A new paradigm in toxicology and teratology: Altering gene activity in the absence of DNA sequence variationIntroductionEpigenetic mechanisms: it is not all in the DNADNA methylationHistone modificationsHistone acetylation/deacetylationHistone phosphorylation/dephosphorylationHistone methylation/demethylationHistone ubiquitination/deubiquitinationHistone sumoylationHistone biotinylationRNA interference (RNAi) or RNA silencingSmall interfering RNAs (siRNAs)microRNAs (miRNAs)Repeat-associated RNAs (rasiRNAs)Piwi-associated RNAs (piRNAs)Epigenetic events in mammalian development (e.g. X-chromosome inactivation, genomic imprinting)X-chromosome inactivationGenomic imprintingEpigenetics in diseasesEpigenetic therapiesThe road ahead: future directions and challengesAcknowledgementReferencesReproductive Toxicology 24 (2007) 20–30ReviewA new paradigm in toxicology and teratology: Altering geneactivity in the absence of DNA sequence variation夽Stella Marie Reamon-Buettnera,J¨urgen Borlaka,b,∗aMolecular Medicine and Medical Biotechnology, Fraunhofer Institute of Toxicology and Experimental Medicine,Nikolai Fuchs Strasse 1, 30625 Hannover, GermanybCenter of Pharmacology and Toxicology, Medical School Hannover, Carl-Neuberg Strasse 1, 30625 Hannover, GermanyReceived 27 April 2007; received in revised form 30 April 2007; accepted 8 May 2007Available online 22 May 2007Abstract‘Epigenetics’ is a heritable phenomenon without change in primary DNA sequence. In recent years, this field has attracted much attentionas more epigenetic controls of gene activities are being discovered. Such epigenetic controls ensue from an interplay of DNA methylation,histone modifications, and RNA-mediated pathways from non-coding RNAs, notably silencing RNA (siRNA) and microRNA (miRNA). Althoughepigenetic regulation is inherent to normal development and differentiation, this can be misdirected leading to a number of diseases includingcancer. All the same, many of the processes can be reversed offering a hope for epigenetic therapies such as inhibitors of enzymes controllingepigenetic modifications, specifically DNA methyltransferases, histone deacetylases, and RNAi therapeutics. ‘In utero’ or early life exposuresto dietary and environmental exposures can have a profound effect on our epigenetic code, the so-called ‘epigenome’, resulting in birth defectsand diseases developed later in life. Indeed, examples are accumulating in which environmental exposures can be attributed to epigenetic causes,an encouraging edge towards greater understanding of the contribution of epigenetic influences of environmental exposures. Routine analysis ofepigenetic modifications as part of the mechanisms of action of environmental contaminants is in order. There is, however, an explosion of researchin the field of epigenetics and to keep abreast of these developments could be a challenge. In this paper, we provide an overview of epigeneticmechanisms focusing on recent reviews and studies to serve as an entry point into the realm of ‘environmental epigenetics’.© 2007 Elsevier Inc. All rights reserved.Keywords: Epigenetics; DNA methylation; Histone modifications; Chromatin remodelling; RNA silencing pathways; Genomic imprinting; Genomic reprogrammingContents1. Introduction ............................................................................................................. 212. Epigenetic mechanisms: it is not all in the DNA ............................................................................. 212.1. DNA methylation .................................................................................................. 212.2. Histone modifications .............................................................................................. 222.2.1. Histone acetylation/deacetylation ............................................................................ 222.2.2. Histone phosphorylation/dephosphorylation .................................................................. 232.2.3. Histone methylation/demethylation .......................................................................... 232.2.4. Histone ubiquitination/deubiquitination ...................................................................... 232.2.5. Histone sumoylation........................................................................................ 242.2.6. Histone biotinylation ....................................................................................... 24夽Plenary paper to be presented by JB for the education course and symposium ‘Epigenetics of normal and abnormal development’ on the occasion of the 35thAnnual Conference of the European Teratology Society, Bratislava, Slovak Republic, September 1–7, 2007.∗Corresponding author at: Molecular Medicine and Medical Biotechnology, Fraunhofer Institute of Toxicology and Experimental Medicine, Nikolai FuchsStrasse 1, 30625 Hannover, Germany. Tel.: +49 511 5350 559; fax: +49 511 5350 573.E-mail address: [email protected] (J. Borlak).0890-6238/$ – see front matter © 2007 Elsevier Inc. All rights reserved.doi:10.1016/j.reprotox.2007.05.002S.M. Reamon-Buettner, J. Borlak / Reproductive Toxicology 24 (2007) 20–30 212.3. RNA interference (RNAi) or RNA silencing .......................................................................... 242.3.1. Small interfering RNAs (siRNAs)............................................................................ 252.3.2. microRNAs (miRNAs) ..................................................................................... 252.3.3. Repeat-associated RNAs (rasiRNAs) ......................................................................... 252.3.4. Piwi-associated RNAs (piRNAs) ............................................................................ 253. Epigenetic events in mammalian development (e.g. X-chromosome inactivation, genomic imprinting) ............................ 263.1. X-chromosome inactivation ......................................................................................... 263.2. Genomic imprinting ................................................................................................ 264. Epigenetics in diseases .................................................................................................... 265. Epigenetic therapies ...................................................................................................... 276. The road ahead: future directions and
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