From Circuits to Chromatin: the Emerging Role of Epigenetics in Mental Health
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Visualizing Morphogenesis with the Processing Programming Language 15
Visualizing Morphogenesis with the Processing Programming Language 15 Visualizing Morphogenesis with the Processing Programming Language Avik Patel, Amar Bains, Richard Millet, and Tamira Elul changing tissue shapes. A powerful technique for elucidating the We used Processing, a visual artists’ programming dynamic cellular mechanisms of morphogenesis is time-lapse video- language developed at MIT Media Lab, to simulate microscopic imaging of cells in embryonic tissues undergoing cellular mechanisms of morphogenesis – the generation morphogenesis (Elul and Keller 2000; Elul et al., 1997; Harris et al., of form and shape in embryonic tissues. Based on 1987). The mechanisms underlying morphogenetic processes can be clarified by observation of cell dynamics from these time-lapse video observations of in vivo time-lapse image sequences, we sequences. Morphometric measurement further defines the created animations of neural cell motility responsible for quantitative and statistical relationships between the cell dynamics that elongating the spinal cord, and of optic axon branching underlie morphogenesis (Kim and Davidson 2011; Marshak et al., dynamics that establish primary visual connectivity. 2007; Elul et al., 1997; Witte et al., 1996). Mathematical These visual models underscore the significance of the decomposition of cell dynamics additionally facilitates the computational decomposition of cellular dynamics computational modeling of cellular mechanisms that drive underlying morphogenesis. morphogenesis (Satulovsky et al., 2008). Methods In this paper, we use the Processing programming language to visualize dynamic cell behaviors driving morphogenesis in the Introduction developing nervous system. Based on in vivo time-lapse image sequences, we created models of cell dynamics underlying two Processing is a Java based software language and environment morphogenetic processes in the developing nervous system. -
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. -
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. -
Transformations of Lamarckism Vienna Series in Theoretical Biology Gerd B
Transformations of Lamarckism Vienna Series in Theoretical Biology Gerd B. M ü ller, G ü nter P. Wagner, and Werner Callebaut, editors The Evolution of Cognition , edited by Cecilia Heyes and Ludwig Huber, 2000 Origination of Organismal Form: Beyond the Gene in Development and Evolutionary Biology , edited by Gerd B. M ü ller and Stuart A. Newman, 2003 Environment, Development, and Evolution: Toward a Synthesis , edited by Brian K. Hall, Roy D. Pearson, and Gerd B. M ü ller, 2004 Evolution of Communication Systems: A Comparative Approach , edited by D. Kimbrough Oller and Ulrike Griebel, 2004 Modularity: Understanding the Development and Evolution of Natural Complex Systems , edited by Werner Callebaut and Diego Rasskin-Gutman, 2005 Compositional Evolution: The Impact of Sex, Symbiosis, and Modularity on the Gradualist Framework of Evolution , by Richard A. Watson, 2006 Biological Emergences: Evolution by Natural Experiment , by Robert G. B. Reid, 2007 Modeling Biology: Structure, Behaviors, Evolution , edited by Manfred D. Laubichler and Gerd B. M ü ller, 2007 Evolution of Communicative Flexibility: Complexity, Creativity, and Adaptability in Human and Animal Communication , edited by Kimbrough D. Oller and Ulrike Griebel, 2008 Functions in Biological and Artifi cial Worlds: Comparative Philosophical Perspectives , edited by Ulrich Krohs and Peter Kroes, 2009 Cognitive Biology: Evolutionary and Developmental Perspectives on Mind, Brain, and Behavior , edited by Luca Tommasi, Mary A. Peterson, and Lynn Nadel, 2009 Innovation in Cultural Systems: Contributions from Evolutionary Anthropology , edited by Michael J. O ’ Brien and Stephen J. Shennan, 2010 The Major Transitions in Evolution Revisited , edited by Brett Calcott and Kim Sterelny, 2011 Transformations of Lamarckism: From Subtle Fluids to Molecular Biology , edited by Snait B. -
Epigenetics in Clinical Practice: the Examples of Azacitidine and Decitabine in Myelodysplasia and Acute Myeloid Leukemia
