DOCSLIB.ORG

Epigenetic Mechanisms in Memory Formation

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Epigenetic Mechanisms in Memory Formation REVIEWS EPIGENETIC MECHANISMS IN MEMORY FORMATION Jonathan M. Levenson and J. David Sweatt Abstract | Discoveries concerning the molecular mechanisms of cell differentiation and development have dictated the definition of a new sub-discipline of genetics known as epigenetics. Epigenetics refers to a set of self-perpetuating, post-translational modifications of DNA and nuclear proteins that produce lasting alterations in chromatin structure as a direct consequence, and lasting alterations in patterns of gene expression as an indirect consequence. The area of epigenetics is a burgeoning subfield of genetics in which there is considerable enthusiasm driving new discoveries. Neurobiologists have only recently begun to investigate the possible roles of epigenetic mechanisms in behaviour, physiology and neuropathology. Strikingly, the relevant data from the few extant neurobiology-related studies have already indicated a theme — epigenetic mechanisms probably have an important role in synaptic plasticity and memory formation. Epigenetic mechanisms typically involve heritable alter- What is epigenetics? ations in chromatin structure, which, in turn, regulate Epigenetics and its associated terminology have several gene expression. Fundamental insights about epigenetic connotations, and specific terms need to be defined heritability have come from studies of cell division and before we can discuss them in detail. We define the development. However, there is increasing evidence that genome as a complete set of haploid DNA and the func- the regulation of chromatin structure through histone tional units that it encodes. In the nucleus, DNA exists as acetylation and DNA methylation might mediate long- a highly compressed structure that consists of DNA and lasting behavioural changes in the context of learning protein, known as chromatin. The epigenome is the and memory. This idea is fascinating because similar sum of both the chromatin structure and the pattern mechanisms are used for triggering and storing long- of DNA methylation, which is the result of an inter- term memories at the cellular level during, for example, action between the genome and the environment. Three cell differentiation. Another intriguing aspect of this definitions for the term ‘epigenetic’ are currently in use hypothesis is that the storage of lifelong behavioural in the literature. memory might involve lasting changes in the physical, The broadest definition includes the transmission three-dimensional structure of DNA itself. and perpetuation of information through meiosis or Epigenetics is unfamiliar to most neurobiologists. mitosis that is not based on the sequence of DNA. This Recently, cellular, molecular and behavioural approaches process is not restricted to DNA-based transmission and have led to several exciting developments in this area can also be protein-based. This definition is broadly Department of that specifically concern neurobiological systems. In this used in the yeast literature, wherein phenotypes that can Neuroscience, Baylor College of Medicine, One Baylor review, we first introduce the topic of epigenetics and be inherited by daughter cells are perpetuated past cell Plaza, S607, Houston, then discuss the idea that the conservation of epigenetic division using protein-based mechanisms1–3. Texas 77030, USA. mechanisms for information storage represents a uni- Developmental biologists and cancer researchers Correspondence to J.D.S. fying model in biology, with epigenetic mechanisms provide a second definition for epigenetic: meiotically e-mail: [email protected] being used for cellular memory at different levels that and mitotically heritable changes in gene expression doi:10.1038/nrn1604 range from cellular differentiation to development to that are not coded in the DNA sequence itself. The Published online 14 January 2005 behavioural memory. altered patterns of gene expression can occur through 108 | FEBRUARY 2005 | VOLUME 6 www.nature.com/reviews/neuro REVIEWS The genome is marked by, for example, DNA methyla- tion or histone acetylation (or lack thereof) at specific ES cell sites that are acquired as part of the differentiation process Determination but are self-perpetuating during DNA replication and cell division. Several hepatic nuclear factors have been shown to be involved in mediating liver-specific gene expression Liver stem