Introduction to Epigenetics Implications for Human Nutrition Outline

Total Page:16

File Type:pdf, Size:1020Kb

Introduction to Epigenetics Implications for Human Nutrition Outline Introduction to Epigenetics Implications for Human Nutrition Outline • Epigenetics in Action • Defining (Epi)genetics • ‘Writers’, ‘Readers’ and ‘Erasers’ of epigenetic information • Environmental Epigenomics Nutri(Epi)genomics Epigenetics: “what makes us different even when we are equal” Agouti viable Rainbow yellow Carbon-copy Epigenetics: “what makes us different even when we are equal” - hundreds of different kinds of cells in our bodies - each one derives from the same starting point and has the same 20000 odd genes - as cells develop, their fate is governed by the selective use and silencing of genes - this process is subject to epigenetic factors http://www.ncbi.nlm.nih.gov/About/primer/genetics_cell.html (Epi)genetics • The study of: ‘Any heritable alteration in gene function that does not result in a change in DNA sequence but will have a significant impact on the development of the organism’ The epigenetic marks • DNA Methylation (Me) • Histone modifications (mod) • Non-coding RNAs (ncRNA) www.Epigenome-noe.net/ Epigenetics deals with modifications of chromatin (DNA and associated proteins) which are heritable, reversible and affect genome function (transcription, replication, recombination, chromosome structure, etc.) Why is Epigenetics important? Epigenetics creates a memory of cell identity www.Epigenome-noe.net/ AHEAD Epigenome project (2008) Nature 454: 711 Why is it important to maintain cellular memory? Differentiated cell (e.g.liver cell) + liver cell + liver cell CH3 CH3 CH3 Ac Ac Ac CH3 CH3 CH3 Ac Ac Ac CH3 CH3 CH3 “Fixed epigenotype” Dedifferentiated cell Cancer Ac Loss of memory Rett Syndrome (“variegating” Ac ICF Syndrome CH3 Fragile X epigenotype) CH3 BWS Ac Prader-Willi Epigenetics and Gene Transcription ON Transcription complex Accessible / Active Nucleosome Active histone modification Repressive histone modification OFF DNA methylation Transcription No transcription Condensed / Silent The 5th Base of DNA: Cytosine DNA methylation Dnmts (1, 3a, 3b, 3L) Methyl binding proteins DNA methylation machinery Passive demethylation (writers, readers & erasers) Active demethylation: - Enzymes? - via DNA repair? Epigenetic phenomena associated with DNA methylation Bulk genomic DNA is subject to low density CpG island methylation mCG CG • Genomic stability and control of transposon activity • Genomic imprinting in plants and mammals • X-inactivation in mammals • Transcriptional regulation (cell differentiation; cancer biology) How is methylated DNA translated into a silencing signal? 1. Repulsion of transcription factors 2. Attraction of Repressors/repulsion of activators Sasai & Defossez (2009) Int J Dev Biol 53:323; Bogdanovic & Veenstra (2009) Chromosoma 118:549 Histones are subject to hundreds of modifications Histone modifications serve to recruit and bind critical DNA-regulatory proteins that control transcription, replication, recombination and repair – an HISTONE CODE? Complex histone modification machinery (writers, readers and erasers) In In Epigenetics (eds. Allis, Jenuwein, Reinberg), CSH Press, 2007 Histone Acetylation In Epigenetics (eds. Allis, Jenuwein, Reinberg), CSH Press, 2007 Histone methylation H3K27 methylation H3K4 methylation (repressive OFF) (activating ON) In Epigenetics (eds. Allis, Jenuwein, Reinberg), CSH Press, 2007 Pharmaco(epi)genomics In Epigenetics (eds. Allis, Jenuwein, Reinberg), CSH Press, 2007 Non-coding RNAs Long non-coding RNAs (> 2Kb long) Short non-coding RNAs (siRNAs, miRNAs, PiwiRNAs, snoRNAs) (21nt to 300 nt) Many Involved in silencing pathways: through chromatin-dependent gene silencing pathways (e.g. lncRNAs) or RNA degradation or translation arrest (e.g. miRNAs) Disruption of ncRNAs linked to human disease: The imprinted Kcnq1ot1 lncRNA How dynamic is the Epigenome? • Epigenetic marks are stably propagated during cell division and contribute to cell lineage determination • But they can switch from being “stable” to