Leukemia (2013) 27, 1803–1812 & 2013 Macmillan Publishers Limited All rights reserved 0887-6924/13 www.nature.com/leu SPOTLIGHT REVIEW Epigenetics in clinical practice: the examples of azacitidine and decitabine in myelodysplasia and acute myeloid leukemia EH Estey Randomized trials have clearly demonstrated that the hypomethylating agents azacitidine and decitabine are more effective than ‘best supportive care’(BSC) in reducing transfusion frequency in ‘low-risk’ myelodysplasia (MDS) and in prolonging survival compared with BSC or low-dose ara-C in ‘high-risk’ MDS or acute myeloid leukemia (AML) with 21–30% blasts. They also appear equivalent to conventional induction chemotherapy in AML with 420% blasts and as conditioning regimens before allogeneic transplant (hematopoietic cell transplant, HCT) in MDS. Although azacitidine or decitabine are thus the standard to which newer therapies should be compared, here we discuss whether the improvement they afford in overall survival is sufficient to warrant a designation as a standard in treating individual patients. We also discuss pre- and post-treatment covariates, including assays of methylation to predict response, different schedules of administration, combinations with other active agents and use in settings other than active disease, in particular post HCT. We note that rational development of this class of drugs awaits delineation of how much of their undoubted effect in fact results from hypomethylation and reactivation of gene expression. Leukemia (2013) 27, 1803–1812; doi:10.1038/leu.2013.173 -
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. -
Nicotinic Receptor Alpha7 Expression During Tooth Morphogenesis Reveals Functional Pleiotropy
Nicotinic Receptor Alpha7 Expression during Tooth Morphogenesis Reveals Functional Pleiotropy Scott W. Rogers1,2*, Lorise C. Gahring1,3 1 Geriatric Research, Education and Clinical Center, Veteran’s Administration, Salt Lake City, Utah, United States of America, 2 Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, Utah, United States of America, 3 Division of Geriatrics, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, United States of America Abstract The expression of nicotinic acetylcholine receptor (nAChR) subtype, alpha7, was investigated in the developing teeth of mice that were modified through homologous recombination to express a bi-cistronic IRES-driven tau-enhanced green fluorescent protein (GFP); alpha7GFP) or IRES-Cre (alpha7Cre). The expression of alpha7GFP was detected first in cells of the condensing mesenchyme at embryonic (E) day E13.5 where it intensifies through E14.5. This expression ends abruptly at E15.5, but was again observed in ameloblasts of incisors at E16.5 or molar ameloblasts by E17.5–E18.5. This expression remains detectable until molar enamel deposition is completed or throughout life as in the constantly erupting mouse incisors. The expression of alpha7GFP also identifies all stages of innervation of the tooth organ. Ablation of the alpha7-cell lineage using a conditional alpha7Cre6ROSA26-LoxP(diphtheria toxin A) strategy substantially reduced the mesenchyme and this corresponded with excessive epithelium overgrowth consistent with an instructive role by these cells during ectoderm patterning. However, alpha7knock-out (KO) mice exhibited normal tooth size and shape indicating that under normal conditions alpha7 expression is dispensable to this process. -
Delta-Notch Signaling: the Long and the Short of a Neuron’S Influence on Progenitor Fates
Journal of Developmental Biology Review Delta-Notch Signaling: The Long and the Short of a Neuron’s Influence on Progenitor Fates Rachel Moore 1,* and Paula Alexandre 2,* 1 Centre for Developmental Neurobiology, King’s College London, London SE1 1UL, UK 2 Developmental Biology and Cancer, University College London Great Ormond Street Institute of Child Health, London WC1N 1EH, UK * Correspondence: [email protected] (R.M.); [email protected] (P.A.) Received: 18 February 2020; Accepted: 24 March 2020; Published: 26 March 2020 Abstract: Maintenance of the neural progenitor pool during embryonic development is essential to promote growth of the central nervous system (CNS). The CNS is initially formed by tightly compacted proliferative neuroepithelial cells that later acquire radial glial characteristics and continue to divide at the ventricular (apical) and pial (basal) surface of the neuroepithelium to generate neurons. While neural progenitors such as neuroepithelial cells and apical radial glia form strong connections with their neighbours at the apical and basal surfaces of the neuroepithelium, neurons usually form the mantle layer at the basal surface. This review will discuss the existing evidence that supports a role for neurons, from early stages of differentiation, in promoting progenitor cell fates in the vertebrates CNS, maintaining tissue homeostasis and regulating spatiotemporal patterning of neuronal differentiation through Delta-Notch signalling. Keywords: neuron; neurogenesis; neuronal apical detachment; asymmetric division; notch; delta; long and short range lateral inhibition 1. Introduction During the development of the central nervous system (CNS), neurons derive from neural progenitors and the Delta-Notch signaling pathway plays a major role in these cell fate decisions [1–4]. -
Development and Evolution