Neural stem cell cell during development through the regulation of histone 6–8 Differentiation acetylation .Moreover, developmentally-induced changes in histone acetylation are stably propagated from mother to daughter cells in mammals9.So,a liver cell Liver cell 1 Liver cell 2 Neural cell 1 Neural cell 2 perpetuates its specific acquired pattern of gene expres- sion across cellular generations and over time through these heritable epigenetic marks — an example of lasting Preservation of Figure 1 | Memory at the cellular level. All embryonic stem epigenetic state (ES) cells begin with identical genotypes and phenotypes. memory at the cellular level. throughout future External signals trigger developmental events that lead to the The formation of epigenetic memory is not limited cell divisions differentiation of cells. Mature cells become phenotypically to mammalian cells. Plants are induced to flower by a distinct, but remain genotypically identical. The differences in process known as vernalization that also involves epige- gene expression persist in the face of numerous cell divisions, netic mechanisms (for a review, see REF.10). For example, which indicates that they are self-sustaining. These a biennial plant must experience a period of cold Liver cell developmentally induced changes in gene expression in mature cells are mediated by epigenetic regulation of gene expression. weather between its first and second years of existence for its flowering to be triggered. Exposure to cold in biennial plants results in the activation of epigenetic several mechanisms that are based on DNA, RNA or mechanisms that involve methylation of DNA-binding proteins (see below)4. proteins and acetylation of histones, and these processes A third definition posits that epigenetics is the trigger mitotically stable changes in the pattern of gene mechanism for the stable maintenance of gene expression. In this way, plant cells ‘remember’ their expression that involves physically ‘marking’ DNA or exposure to the winter cold and are prepared for the its associated proteins. This allows genotypically iden- plant to flower during the next spring. tical cells (such as all cells in an individual human) to Another example involves T cells of the mammalian be phenotypically distinct (for example, a neuron is immune system. The commitment of T-lymphocyte phenotypically distinct from a liver cell). The mole- precursors to a wide variety of differentiated states with cular and physical basis for this type of change in different patterns of gene expression is triggered by DNA or chromatin structure5 is the focus of this numerous epigenetic mechanisms that involve DNA review. By this definition, the regulation of chromatin methylation and histone modifications (for a review, see structure is equivalent to epigenetics. REF.11). These processes are important in the formation of long-lasting immunological memory in response to a Epigenetics for information storage transient signal from the environment. Several classic examples illustrate the importance of Are these epigenetic mechanisms also extant and epigenetic mechanisms in information storage at the operable in non-dividing, terminally differentiated cellular level. They indicate that epigenetic mechanisms neurons in the adult CNS? Adult neurons no longer are widely used for the formation and storage of cellular have the problem of heritability. However, are the basic information in response to transient environmental epigenetic mechanisms that are important for infor- signals. We present these examples to emphasize that the mation storage during development also important for storage of cellular information is in some ways analo- storing memories that manifest themselves behav- gous to memory storage in the adult nervous system. iourally in the adult? We predict that these mechanisms Moreover, the lasting cellular changes are triggered by a are conserved in the adult nervous system, where they transient signal in each case, which is also analogous to have been co-opted to serve the formation of behav- the formation of behavioural memory in the CNS. ioural memories. Epigenetic mechanisms subserve A prototype example is mammalian cellular differ- changes in neuronal function in the adult that are entiation. Once an embryonic precursor cell is triggered components of memory at the behavioural level. We to differentiate into a particular cell type (for example, a propose that epigenetic processes constitute a unified liver cell), that cell and its subsequent daughter cells set of molecular mechanisms that allow information might be required to undergo thousands of cell divi- storage in systems as diverse as yeast, plants, cellular sions over the lifetime of the animal. How does a liver differentiation and memory storage in the mammalian cell remember that it is a liver cell when, over the course CNS. To this end, we view chromatin as a dynamic of cell division, it must replicate de novo its entire structure that can integrate potentially hundreds of genome? The information clearly cannot be contained signals from the cell surface and effect a coordinated in the DNA sequence itself. As mentioned