being “flexible”: Reprogramming of the epigenetic information during development (somatic epigenetic patterns need to be ‘reset’ or ‘reprogrammed in germ cells and also in early embryos in order to achieve developmental pluripotency) Jirtle RL and Skinner MK (2007) Nat Rev Genet 8:253-262 How dynamic is the Epigenome? Epigenetic states can undergo regulated change in response to particular stimuli in order to modulate gene expression as the need arises (e.g. response to external environmental factors) Genome how the genome integrates intrinsic and environmental signals Epigenetics Environment Environmental Epigenomics • Evidence that links epigenetics as potential mechanistic explanation for the long- term impact of the environment on physiology and behavior: Royal Jelly – the ultimate Vernalization in Epigenetic studies in diet evolution plants in Monozygous twins 3year-old 50 year-old Nutritional control of Epigenetic responses to reproductive status in cold temperatures & Divergent Disease honeybees via DNA long-term memory susceptibility? methylation Environmental Epigenomics II “A mother’s behaviour can Endocrine disruptors and affect the chemistry of DNA in transgenerational effects her offspring…” of environmental insults Maternal care controls level of DNA methylation Decrease in spermatogenesis not only of the glucocorticoid receptor in the in treated animals but in males of Hypocampus of offspring, with long- several subsequent generations (F1- term effects F4)- Altered DNA methylation? Effect of diet on DNA methylation and phenotype in offspring Maternal Nutrition in Avy mice: Jirtle RL and Skinner MK (2007) Nat Rev Genet 8:253-262 Maternal diet and offspring health Suboptimal diet Gene expression changes in fetus Cellular memory of suboptimal early nutrition Aging Effects on tissue function Metabolic Disease HNF4a – Master Regulator Pancreatic tissue development Pancreatic tissue function (fetal life) (adult life) Nutritional programming model Dietary effects on Epigenetic Regulation of Enhancer-Promoter Interactions YOUNG ADULTS OLD ADULTS Normal diet Enh P2 Enh P2 +++ ++ Activating Enhancer P Promoter Silencing Low protein diet P2 Enh P2 Enh ++ Enhancer-specific + epigenetic modifications Ozanne S et al. (2011) Aging 5:548 Sandovici I et al. (2011) Proc Natl Acad Sci 108:5449 Conclusions • Maternal diet and age reduces Hnf4a expression • The mechanism of this reduction is epigenetic • Maternal diet exacerbates the epigenetic silencing during aging • These changes explain why poor diet during pregnancy leads to increased risk of diabetes in the offspring • Similar mechanisms operate in human islets Nutri(Epi)genomics • There is now clear evidence that dietary factors influence epigenetic marking of genes, both in animal and human population studies (e.g. folic acid, methyl donors, choline, selenium, genistein, protein, butyrate, etc.) • However little is known about precise mechanisms, doses of dietary factors and duration of exposure/depletion needed to provoked changes and the extent of which these are tissue-specific • Likely that epigenetic changes will occur by (i) altering abundance or efficacy of the “writers” and “erasers” of epigenetic information, and/or by (ii) altering the availibility of substrates Points for discussion - epigenetic factors govern the interpretation of DNA within each living cell - understanding these factors will revolutionize evolutionary and developmental biology, and thus affect practices from medicine to agriculture - hereditary, environmental and stochastic factors determine the accumulation of epigenetic variation over time – their relative contribution to phenotypic variation and increased risk of common diseases remains largely unknown - epigenetics is a potential mechanistic explanation for the long-term impact of the environment on physiology and behavior (e.g acting on windows of epigenetic “reprogramming”) - potential applications in clinical practice: epigenetic biomarkers for early diagnosis of disease preventive measures based on diet drugs that target epigenetic marking of specific genes .