AccessScience from McGraw-Hill Education Page 1 of 4 www.accessscience.com Development and evolution Contributed by: Brian K. Hall Publication year: 2010 The disciplines of developmental biology (or embryology) and evolutionary biology have come together twice—once as evolutionary embryology in the late nineteenth century and again as evolutionary developmental biology (evo-devo, as it is typically known) in the late twentieth century. The current intersections of development and evolution are proving to be of paramount importance for creating a fully integrated theory of biology. History Prior to and into the nineteenth century, the word “evolution” had a completely different meaning from its usage today. Then, it was used to describe a particular type of embryonic or larval development—the preformation and unfolding of a more or less fully formed organism from an embryonic or larval stage (for example, a butterfly from a caterpillar, or aphids from the body of an adult female). In fact, Charles Darwin did not use the word “evolution” per se in On the Origin of Species , which was published in 1859, although “evolved” was the final word of his book. To reach its present-day definition, the term “evolution” had to undergo a slow transformation from development within a single generation to transformation (transmutation) between generations. As for the field of developmental biology, in the nineteenth century, embryology (referring to the study of embryonic development) was a progressive field in biology, with researchers describing normal development and then manipulating animal embryos [ experimental or physiological embryology (also known as developmental mechanics)] in search of altered outcomes that would help explain how development occurred. -
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 -
Clinical Implications of Epigenetics Research
Clinical Implications of Epigenetics Research Nita Ahuja MD FACS Associate Professor of Surgery, Oncology and Urology Vice Chair of Academic Affairs Chief: Section of GI Oncology & BME Services Epigenetics: Our Software August 1, 2014 2 What is Epigenetics? . Heritable changes in gene expression not due to changes in the DNA sequence . DNA methylation . Chromatin structure or histone code . Role in normal and pathological processes, such as aging, mental health, and cancer, among others. DNA Methylation changes in Neoplasia Normal 1 2 3 Cancer 1 2 3 Epigenetic changes in Neoplasia Normal 1 2 3 AcK9 AcK9 MeK9 MeK9 MeK4 MeK4 MeK27 MeK27 Cancer 1 2 3 MeK9 MeK9 MeK9 MeK9 MeK9 MeK27 MeK27 MeK27 MeK27 MeK27 ?? Epigenetic changes in Neoplasia HATs HDemethylases Normal 1 2 3 AcK9 AcK9 MeK9 MeK9 MeK4 MeK4 MeK27 Aging MeK27 Inflammation HDACs H MTases Cancer 1 2 3 MeK9 MeK9 MeK9 MeK9 MeK9 MeK27 MeK27 MeK27 MeK27 MeK27 ?? Ahuja et. al. Cancer Res. 1998 Issa et. al Cancer Res 2001 Cancer Epigenetics: ApplicationsProtein Repressor proteins RNA (MBD, HDAC) DNA Promoter Gene Cancer Marker for Prognostic Reversal of Gene Silencing Molecular Staging And Predictive Epigenetic Early Detection Biomarkers Therapy Colon Cancer Functional Methylome • Each colon cancer has ~150 to 450 DAC methylated genes/tumor TSA Yellow spots indicate genes from DKO cells with 2 fold changes and above. Green spots indicate experimentally verified genes. Red spots indicate those that did not verify. Blue spots indicate the location of the 11 guide genes used in this study. Schuebel -
Bronchial Biopsy Specimen As a Surrogate for DNA Methylation Analysis in Inoperable Lung Cancer
Um et al. Clinical Epigenetics (2017) 9:131 DOI 10.1186/s13148-017-0432-5 RESEARCH Open Access Bronchial biopsy specimen as a surrogate for DNA methylation analysis in inoperable lung cancer Sang-Won Um1†, Hong Kwan Kim2†, Yujin Kim3, Bo Bin Lee3, Dongho Kim3, Joungho Han4, Hojoong Kim1, Young Mog Shim2 and Duk-Hwan Kim3,5* Abstract Background: This study was aimed at understanding whether bronchial biopsy specimen can be used as a surrogate for DNA methylation analysis in surgically resected lung cancer. Methods: A genome-wide methylation was analyzed in 42 surgically resected tumor tissues, 136 bronchial washing, 12 sputum, and 8 bronchial biopsy specimens using the Infinium HumanMethylation450 BeadChip, and models for prediction of lung cancer were evaluated using TCGA lung cancer data. Results: Four thousand seven hundred and twenty-six CpGs (P < 1.0E-07) that were highly methylated in tumor tissues were identified from 42 lung cancer patients. Ten CpGs were selected for prediction of lung cancer. Genes including the 10 CpGs were classified into three categories: (i) transcription (HOXA9, SOX17, ZNF154, HOXD13); (ii) cell signaling (HBP1, SFRP1, VIPR2); and (iii) adhesion (PCDH17, ITGA5, CD34). Three logistic regression models based on the 10 CpGs classified 897 TCGA primary lung tissues with a sensitivity of 95.0~97.8% and a specificity of 97.4~98. 7%. However, the classification performance of the models was very poor in bronchial washing samples: the area under the curve (AUC) was equal to 0.72~0.78. The methylation levels of the 10 CpGs in bronchial biopsy were not significantly different from those in surgically resected tumor tissues (P > 0.05, Wilcoxon rank-sum test).