Load more

Recommended publications
  • SHARP1 (BHLHE41) Mouse Monoclonal Antibody [Clone ID: OTI3H4] Product Data
    OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for TA806354 SHARP1 (BHLHE41) Mouse Monoclonal Antibody [Clone ID: OTI3H4] Product data: Product Type: Primary Antibodies Clone Name: OTI3H4 Applications: IHC, WB Recommended Dilution: WB 1:2000, IHC 1:150 Reactivity: Human Host: Mouse Isotype: IgG1 Clonality: Monoclonal Immunogen: Human recombinant protein fragment corresponding to amino acids 1-297 of human BHLHE41(NP_110389) produced in E.coli. Formulation: PBS (PH 7.3) containing 1% BSA, 50% glycerol and 0.02% sodium azide. Concentration: 1 mg/ml Purification: Purified from mouse ascites fluids or tissue culture supernatant by affinity chromatography (protein A/G) Conjugation: Unconjugated Storage: Store at -20°C as received. Stability: Stable for 12 months from date of receipt. Predicted Protein Size: 50.3 kDa Gene Name: basic helix-loop-helix family member e41 Database Link: NP_110389 Entrez Gene 79365 Human Q9C0J9 Background: This gene encodes a basic helix-loop-helix protein expressed in various tissues. The encoded protein can interact with ARNTL or compete for E-box binding sites in the promoter of PER1 and repress CLOCK/ARNTL's transactivation of PER1. This gene is believed to be involved in the control of circadian rhythm and cell differentiation. Defects in this gene are associated with the short sleep phenotype. [provided by RefSeq, Feb 2014] This product is to be used for laboratory only. Not for diagnostic or therapeutic use. View online » ©2021 OriGene Technologies, Inc., 9620 Medical Center Drive, Ste 200, Rockville, MD 20850, US 1 / 2 SHARP1 (BHLHE41) Mouse Monoclonal Antibody [Clone ID: OTI3H4] – TA806354 Synonyms: BHLHB3; DEC2; hDEC2; SHARP1 Protein Families: Transcription Factors Protein Pathways: Circadian rhythm - mammal Product images: HEK293T cells were transfected with the pCMV6- ENTRY control (Left lane) or pCMV6-ENTRY BHLHE41 ([RC206882], Right lane) cDNA for 48 hrs and lysed.
    [Show full text]
  • A Wheel of Time: the Circadian Clock, Nuclear Receptors, and Physiology
    Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press PERSPECTIVE A wheel of time: the circadian clock, nuclear receptors, and physiology Xiaoyong Yang1 Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06519, USA It is a long-standing view that the circadian clock func- The rhythmic production and circulation of many tions to proactively align internal physiology with the hormones and metabolites within the endocrine system 24-h rotation of the earth. Recent studies, including one is instrumental in regulating regular physiological pro- by Schmutz and colleagues (pp. 345–357) in the February cesses such as reproduction, blood pressure, and metabo- 15, 2010, issue of Genes & Development, delineate strik- lism. Levels of circulating estrogen and progesterone ingly complex connections between molecular clocks and fluctuate with the menstrual cycle, which in turn affect nuclear receptor signaling pathways, implying the exis- circadian rhythms in women (Shechter and Boivin 2010). tence of a large-scale circadian regulatory network co- In parallel with a diurnal rhythm in circulating adrenocor- ordinating a diverse array of physiological processes to ticotropic hormone, secretion of glucocorticoids and aldo- maintain dynamic homeostasis. sterone from the adrenal gland rises before awakening (Weitzman 1976). Glucocorticoids boost energy produc- tion, and aldosterone increases blood pressure, together gearing up the body for the activity phase. Similarly, Light from the sun sustains life on earth. The 24-h plasma levels of thyroid-stimulating hormone and triiodo- rotation of the earth exposes a vast number of plants thyronine have a synchronous diurnal rhythm (Russell and animals to the light/dark cycle.