Recommended publications
  • Epigenome Chaos: Stochastic and Deterministic DNA Methylation Events Drive Cancer Evolution
    cancers Review Epigenome Chaos: Stochastic and Deterministic DNA Methylation Events Drive Cancer Evolution Giusi Russo 1, Alfonso Tramontano 2, Ilaria Iodice 1, Lorenzo Chiariotti 1 and Antonio Pezone 1,* 1 Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli “Federico II”, 80131 Naples, Italy; [email protected] (G.R.); [email protected] (I.I.); [email protected] (L.C.) 2 Department of Precision Medicine, University of Campania “L. Vanvitelli”, 80138 Naples, Italy; [email protected] * Correspondence: [email protected] or [email protected]; Tel.: +39-081-746-3614 Simple Summary: Cancer is a group of diseases characterized by abnormal cell growth with a high potential to invade other tissues. Genetic abnormalities and epigenetic alterations found in tumors can be due to high levels of DNA damage and repair. These can be transmitted to daughter cells, which assuming other alterations as well, will generate heterogeneous and complex populations. Deciphering this complexity represents a central point for understanding the molecular mechanisms of cancer and its therapy. Here, we summarize the genomic and epigenomic events that occur in cancer and discuss novel approaches to analyze the epigenetic complexity of cancer cell populations. Abstract: Cancer evolution is associated with genomic instability and epigenetic alterations, which contribute to the inter and intra tumor heterogeneity, making genetic markers not accurate to monitor tumor evolution. Epigenetic changes, aberrant DNA methylation and modifications of chromatin proteins, determine the “epigenome chaos”, which means that the changes of epigenetic traits are Citation: Russo, G.; Tramontano, A.; randomly generated, but strongly selected by deterministic events.
    [Show full text]
  • The International Human Epigenome Consortium (IHEC): a Blueprint for Scientific Collaboration and Discovery
    The International Human Epigenome Consortium (IHEC): A Blueprint for Scientific Collaboration and Discovery Hendrik G. Stunnenberg1#, Martin Hirst2,3,# 1Department of Molecular Biology, Faculties of Science and Medicine, Radboud University, Nijmegen, The Netherlands 2Department of Microbiology and Immunology, Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada V6T 1Z4. 3Canada’s Michael Smith Genome Science Center, BC Cancer Agency, Vancouver, BC, Canada V5Z 4S6 #Corresponding authors [email protected] [email protected] Abstract The International Human Epigenome Consortium (IHEC) coordinates the generation of a catalogue of high-resolution reference epigenomes of major primary human cell types. The studies now presented (cell.com/XXXXXXX) highlight the coordinated achievements of IHEC teams to gather and interpret comprehensive epigenomic data sets to gain insights in the epigenetic control of cell states relevant for human health and disease. One of the great mysteries in developmental biology is how the same genome can be read by cellular machinery to generate the plethora of different cell types required for eukaryotic life. As appreciation grew for the central roles of transcriptional and epigenetic mechanisms in specification of cellular fates and functions, researchers around the world encouraged scientific funding agencies to develop an organized and standardized effort to exploit epigenomic assays to shed additional light on this process (Beck, Olek et al. 1999, Jones and Martienssen 2005, American Association for Cancer Research Human Epigenome Task and European Union 2008). In March 2009, leading scientists and international health research funding agency representatives were invited to a meeting in Bethesda (MD, USA) to gauge the level of interest in an international epigenomics project and to identify potential areas of focus.
