilution after DNA replication. However, during the last decade, different active lysine demethylation mechanisms have been identified. Three different classes of lysine-specific demethylases catalyze these mechanisms: the lysine (K)-specific demethylase Epigenomes 2017, 1, 4; doi:10.3390/epigenomes1010004 www.mdpi.com/journal/epigenomes Epigenomes 2017, 1, 4 2 of 25 Epigenomes 2017, 1, 4 2 of 26 identified. Three different classes of lysine‐specific demethylases catalyze these mechanisms: the lysine (K)‐specific demethylase 1 (KDM1A‐B, also known as LSD1‐2), the Jumonji C domain‐ containing1 (KDM1A-B, demethylases also known (KDM2–7; as LSD1-2), also the known Jumonji as C JHDM), domain-containing and lysyl oxidase demethylases‐like 2 (LOXL2). (KDM2–7; Each also of theseknown enzyme as JHDM), groups and specifically lysyl oxidase-like removes 2 (LOXL2). one or more Each lysine of these histone enzyme methylation groups specifically groups and removes plays aone key or role more in lysinegene transcription histone methylation (Fig. 1). groups and plays a key role in gene transcription (Figure1). Fig. 1. Lysine‐specific histone methylation and the activity of histone demethylases. Schematic Figure 1. Lysine-specific histone methylation and the activity of histone demethylases. Schematic representation of H3 and H4 histone tails, showing the most frequent lysine residues involved in representation of H3 and H4 histone tails, showing the most frequent lysine residues involved in mono‐, di‐, and trimethylation (stars). The lysine‐histone demethylases KDM1A/B, JHDM clusters mono-, di-, and trimethylation (stars). The lysine-histone demethylases KDM1A/B, JHDM clusters (KDM2–KDM7), and LOXL2, involved in demethylation of specificspecific methyl markers, areare shown.shown. In this review, we describe the mechanisms that these enzymes use to remove the lysine histone methylationIn this review, and discuss we describe their roles the during mechanisms both cell that differentiation these enzymes and use carcinogenesis. to remove the lysine histone methylation and discuss their roles during both cell differentiation and carcinogenesis. 2. Lysine‐Specific Demethylase 1 2. Lysine-Specific Demethylase 1 2.1. KDM1A KDM1A The first first histone demethylase to be discovered was KDM1A (also known as LSD1), which removesremoves methylation fromfrom mono-mono‐ andand dimethylated dimethylated lysine lysine 4 4 (H3K4me1/me2) (H3K4me1/me2) and and lysine lysine 9 9 of of histone histone 3 3(H3K9me1/me2) (H3K9me1/me2) [ 8[8,9].,9]. BasedBased onon itsits sequencesequence analysis,analysis, KDM1A is classifiedclassified as a flavin-dependentflavin‐dependent monoamine oxidaseoxidase (MAO) (MAO) homolog, homolog, and and it uses it uses the cofactorthe cofactor flavin flavin adenine adenine dinucleotide dinucleotide (FAD) during(FAD) duringdemethylation demethylation catalysis catalysis [8,10]. The [8,10]. chemistry The ofchemistry the reaction of followsthe reaction the classical follows amine the classical oxidase scheme: amine oxidasemolecular scheme: oxygen molecular is consumed oxygen during is consumed methyl removalduring methyl to produce removal formaldehyde to produce andformaldehyde hydrogen andperoxide. hydrogen Two peroxide. electrons Two are transferred electrons are from transferred the methyl from carbon the methyl of the dimethylatedcarbon of the residuedimethylated of the residuehistone of to the histone flavin in to the the form flavin of in a hydridethe form anion.of a hydride Molecular anion. oxygen Molecular then oxygen reacts with then the reacts reduced with theFAD, reduced generating FAD, hydrogen generating peroxide. hydrogen The peroxide. resulting The imine-containing resulting imine peptide‐containing is then peptide hydrolyzed, is then hydrolyzed,releasing formaldehyde releasing formaldehyde and the demethylated and the demethylated histone 3 [11 histone,12] (Figure 3 [11,12]2A). (Fig. Structurally, 2 A). Structurally, KDM1A KDM1Acomprises comprises four domains: four domains: an N-terminal an