    [Show full text]
  • Role of the Nuclear Receptor Rev-Erb Alpha in Circadian Food Anticipation and Metabolism Julien Delezie
    Role of the nuclear receptor Rev-erb alpha in circadian food anticipation and metabolism Julien Delezie To cite this version: Julien Delezie. Role of the nuclear receptor Rev-erb alpha in circadian food anticipation and metabolism. Neurobiology. Université de Strasbourg, 2012. English. NNT : 2012STRAJ018. tel- 00801656 HAL Id: tel-00801656 https://tel.archives-ouvertes.fr/tel-00801656 Submitted on 10 Apr 2013 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSITÉ DE STRASBOURG ÉCOLE DOCTORALE DES SCIENCES DE LA VIE ET DE LA SANTE CNRS UPR 3212 · Institut des Neurosciences Cellulaires et Intégratives THÈSE présentée par : Julien DELEZIE soutenue le : 29 juin 2012 pour obtenir le grade de : Docteur de l’université de Strasbourg Discipline/ Spécialité : Neurosciences Rôle du récepteur nucléaire Rev-erbα dans les mécanismes d’anticipation des repas et le métabolisme THÈSE dirigée par : M CHALLET Etienne Directeur de recherche, université de Strasbourg RAPPORTEURS : M PFRIEGER Frank Directeur de recherche, université de Strasbourg M KALSBEEK Andries
    [Show full text]
  • Correlation Between Circadian Gene Variants and Serum Levels of Sex Steroids and Insulin-Like Growth Factor-I
    3268 Correlation between Circadian Gene Variants and Serum Levels of Sex Steroids and Insulin-like Growth Factor-I Lisa W. Chu,1,2 Yong Zhu,3 Kai Yu,1 Tongzhang Zheng,3 Anand P. Chokkalingam,4 Frank Z. Stanczyk,5 Yu-Tang Gao,6 and Ann W. Hsing1 1Division of Cancer Epidemiology and Genetics and 2Cancer Prevention Fellowship Program, Office of Preventive Oncology, National Cancer Institute, NIH, Bethesda, Maryland; 3Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut; 4Division of Epidemiology, School of Public Health, University of California at Berkeley, Berkeley, California; 5Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, California; and 6Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China Abstract A variety of biological processes, including steroid the GG genotype. In addition, the PER1 variant was hormone secretion, have circadian rhythms, which are associated with higher serum levels of sex hormone- P influenced by nine known circadian genes. Previously, binding globulin levels ( trend = 0.03), decreasing we reported that certain variants in circadian genes 5A-androstane-3A,17B-diol glucuronide levels P P were associated with risk for prostate cancer. To pro- ( trend = 0.02), and decreasing IGFBP3 levels ( trend = vide some biological insight into these findings, we 0.05). Furthermore, the CSNK1E variant C allele was examined the relationship of five variants of circadian associated with higher
    [Show full text]
  • BMAL1 and Modulates Tissue-Specific Circadian Networks
    Nuclear receptor HNF4A transrepresses CLOCK: BMAL1 and modulates tissue-specific circadian networks Meng Qua, Tomas Duffyb, Tsuyoshi Hirotac, and Steve A. Kaya,1 aKeck School of Medicine, University of Southern California, Los Angeles, CA 90089; bDepartment of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037; and cInstitute of Transformative Bio-Molecules, Nagoya University, 464-8602 Nagoya, Japan Contributed by Steve A. Kay, November 6, 2018 (sent for review September 24, 2018; reviewed by Carla B. Green and John B. Hogenesch) Either expression level or transcriptional activity of various nuclear NRs canonically function as ligand-activated transcription receptors (NRs) have been demonstrated to be under circadian factors that regulate the expression of their target genes to control. With a few exceptions, little is known about the roles of affect physiological pathways (19). The importance of NRs in NRs as direct regulators of the circadian circuitry. Here we show maintaining optimal physiological homeostasis is illustrated in that the nuclear receptor HNF4A strongly transrepresses the their identification as potential targets for therapeutic drug transcriptional activity of the CLOCK:BMAL1 heterodimer. We development to combat a diverse array of diseases, including define a central role for HNF4A in maintaining cell-autonomous reproductive disorders, inflammation, cancer, diabetes, car- circadian oscillations in a tissue-specific manner in liver and colon diovascular disease, and obesity (20). Various NRs have been cells. Not only transcript level but also genome-wide chromosome implicated as targets of the circadian clock, which may con- binding of HNF4A is rhythmically regulated in the mouse liver. tribute to the circadian regulation of nutrient and energy me- ChIP-seq analyses revealed cooccupancy of HNF4A and CLOCK: tabolism.