    [Show full text]
  • Epigenome-Wide Association Study (EWAS) on Lipids: the Rotterdam Study Kim V
    Braun et al. Clinical Epigenetics (2017) 9:15 DOI 10.1186/s13148-016-0304-4 RESEARCH Open Access Epigenome-wide association study (EWAS) on lipids: the Rotterdam Study Kim V. E. Braun1, Klodian Dhana1, Paul S. de Vries1,2, Trudy Voortman1, Joyce B. J. van Meurs3,4, Andre G. Uitterlinden1,3,4, BIOS consortium, Albert Hofman1,5, Frank B. Hu5,6, Oscar H. Franco1 and Abbas Dehghan1* Abstract Background: DNA methylation is a key epigenetic mechanism that is suggested to be associated with blood lipid levels. We aimed to identify CpG sites at which DNA methylation levels are associated with blood levels of triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and total cholesterol in 725 participants of the Rotterdam Study, a population-based cohort study. Subsequently, we sought replication in a non-overlapping set of 760 participants. Results: Genome-wide methylation levels were measured in whole blood using the Illumina Methylation 450 array. Associations between lipid levels and DNA methylation beta values were examined using linear mixed-effect models. All models were adjusted for sex, age, smoking, white blood cell proportions, array number, and position on array. A Bonferroni-corrected p value lower than 1.08 × 10−7 was considered statistically significant. Five CpG sites annotated to genes including DHCR24, CPT1A, ABCG1,andSREBF1 were identified and replicated. Four CpG sites were associated with triglycerides, including CpG sites annotated to CPT1A (cg00574958 and cg17058475), ABCG1 (cg06500161), and SREBF1 (cg11024682). Two CpG sites were associated with HDL-C, including ABCG1 (cg06500161) and DHCR24 (cg17901584). No significant associations were observed with LDL-C or total cholesterol.
    [Show full text]
  • Chromatin Accessibility and the Regulatory Epigenome
    REVIEWS EPIGENETICS Chromatin accessibility and the regulatory epigenome Sandy L. Klemm1,4, Zohar Shipony1,4 and William J. Greenleaf1,2,3* Abstract | Physical access to DNA is a highly dynamic property of chromatin that plays an essential role in establishing and maintaining cellular identity. The organization of accessible chromatin across the genome reflects a network of permissible physical interactions through which enhancers, promoters, insulators and chromatin-binding factors cooperatively regulate gene expression. This landscape of accessibility changes dynamically in response to both external stimuli and developmental cues, and emerging evidence suggests that homeostatic maintenance of accessibility is itself dynamically regulated through a competitive interplay between chromatin- binding factors and nucleosomes. In this Review , we examine how the accessible genome is measured and explore the role of transcription factors in initiating accessibility remodelling; our goal is to illustrate how chromatin accessibility defines regulatory elements within the genome and how these epigenetic features are dynamically established to control gene expression. Chromatin- binding factors Chromatin accessibility is the degree to which nuclear The accessible genome comprises ~2–3% of total Non- histone macromolecules macromolecules are able to physically contact chroma­ DNA sequence yet captures more than 90% of regions that bind either directly or tinized DNA and is determined by the occupancy and bound by TFs (the Encyclopedia of DNA elements indirectly to DNA. topological organization of nucleosomes as well as (ENCODE) project surveyed TFs for Tier 1 ENCODE chromatin- binding factors 13 Transcription factor other that occlude access to lines) . With the exception of a few TFs that are (TF). A non- histone protein that DNA.