N‐terminal disordered disordered segment, segment, a SWIRM a SWIRM (SWI3p, (SWI3p, Rsc8p, andRsc8p, Moira) and Moira)domain, domain, an amine an oxidase amine domain oxidase (AOD), domain and (AOD), a Tower and domain a Tower (Figure domain2B). The (Fig. N-terminal 2B). The N disordered‐terminal disorderedsegment contains segment about contains 150 amino about acids 150 and amino is subjected acids to and post-translational is subjected modificationsto post‐translational [13–16]. modificationsThis domain is[13 required‐16]. This for domain KDM1A is required nuclear localizationfor KDM1A andnuclear protein–protein localization and interactions protein–protein [17,18]. interactions [17,18]. The SWIRM domain, comprising six α helices and a 310 helix, contributes to the The SWIRM domain, comprising six α helices and a 310 helix, contributes to the structural stability structuralof KDM1A stability and, compressed of KDM1A against and, compressed AOD, forms against a groove AOD, that forms allows a groove a larger that interaction allows a regionlarger interactionwith the histone region 3 tailwith [11 ,the19]. histone AOD contains 3 tail the[11,19]. catalytic AOD activity contains for thethe demethylation catalytic activity reaction for andthe demethylationis divided into reaction two different and is halvesdivided by into the two Tower different domain. halves The by two the Tower halves domain. of AOD The form two a unique halves ofglobular AOD form domain a unique consisting globular of two domain lobes. The consisting first lobe, of comprisingtwo lobes. The a six-stranded first lobe, βcomprising-sheet and fivea sixα‐ stranded β‐sheet and five α helices, enables KDM1A to bind to its substrates [20]. The second lobe Epigenomes 2017, 1, 4 3 of 26 Epigenomes 2017, 1, 4 3 of 25 helices, enables KDM1A to bind to its substrates [20]. The second lobe allows KDM1A to bind to the FADallows cofactor KDM1A and to contains bind to the an expandedFAD cofactor Rossmann and contains fold, commonly an expanded found Rossmann in dinucleotide fold, commonly binding modulesfound in [dinucleotide10,19]. Finally, binding the Tower modules domain, [10,19]. comprising
Load more

Recommended publications
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • TITLE Lysine Demethylase 7A Regulates the Anterior-Posterior Development in Mouse by Modulating the Transcription of Hox Gene Cluster
    bioRxiv preprint doi: https://doi.org/10.1101/707125; this version posted July 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. TITLE Lysine demethylase 7a regulates the anterior-posterior development in mouse by modulating the transcription of Hox gene cluster AUTHOR LIST FOOTNOTES Yoshiki Higashijima1,2, Nao Nagai3, Taro Kitazawa4,5, Yumiko Kawamura4,5, Akashi Taguchi2, Natsuko Nakada2, Masaomi Nangaku6, Tetsushi Furukawa1, Hiroyuki Aburatani7, Hiroki Kurihara5, Youichiro Wada2, Yasuharu Kanki2,* 1Department of Bioinformational Pharmacology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan. 2Isotope Science Center, The University of Tokyo, Tokyo 113-0032, Japan. 3Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan. 4Friedrich Miescher Institute for Biomedical Research, Basel 4051, Switzerland. 5Department of Physiological Chemistry and Metabolism, The University of Tokyo, Tokyo 113-0033, Japan. 6Division of Nephrology and Endocrinology, The University of Tokyo, 113-0033 Tokyo, Japan. 7Division of Genome Science, RCAST, The University of Tokyo, Tokyo 153-8904, Japan. *Correspondence: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/707125; this version posted July 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. SUMMARY Temporal and spatial colinear expression of the Hox genes determines the specification of positional identities during vertebrate development. Post-translational modifications of histones contribute to transcriptional regulation. Lysine demethylase 7A (Kdm7a) demethylates lysine 9 di-methylation of histone H3 (H3K9me2) and participates in the transcriptional activation of developmental genes.