    [Show full text]
  • Dissociation of Per1 and Bmal1 Circadian Rhythms in The
    Dissociation of Per1 and Bmal1 circadian rhythms in PNAS PLUS the suprachiasmatic nucleus in parallel with behavioral outputs Daisuke Onoa,1,2, Sato Honmab,1,3, Yoshihiro Nakajimac, Shigeru Kurodad, Ryosuke Enokia,b,e, and Ken-ichi Honmab aPhotonic Bioimaging Section, Research Center for Cooperative Projects, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan; bDepartment of Chronomedicine, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan; cHealth Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Takamatsu, Kagawa 761-0395, Japan; dResearch Institute for Electronic Science, Hokkaido University, Sapporo, 001-0020, Japan; and ePrecursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan Edited by Joseph S. Takahashi, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, and approved March 28, 2017 (received for review August 11, 2016) The temporal order of physiology and behavior in mammals is The expression of Per genes in the SCN is activated by a timed primarily regulated by the circadian pacemaker located in the exposure to light, which phase shifts the circadian pacemaker (8, hypothalamic suprachiasmatic nucleus (SCN). Taking advantage of 9). The phase-dependent phase shifts of clock gene expression bioluminescence reporters, we monitored the circadian rhythms of are regarded as a key mechanism by which the circadian pace- the expression of clock genes Per1 and Bmal1 in the SCN of freely maker is entrained to a LD cycle. Light signals from the retina moving mice and found that the rate of phase shifts induced by a stimulate the expression of Per genes, perturbing the core loop single light pulse was different in the two rhythms.
    [Show full text]
  • Molecular Oscillation of Per1 and Per2 Genes in the Rodent Brain: an in Situ Hybridization and Molecular Biological Study
    Kobe J. Med. Sci., Vol. 51, No. 6, pp. 85-93, 2005 Molecular Oscillation of Per1 and Per2 Genes in the Rodent Brain: An In Situ Hybridization and Molecular Biological Study DAISUKE MATSUI, SEIICHI TAKEKIDA, and HITOSHI OKAMURA Division of Molecular Brain Science, Department of Brain Science/Neuroscience, Kobe University Graduate School of Medicine Received 20 December 2005 /Accepted 26 December 2005 Key Words: in situ hybridization, cerebral cortex, clock genes, circadian rhythms, E-box, rat The circadian rhythm is originally generated by a transcription-translation based oscillatory loop where Per1 and Per2 genes locate in its central. In the rat brain, rhythmic expressions of Per1 and Per2 were observed not only in neurons of the hypothalamic suprachiasmatic nucleus (SCN) but also in those of non-SCN regions including the cerebral cortex. The E-box enhancer elements possible to regulate transcription of Per1 and Per2 genes were highly conserved in rats and mice. When E-box-activating transcription factors, CLOCK and BMAL1, were coexpressed, each of both proteins showed two molecular forms. The presence of these higher molecular weight forms seems to be correlated with the E-box mediated transcription activation. This mechanism might not be involved in the PER2 mediated suppression of E-box, since adding PER2 did not change the content of the higher molecular forms of CLOCK and BMAL1. Circadian core oscillator is thought to be composed of an autoregulatory transcription- (post) translation-based feedback loop involving a set of clock genes (3, 4, 10, 16). In this loop, Per1 and Per2 genes are located in the center of this loop, and the transcriptional oscillation of these genes reflects rhythms at cells, tissues, and system levels (10, 16).