    [Show full text]
  • Epigenetic Regulation of Circadian Clocks and Its Involvement in Drug Addiction
    G C A T T A C G G C A T genes Review Epigenetic Regulation of Circadian Clocks and Its Involvement in Drug Addiction Lamis Saad 1,2,3, Jean Zwiller 1,4, Andries Kalsbeek 2,3 and Patrick Anglard 1,5,* 1 Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364 CNRS, Université de Strasbourg, Neuropôle de Strasbourg, 67000 Strasbourg, France; [email protected] (L.S.); [email protected] (J.Z.) 2 The Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW), 1105 BA Amsterdam, The Netherlands; [email protected] 3 Department of Endocrinology and Metabolism, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands 4 Centre National de la Recherche Scientifique (CNRS), 75016 Paris, France 5 Institut National de la Santé et de la Recherche Médicale (INSERM), 75013 Paris, France * Correspondence: [email protected]; Tel.: +33-03-6885-2009 Abstract: Based on studies describing an increased prevalence of addictive behaviours in several rare sleep disorders and shift workers, a relationship between circadian rhythms and addiction has been hinted for more than a decade. Although circadian rhythm alterations and molecular mechanisms associated with neuropsychiatric conditions are an area of active investigation, success is limited so far, and further investigations are required. Thus, even though compelling evidence connects the circadian clock to addictive behaviour and vice-versa, yet the functional mechanism behind this interaction remains largely unknown. At the molecular level, multiple mechanisms have been proposed to link the circadian timing system to addiction. The molecular mechanism of the circadian Citation: Saad, L.; Zwiller, J.; clock consists of a transcriptional/translational feedback system, with several regulatory loops, that Kalsbeek, A.; Anglard, P.
    [Show full text]
  • The Epigenome Impacts Our Health in a Big Way
    Anne Johnson: Welcome to Environmental Health Chat, a podcast about how the environment affects our health, from the National Institute of Environmental Health Sciences. I’m your host Anne Johnson. I’m going to start with a familiar story. From our parents, we inherit genes, which are made of DNA. Those genes, the so-called “code of life,” make us who we are. But that story has gotten a lot more complicated recently. It turns out that proteins really do the heavy lifting in our cells, by interpreting the genome and carrying out the functions that keep us alive. And those proteins get their marching orders from all these little marks that are scattered along the genome, telling the proteins when and where to activate certain genes. All those little marks together make up what’s now called the “epigenome.” Today’s guest, Dr. Randy Jirtle, says the epigenome impacts our health in a big way. Randy is a Visiting Scientist at the University of Wisconsin, Madison and Professor of Epigenetics at the University of Bedfordshire in the United Kingdom. Given his background in computer science, he likes to explain it this way. Jirtle: The genome is comparable to the hardware of the computer. Now, the epigenome is comparable to the software, telling the genome when, where, and how to work. Even though every cell in our body has the same genome, we have 250-300 different cell types in our body and the reason we have that is that during early development, the developmental process involved layering down and setting down these different chemical marks that tells the cell that ‘you are now going to be a liver cell, a skin cell, an eye cell, a hair cell, etc.’ So we’re a conglomeration of cells that have very different functions.
    [Show full text]
  • Profiling DNA Methylation Based on Next-Generation Sequencing Approaches
    G C A T T A C G G C A T genes Review Profiling DNA Methylation Based on Next-Generation Sequencing Approaches: New Insights and Clinical Applications Daniela Barros-Silva 1 ID , C. Joana Marques 2,3 ID , Rui Henrique 1,4,5 ID and Carmen Jerónimo 1,5,* ID 1 Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Rua António Bernardino Almeida, 4200-072 Porto, Portugal; [email protected] (D.B.-S.); [email protected] (R.H.) 2 Genetics, Department of Pathology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal; [email protected] 3 I3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal 4 Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal 5 Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS)—University of Porto, 4050-313 Porto, Portugal * Correspondence: [email protected]; Tel.: +351-225084000; Fax: +351-225084199 Received: 23 May 2018; Accepted: 20 August 2018; Published: 23 August 2018 Abstract: DNA methylation is an epigenetic modification that plays a pivotal role in regulating gene expression and, consequently, influences a wide variety of biological processes and diseases. The advances in next-generation sequencing technologies allow for genome-wide profiling of methyl marks both at a single-nucleotide and at a single-cell resolution. These profiling approaches vary in many aspects, such as DNA input, resolution, coverage, and bioinformatics analysis. Thus, the selection of the most feasible method according with the project’s purpose requires in-depth knowledge of those techniques.