    [Show full text]
  • Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
    BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in
    [Show full text]
  • The Tale of Histone Modifications and Its Role in Multiple Sclerosis Hui He, Zhiping Hu, Han Xiao, Fangfang Zhou and Binbin Yang*
    He et al. Human Genomics (2018) 12:31 https://doi.org/10.1186/s40246-018-0163-5 REVIEW Open Access The tale of histone modifications and its role in multiple sclerosis Hui He, Zhiping Hu, Han Xiao, Fangfang Zhou and Binbin Yang* Abstract Epigenetics defines the persistent modifications of gene expression in a manner that does not involve the corresponding alterations in DNA sequences. It includes modifications of DNA nucleotides, nucleosomal remodeling, and post-translational modifications (PTMs). It is becoming evident that PTMs which act singly or in combination to form “histone codes” orchestrate the chromatin structure and dynamic functions. PTMs of histone tails have been demonstrated to influence numerous biological developments, as well as disease onset and progression. Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating and neurodegenerative disease of the central nervous system, of which the precise pathophysiological mechanisms remain to be fully elucidated. There is a wealth of emerging evidence that epigenetic modifications may confer risk for MS, which provides new insights into MS. Histone PTMs, one of the key events that regulate gene activation, seem to play a prominent role in the epigenetic mechanism of MS. In this review, we summarize recent studies in our understanding of the epigenetic language encompassing histone, with special emphasis on histone acetylation and histone lysine methylation, two of the best characterized histone modifications. We also discuss how the current studies address histone
    [Show full text]
  • Epigenetic Mechanisms in Developmental Alcohol-Induced Neurobehavioral Deficits
    brain sciences Review Epigenetic Mechanisms in Developmental Alcohol-Induced Neurobehavioral Deficits Balapal S. Basavarajappa 1,2,3,* and Shivakumar Subbanna 1 1 Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA; [email protected] 2 New York State Psychiatric Institute, New York, NY 10032, USA 3 Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA * Correspondence: [email protected]; Tel.: +1-845-398-3234; Fax: +1-845-398-5451 Academic Editor: Marieta B. Heaton Received: 3 February 2016; Accepted: 5 April 2016; Published: 8 April 2016 Abstract: Alcohol consumption during pregnancy and its damaging consequences on the developing infant brain are significant public health, social, and economic issues. The major distinctive features of prenatal alcohol exposure in humans are cognitive and behavioral dysfunction due to damage to the central nervous system (CNS), which results in a continuum of disarray that is collectively called fetal alcohol spectrum disorder (FASD). Many rodent models have been developed to understand the mechanisms of and to reproduce the human FASD phenotypes. These animal FASD studies have provided several molecular pathways that are likely responsible for the neurobehavioral abnormalities that are associated with prenatal alcohol exposure of the developing CNS. Recently, many laboratories have identified several immediate, as well as long-lasting, epigenetic modifications of DNA methylation, DNA-associated histone proteins and microRNA (miRNA) biogenesis by using a variety of epigenetic approaches in rodent FASD models. Because DNA methylation patterns, DNA-associated histone protein modifications and miRNA-regulated gene expression are crucial for synaptic plasticity and learning and memory, they can therefore offer an answer to many of the neurobehavioral abnormalities that are found in FASD.