    [Show full text]
  • The Role of Circadian Timing System on Drug Metabolism and Detoxification
    The role of circadian timing system on drug metabolism and detoxification Abstract Introduction: It has been known for a long time that the efficiency and toxicity of drugs change during a 24-hour period. However, the molecular mechanisms involved in these regulations have started to emerge only recently. Areas covered: This review aims to highlight recent discoveries showing the direct role of the molecular circadian clock on xenobiotic metabolism at the transcriptional and post- transcriptional level in the liver and intestine, but also the different ways of elimination of these metabolized drugs via biliary and urine excretion. Most of the related literature focuses on transcriptional regulation by the circadian clock of xenobiotic metabolism in the liver, however the role of this timing system on metabolized drugs excretion and the importance of the kidney on this phenomenon are generally neglected. The goal of this review is to describe the molecular mechanisms involved in rhythmic drug metabolism and excretion. Expert opinion: Chronopharmacology analyses the metabolism of drugs in mammals according to the time of day. The circadian timing system plays a key role in these changes of toxicity of drugs by influencing their metabolisms in the liver and intestine in addition to their excretion via bile flow and urine. Article Highlights ● It has been known for a long time that drug efficiency and toxicity depend on the time of administration, however the mechanisms involved have only started to emerge recently. ● There is clear evidence that the molecular circadian clock is involved in this process. ● The molecular clock acts either directly or through the rhythmic expression of clock- controlled transcription factors that regulate the expression of detoxification enzymes or indirect pathways.
    [Show full text]
  • Identification of Genomic Targets of Krüppel-Like Factor 9 in Mouse Hippocampal
    Identification of Genomic Targets of Krüppel-like Factor 9 in Mouse Hippocampal Neurons: Evidence for a role in modulating peripheral circadian clocks by Joseph R. Knoedler A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Neuroscience) in the University of Michigan 2016 Doctoral Committee: Professor Robert J. Denver, Chair Professor Daniel Goldman Professor Diane Robins Professor Audrey Seasholtz Associate Professor Bing Ye ©Joseph R. Knoedler All Rights Reserved 2016 To my parents, who never once questioned my decision to become the other kind of doctor, And to Lucy, who has pushed me to be a better person from day one. ii Acknowledgements I have a huge number of people to thank for having made it to this point, so in no particular order: -I would like to thank my adviser, Dr. Robert J. Denver, for his guidance, encouragement, and patience over the last seven years; his mentorship has been indispensable for my growth as a scientist -I would also like to thank my committee members, Drs. Audrey Seasholtz, Dan Goldman, Diane Robins and Bing Ye, for their constructive feedback and their willingness to meet in a frequently cold, windowless room across campus from where they work -I am hugely indebted to Pia Bagamasbad and Yasuhiro Kyono for teaching me almost everything I know about molecular biology and bioinformatics, and to Arasakumar Subramani for his tireless work during the home stretch to my dissertation -I am grateful for the Neuroscience Program leadership and staff, in particular
    [Show full text]
  • Crosstalk Between Xenobiotics Metabolism and Circadian Clock
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector FEBS Letters 581 (2007) 3626–3633 Minireview Crosstalk between xenobiotics metabolism and circadian clock Thierry Claudela, Gaspard Cretenetb,c, Anne Saumetb,c, Fre´de´ric Gachonb,c,* a Department of Pediatrics, Research Laboratory, University Medical Center Groningen, Groningen, ND-9700 RB, The Netherlands b Inserm, Equipe Avenir, Montpellier F-34396, France c CNRS, Institut de Ge´ne´tique Humaine, UPR 1142, Montpellier F-34396, France Received 22 February 2007; revised 30 March 2007; accepted 3 April 2007 Available online 17 April 2007 Edited by Robert Barouki metabolism and detoxification are regulated in an anticipatory Abstract Many aspects of physiology and behavior in organ- isms from bacteria to man are subjected to circadian regulation. fashion by the circadian clock [2]. For example, rest and activ- Indeed, the major function of the circadian clock consists in the ity cycles, heart rate, blood pressure, bile and urine produc- adaptation of physiology to daily environmental change and the tion, drug metabolism and transport in liver and intestine as accompanying stresses such as exposition to UV-light and food- well as endocrine functions are all subjected to daily fluctua- contained toxic compounds. In this way, most aspects of xenobi- tions. The mammalian timing system is organized in a hierar- otic detoxification are subjected to circadian regulation. These chical manner with a central pacemaker located in the phenomena are now considered as the molecular basis for the suprachiasmatic nucleus (SCN) of the hypothalamus which time-dependence of drug toxicities and efficacy.