    [Show full text]
  • Methylated DNA Immunoprecipitation and High-Throughput Sequencing (Medip-Seq) Using Low Amounts of Genomic DNA
    CELLULAR REPROGRAMMING Volume 16, Number 3, 2014 Original Article ª Mary Ann Liebert, Inc. DOI: 10.1089/cell.2014.0002 Methylated DNA Immunoprecipitation and High-Throughput Sequencing (MeDIP-seq) Using Low Amounts of Genomic DNA Ming-Tao Zhao,1 Jeffrey J. Whyte,1 Garrett M. Hopkins,2 Mark D. Kirk,2 and Randall S. Prather1 Abstract DNA modifications, such as methylation and hydroxymethylation, are pivotal players in modulating gene ex- pression, genomic imprinting, X-chromosome inactivation, and silencing repetitive sequences during embryonic development. Aberrant DNA modifications lead to embryonic and postnatal abnormalities and serious human diseases, such as cancer. Comprehensive genome-wide DNA methylation and hydroxymethylation studies provide a way to thoroughly understand normal development and to identify potential epigenetic mutations in human diseases. Here we established a working protocol for methylated DNA immunoprecipitation combined with next-generation sequencing [methylated DNA immunoprecipitation (MeDIP)-seq] for low starting amounts of genomic DNA. By using spike-in control DNA sets with standard cytosine, 5-methylcytosine (5mC), and 5- hydroxymethylcytosine (5hmC), we demonstrate the preferential binding of antibodies to 5mC and 5hmC, respectively. MeDIP-PCRs successfully targeted highly methylated genomic loci with starting genomic DNA as low as 1 ng. The enrichment efficiency declined for constant spiked-in controls but increased for endogenous methylated regions. A MeDIP-seq library was constructed starting with 1 ng of DNA, with the majority of fragments between 250 bp and 600 bp. The MeDIP-seq reads showed higher quality than the Input control. However, after being preprocessed by Cutadapt, MeDIP (97.53%) and Input (94.98%) reads showed comparable alignment rates.
    [Show full text]
  • Protocol: Methylated DNA Immunoprecipitation
    Methylated DNA Immunoprecipitation (MeDIP) (PROT33) Michaël Weber and Dirk Schübeler CNRS UMR 5535 1919 Route de Mende 34293 Montpellier, France Email feedback to: [email protected] Last reviewed : 01 Aug 2007 by Daniel Zilberman, University of California, Berkeley, CA 94720, [email protected] Introduction Methylation of cytosines can mediate epigenetic gene silencing and is the most prominent DNA modification in eukaryotes. MeDIP is an immunocapturing approach to enrich DNA that is methylated. The principle is that genomic DNA is randomly sheared by sonication and immunoprecipitated with an antibody that specifically recognizes 5-methylcytidine (5mC) (Figure 1). This protocol has been used to generate comprehensive DNA methylation profiles on a genome scale in mammals and plants[1-3], and to identify abnormally methylated genes in cancer cells [1]. Procedure Preparation of genomic DNA The MeDIP protocol has been successfully used with genomic DNA from various organisms that contain methylated cytosines in their genome (human, mouse, Arabidopsis thaliana, Neurospora crassa). 1. Resuspend the cell pellet or the homogenized tissue in 300 µl TE in a 2 ml eppendorf tube (the volume should be increased for big cell pellets or tissue samples) 2. Add 300 µl Lysis buffer containing 20 µl proteinase K (10 mg/ml stock) (note 1) 3. Incubate at 55°C for at least 5 hours 4. Extract with 1 volume phenol (600 µl) 5. Extract with 1 volume chloroform (600 µl) 6. Precipitate the DNA with 2 volumes ethanol 75 mM NaAcetate (1.2 ml) 7. Resuspend the DNA pellet in TE containing 20 µg/ml RNAse A (note 2) Sonication of genomic DNA Genomic DNA is randomly sheared by sonication to generate fragments between 300 and 1000 bp.