    [Show full text]
  • Histone Methylation Regulation in Neurodegenerative Disorders
    International Journal of Molecular Sciences Review Histone Methylation Regulation in Neurodegenerative Disorders Balapal S. Basavarajappa 1,2,3,4,* and Shivakumar Subbanna 1 1 Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA; [email protected] 2 New York State Psychiatric Institute, New York, NY 10032, USA 3 Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA 4 New York University Langone Medical Center, Department of Psychiatry, New York, NY 10016, USA * Correspondence: [email protected]; Tel.: +1-845-398-3234; Fax: +1-845-398-5451 Abstract: Advances achieved with molecular biology and genomics technologies have permitted investigators to discover epigenetic mechanisms, such as DNA methylation and histone posttransla- tional modifications, which are critical for gene expression in almost all tissues and in brain health and disease. These advances have influenced much interest in understanding the dysregulation of epigenetic mechanisms in neurodegenerative disorders. Although these disorders diverge in their fundamental causes and pathophysiology, several involve the dysregulation of histone methylation- mediated gene expression. Interestingly, epigenetic remodeling via histone methylation in specific brain regions has been suggested to play a critical function in the neurobiology of psychiatric disor- ders, including that related to neurodegenerative diseases. Prominently, epigenetic dysregulation currently brings considerable interest as an essential player in neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Amyotrophic lateral sclerosis (ALS) and drugs of abuse, including alcohol abuse disorder, where it may facilitate connections between genetic and environmental risk factors or directly influence disease-specific Citation: Basavarajappa, B.S.; Subbanna, S.
    [Show full text]
  • Role of the Histone Demethylase PHF2 During Early Neurogenesis
    Role of the histone demethylase PHF2 during early neurogenesis Stella Pappa ADVERTIMENT. La consulta d’aquesta tesi queda condicionada a l’acceptació de les següents condicions d'ús: La difusió d’aquesta tesi per mitjà del servei TDX (www.tdx.cat) i a través del Dipòsit Digital de la UB (diposit.ub.edu) ha estat autoritzada pels titulars dels drets de propietat intel·lectual únicament per a usos privats emmarcats en activitats d’investigació i docència. No s’autoritza la seva reproducció amb finalitats de lucre ni la seva difusió i posada a disposició des d’un lloc aliè al servei TDX ni al Dipòsit Digital de la UB. No s’autoritza la presentació del seu contingut en una finestra o marc aliè a TDX o al Dipòsit Digital de la UB (framing). Aquesta reserva de drets afecta tant al resum de presentació de la tesi com als seus continguts. En la utilització o cita de parts de la tesi és obligat indicar el nom de la persona autora. ADVERTENCIA. La consulta de esta tesis queda condicionada a la aceptación de las siguientes condiciones de uso: La difusión de esta tesis por medio del servicio TDR (www.tdx.cat) y a través del Repositorio Digital de la UB (diposit.ub.edu) ha sido autorizada por los titulares de los derechos de propiedad intelectual únicamente para usos privados enmarcados en actividades de investigación y docencia. No se autoriza su reproducción con finalidades de lucro ni su difusión y puesta a disposición desde un sitio ajeno al servicio TDR o al Repositorio Digital de la UB.
    [Show full text]
  • Egr2 Upregulation Induced Mitochondrial Iron Overload Implicating in Cognitive Defcits After Sevofurane Administration
    Egr2 Upregulation Induced Mitochondrial Iron Overload Implicating in Cognitive Decits after Sevourane Administration Piao Zhang Zhejiang University Yeru Chen Zhejiang University Shuxia Zhang Zhejiang University Man Fang Zhejiang University Xianyi Lin Zhejiang University Tieshuai Liu Zhejiang University Youfa Zhou Zhejiang University Xin Yu Zhejiang University Gang Chen ( [email protected] ) Zhejiang University Research Keywords: Sevourane, Cognitive dysfunction, Early growth response 2, Mitochondrial, Iron overload Posted Date: November 13th, 2020 DOI: https://doi.org/10.21203/rs.3.rs-104467/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/37 Abstract Background: Sevourane inhalation initiated cognitive decits implicated in mitochondrial dysfunction, synaptogenesis impairment and neuroinammation. Egr2 plays a crucial role in maintaining cognitive function. Therefore, we attempted to clarify the potential correlation regarding Egr2 expression and cognitive decits induced by sevourane administration. Methods: Animals received sevourane anesthesia, and the behavioral tests including Morris water maze, novel object recognition test and trace fear conditioning were performed. Then, the Golgi-Cox staining and Nissl staining were employed to detect the effect of sevourane inhalation in hippocampal neurons. Meanwhile, bioinformatics analysis was implemented, and western blot (WB) and bisulte sequencing PCR (BSP) technique were utilized to validate this hypothesis. Moreover, the level of lipid peroxidation, mitochondrial membrane potential, morphology and membrane permeability, and cytoplasm calcium levels were investigated after Egr2 interference by using JC-1 probe, MitoTracker staining, Mitochondrial permeability transition pore (mPTP) assay, and Fluo calcium indicators, respectively. Additionally, Prussian blue staining was used to evaluate the iron content. Results: The behavioral tests indicated that the cognitive function was signicantly attenuated after sevourane administration.