    [Show full text]
  • Up-Regulation of PER3 Expression Is Correlated with Better Clinical Outcome in Acute Leukemia
    ANTICANCER RESEARCH 35: 6615-6622 (2015) Up-regulation of PER3 Expression Is Correlated with Better Clinical Outcome in Acute Leukemia MING-YU YANG1, PAI-MEI LIN2, HUI-HUA HSIAO3,4, JUI-FENG HSU5, HUGO YOU-HSIEN LIN5,6, CHENG-MING HSU1,7, I-YA CHEN1, SHENG-WEN SU1, YI-CHANG LIU3,4 and SHENG-FUNG LIN3,4 1Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, R.O.C.; 2Department of Nursing, I-Shou University, Kaohsiung City, Taiwan, R.O.C.; 3Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung City, Taiwan, R.O.C.; 4Faculty of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan, R.O.C.; 5Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan, R.O.C.; 6Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan, R.O.C.; 7Department of Otolaryngology, Kaoshiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, R.O.C. Abstract. Background: Altered expression of circadian treatment. Conclusion: Circadian clock genes are altered in clock genes has been linked to various types of cancer. This patients with acute leukemia and up-regulation of PER3 is study aimed to investigate whether these genes are also correlated with a better clinical outcome. altered in acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). Materials and Methods: The expression Acute leukemia comprises about 20,000 cancer diagnoses profiles of nine circadian clock genes of peripheral blood and 10,000 deaths in the United States each year (1).
    [Show full text]
  • P53 Regulates Period2 Expression and the Circadian Clock
    ARTICLE Received 27 Feb 2013 | Accepted 15 Aug 2013 | Published 20 Sep 2013 DOI: 10.1038/ncomms3444 p53 regulates Period2 expression and the circadian clock Takao Miki1,w, Tomoko Matsumoto1, Zhaoyang Zhao1 & Cheng Chi Lee1 The mechanistic interconnectivity between circadian regulation and the genotoxic stress response remains poorly understood. Here we show that the expression of Period 2 (Per2),a circadian regulator, is directly regulated by p53 binding to a response element in the Per2 promoter. This p53 response element is evolutionarily conserved and overlaps with the E-Box element critical for BMAL1/CLOCK binding and its transcriptional activation of Per2 expression. Our studies reveal that p53 blocks BMAL1/CLOCK binding to the Per2 promoter, leading to repression of Per2 expression. In the suprachiasmatic nucleus (SCN), p53 expression and its binding to the Per2 promoter are under circadian control. Per2 expression in the SCN is altered by p53 deficiency or stabilization of p53 by Nutlin-3. Behaviourally, p53 À / À mice have a shorter period length that lacks stability, and they exhibit impaired photo-entrainment to a light pulse under a free-running state. Our studies demonstrate that p53 modulates mouse circadian behaviour. 1 Department of Biochemistry and Molecular Biology, Medical School, University of Texas Health Science Center-Houston, Houston, Texas 77030, USA. w Present address: Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan. Correspondence and requests for materials should be addressed to C.C.L. (email: [email protected]). NATURE COMMUNICATIONS | 4:2444 | DOI: 10.1038/ncomms3444 | www.nature.com/naturecommunications 1 & 2013 Macmillan Publishers Limited.
    [Show full text]