    [Show full text]
  • Epigenome Prediction of Gene Expression Using a Dynamical System Approach
    bioRxiv preprint doi: https://doi.org/10.1101/2020.08.03.234740; this version posted August 4, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Epigenome Prediction of Gene Expression using a Dynamical System Approach James Brunnery Center for Individualized Medicine Microbiome Program, Mayo Clinic Rochester, MN 55901, USA yE-mail: [email protected] www.mayo.edu Jacob Kim Department of Biological Sciences, Columbia University New York, NY 10027, USA www.columbia.edu Timothy Downing The Henry Samueli School of Engineering, University of California Irvine Irvine, CA 92697, USA www.uci.edu Eric Mjolsness Departments of Computer Science and Mathematics, University of California Irvine Irvine, CA 92697, USA www.uci.edu Kord M. Koberz Department of Physiological Nursing and Bakar Computational Health Sciences Institute, University of California San Francisco San Francisco, CA 94143, USA zE-mail: [email protected] www.ucsf.edu Gene regulation is an important fundamental biological process. The regulation of gene ex- pression is managed through a variety of methods including epigentic processes (e.g., DNA methylation). Understanding the role of epigenetic changes in gene expression is a funda- mental question of molecular biology. Predictions of gene expression values from epigenetic data have tremendous research and clinical potential. Dynamical systems can be used to generate a model to predict gene expression using epigenetic data and a gene regulatory network (GRN).
    [Show full text]
  • Genome-Wide DNA Methylation Profiling with Medip-Seq Using Archived Dried Blood Spots Nicklas H
    Staunstrup et al. Clinical Epigenetics (2016) 8:81 DOI 10.1186/s13148-016-0242-1 RESEARCH Open Access Genome-wide DNA methylation profiling with MeDIP-seq using archived dried blood spots Nicklas H. Staunstrup1,2,4*, Anna Starnawska1,4,5, Mette Nyegaard1,4,5, Lene Christiansen6, Anders L. Nielsen1,4, Anders Børglum1,3,4,5 and Ole Mors2,3,4 Abstract Background: In utero and early-life experienced environmental exposures are suggested to play an important role in many multifactorial diseases potentially mediated through lasting effects on the epigenome. As the epigenome in addition remains modifiable throughout life, identifying specific disease-relevant biomarkers may prove challenging. This has led to an increased interest in epigenome-wide association studies using dried blood spots (DBS) routinely collected in perinatal screening programs. Such programs are in place in numerous countries around the world producing large and unique biobanks. However, availability of this biological material is highly limited as each DBS is made only from a few droplets of blood and storage conditions may be suboptimal for epigenetic studies. Furthermore, as relevant markers may reside outside gene bodies, epigenome-wide interrogation is needed. Results: Here we demonstrate, as a proof of principle, that genome-wide interrogation of the methylome based on methylated DNA immunoprecipitation coupled with next-generation sequencing (MeDIP-seq) is feasible using asingle3.2mmDBSpunch(60ngDNA)fromfiltercardsarchived for up to 16 years. The enrichment profile, sequence quality and distribution of reads across genetic regions were comparable between samples archived 16 years, 4 years and a freshly prepared control sample. Conclusions: In summary, we show that high-quality MeDIP-seq data is achievable from neonatal screening filter cards stored at room temperature, thereby providing information on annotated as well as on non-RefSeq genes and repetitive elements.
    [Show full text]
  • Transgenerational Epigenetics
    CHAPTER Paternal epigenetic inheritance 6 Rahia Mashoodh1, Frances A. Champagne2 Department of Zoology, University of Cambridge, Cambridge, United Kingdom1; Department of Psychology, University of Texas at Austin, Austin, TX, United States2 Chapter outline Introduction.........................................................................................................................................107 Paternal intergenerational and transgenerational effects........................................................................108 Nutritional effects ................................................................................................................ 108 Drugs and toxins .................................................................................................................. 108 Social environments ............................................................................................................. 109 Paternal age......................................................................................................................... 110 Mechanisms of paternal intergenerational and transgenerational effects.................................................111 Genetic modification............................................................................................................. 111 Epigenetic modifications ....................................................................................................... 113 DNA methylation .................................................................................................................
    [Show full text]