    [Show full text]
  • Downloaded from the NHGRI-EBI GWAS Catalog (Welter Et Al., 2014)
    bioRxiv preprint doi: https://doi.org/10.1101/456491; this version posted November 11, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. TITLE Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells AUTHOR LIST FOOTNOTES Yoshiki Higashijima1, 2, Yusuke Matsui3, Teppei Shimamura3, Shuichi Tsutsumi4, Ryo Nakaki4, Yohei Abe5, Verena M. Link5, 6, Mizuko Osaka7, 8, Masayuki Yoshida8, Ryo Watanabe9, Toshihiro Tanaka9, 10, Akashi Taguchi2, Mai Miura2, Tsuyoshi Inoue11, Masaomi Nangaku11, Hiroshi Kimura12, Tetsushi Furukawa1, Hiroyuki Aburatani4, Youichiro Wada2, Christopher K. Glass5, 13, Yasuharu Kanki2, 14 * 1Department of Bioinformational Pharmacology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan. 2Isotope Science Center, The University of Tokyo, Tokyo 113-0032, Japan. 3Department of Systems Biology, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan. 4Division of Genome Sciences, RCAST, The University of Tokyo, Tokyo 153-8904, Japan. 5Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. 6Faculty of Biology, Division of Evolutionary Biology, Ludwig-Maximilian University of Munich, Munich, Germany. 7Department of Nutrition in Cardiovascular Disease, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. 8Department of Life Sciences and Bioethics, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. bioRxiv preprint doi: https://doi.org/10.1101/456491; this version posted November 11, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder.
    [Show full text]
  • The Changing Chromatome As a Driver of Disease: a Panoramic View from Different Methodologies
    The changing chromatome as a driver of disease: A panoramic view from different methodologies Isabel Espejo1, Luciano Di Croce,1,2,3 and Sergi Aranda1 1. Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain 2. Universitat Pompeu Fabra (UPF), Barcelona, Spain 3. ICREA, Pg. Lluis Companys 23, Barcelona 08010, Spain *Corresponding authors: Luciano Di Croce ([email protected]) Sergi Aranda ([email protected]) 1 GRAPHICAL ABSTRACT Chromatin-bound proteins regulate gene expression, replicate and repair DNA, and transmit epigenetic information. Several human diseases are highly influenced by alterations in the chromatin- bound proteome. Thus, biochemical approaches for the systematic characterization of the chromatome could contribute to identifying new regulators of cellular functionality, including those that are relevant to human disorders. 2 SUMMARY Chromatin-bound proteins underlie several fundamental cellular functions, such as control of gene expression and the faithful transmission of genetic and epigenetic information. Components of the chromatin proteome (the “chromatome”) are essential in human life, and mutations in chromatin-bound proteins are frequently drivers of human diseases, such as cancer. Proteomic characterization of chromatin and de novo identification of chromatin interactors could thus reveal important and perhaps unexpected players implicated in human physiology and disease. Recently, intensive research efforts have focused on developing strategies to characterize the chromatome composition. In this review, we provide an overview of the dynamic composition of the chromatome, highlight the importance of its alterations as a driving force in human disease (and particularly in cancer), and discuss the different approaches to systematically characterize the chromatin-bound proteome in a global manner.
    [Show full text]
  • Novel Skin Phenotypes Revealed by a Genome-Wide Mouse Reverse Genetic Screen
    ARTICLE Received 9 Jan 2014 | Accepted 4 Mar 2014 | Published 11 Apr 2014 DOI: 10.1038/ncomms4540 OPEN Novel skin phenotypes revealed by a genome-wide mouse reverse genetic screen Kifayathullah Liakath-Ali1,2,3, Valerie E. Vancollie4, Emma Heath1, Damian P. Smedley4, Jeanne Estabel4, David Sunter4, Tia DiTommaso5,w, Jacqueline K. White4, Ramiro Ramirez-Solis4, Ian Smyth5, Karen P. Steel4,6 & Fiona M. Watt1 Permanent stop-and-shop large-scale mouse mutant resources provide an excellent platform to decipher tissue phenogenomics. Here we analyse skin from 538 knockout mouse mutants generated by the Sanger Institute Mouse Genetics Project. We optimize immunolabelling of tail epidermal wholemounts to allow systematic annotation of hair follicle, sebaceous gland and interfollicular epidermal abnormalities using ontology terms from the Mammalian Phenotype Ontology. Of the 50 mutants with an epidermal phenotype, 9 map to human genetic conditions with skin abnormalities. Some mutant genes are expressed in the skin, whereas others are not, indicating systemic effects. One phenotype is affected by diet and several are incompletely penetrant. In-depth analysis of three mutants, Krt76, Myo5a (a model of human Griscelli syndrome) and Mysm1, provides validation of the screen. Our study is the first large-scale genome-wide tissue phenotype screen from the International Knockout Mouse Consortium and provides an open access resource for the scientific community. 1 Centre for Stem Cells and Regenerative Medicine, King’s College London, Guy’s Hospital, London SE1 9RT, UK. 2 Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, UK. 3 Wellcome Trust—Medical Research Council Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
    [Show full text]
  • Epigenome Alterations in Aortic Valve Stenosis and Its Related Left
    Gošev et al. Clinical Epigenetics (2017) 9:106 DOI 10.1186/s13148-017-0406-7 REVIEW Open Access Epigenome alterations in aortic valve stenosis and its related left ventricular hypertrophy Igor Gošev1, Martina Zeljko2, Željko Đurić3, Ivana Nikolić4, Milorad Gošev5, Sanja Ivčević6, Dino Bešić7, Zoran Legčević7 and Frane Paić7* Abstract Aortic valve stenosis is the most common cardiac valve disease, and with current trends in the population demographics, its prevalence is likely to rise, thus posing a major health and economic burden facing the worldwide societies. Over the past decade, it has become more than clear that our traditional genetic views do not sufficiently explain the well-known link between AS, proatherogenic risk factors, flow-induced mechanical forces, and disease-prone environmental influences. Recent breakthroughs in the field of epigenetics offer us a new perspective on gene regulation, which has broadened our perspective on etiology of aortic stenosis and other aortic valve diseases. Since all known epigenetic marks are potentially reversible this perspective is especially exciting given the potential for development of successful and non-invasive therapeutic intervention and reprogramming of cells at the epigenetic level even in the early stages of disease progression. This review will examine the known relationships between four major epigenetic mechanisms: DNA methylation, posttranslational histone modification, ATP-dependent chromatin remodeling, and non-coding regulatory RNAs, and initiation and progression of AS. Numerous profiling and functional studies indicate that they could contribute to endothelial dysfunctions, disease-prone activation of monocyte-macrophage and circulatory osteoprogenitor cells and activation and osteogenic transdifferentiation of aortic valve interstitial cells, thus leading to valvular inflammation, fibrosis, and calcification, and to pressure overload-induced maladaptive myocardial remodeling and left ventricular hypertrophy.
    [Show full text]