Molecular Medicine: How Science Works

Description

The fascinating area of molecular medicine provides a molecular and cellular description of health and disease. Starting with the understanding of gene regulation and epigenetics, i.e., the interplay of transcription factors and chromatin, this book will provide an fundamental basis of nearly all processes in physiology, both in health as well as in most common disorders, such as cancer, diabetes as well as in autoimmune diseases. Most non-communicable human diseases have a genetic (= inherited) as well as an epigenetic component. The later one is based on our lifestyle choices and environmental exposures. Many common diseases, such as type 2 diabetes, can be explained only to some 20% via a genetic predisposition. We cannot change the genes that we are born with but we can take care of the remaining 80% being primarily based on our epigenome. Therefore, there is a high level of individual responsibility for staying healthy. Thus, not only biologists and biochemists should be aware of this topic, but all students of biomedical disciplines will benefit from being introduced into the concepts of molecular medicine. This will provide them with a good basis for their specialized disciplines of modern life science research. The book is subdivided into 42 chapters that are linked to a series of lecture courses in “Molecular Medicine and Genetics”, “Molecular Immunology”, “Cancer Biology” and “Nutrigenomics” that is given by one of us (C. Carlberg) in different forms since 2002 at the University of Eastern Finland in Kuopio. This book represents an updated version and fusion of the books textbooks “Mechanisms of Gene Regulation: How Science Works” (ISBN 978-3-030-52321-3), “Human Epigenetics: How Science Works” (ISBN 978-3-030-22907-8). “Molecular Immunology: How Science Works” (ISBN 978-3-031-04024-5), “Cancer Biology: How Science Works” (ISBN 978-3-030-75699-4) and “Nutrigenomics: How Science Works” (ISBN 978-3-030-36948-4). By combining basic understanding of cellular mechanism with clinical examples, the authors hope to make this textbook a personal experience. A glossary in the appendix will explain the major specialist’s terms. Preface Contents Abbreviations 1 The Human Genome and Its Variations 1.1 Migration of Homo Sapiens and the Diversity of Human Populations 1.2 Genetic Variants of the Human Genome 1.3 Measuring Human Genetic Variations Additional Reading 2 Gene Expression and Chromatin 2.1 Central Dogma of Molecular Biology 2.2 Nucleosomes: Central Units of Chromatin 2.3 Chromatin Structure and Epigenetics 2.4 Epigenetics Enables Gene Expression 2.5 Gene Regulation in the Context of Nuclear Architecture Additional Reading 3 Basal Transcriptional Machinery 3.1 Core Promoter 3.2 TATA Box and Other Core Promoter Elements 3.3 Genome-Wide Core Promoter Identification 3.4 TFIID and MED as Paradigms of Multiprotein Complexes Additional Reading 4 Transcription Factors and Signal Transduction 4.1 Site-Specific Transcription Factors and Their Domains 4.2 Classification of Transcription Factors 4.3 Activation of Transcription Factors 4.4 Inflammatory Signaling via NFκB 4.5 Sensing Cellular Stress via P53 Additional Reading 5 A Key Transcription Factor Family: Nuclear Receptors 5.1 The Nuclear Receptor Superfamily 5.2 Molecular Interactions of Nuclear Receptors 5.3 Nuclear Receptors as Nutrient Sensors 5.4 Integration of Lipid Metabolism by PPARs, LXRs and FXR 5.5 Coordination of the Immune Response by VDR Additional Reading 6 DNA Methylation 6.1 Cytosines and Their Methylation 6.2 The DNA Methylome 6.3 CTCF and Genetic Imprinting 6.4 DNA Methylation and Disease Additional Reading 7 Histone Modifications 7.1 Histones and Their Modifications 7.2 Genome-Wide Interpretation of the Histone Code 7.3 Chromatin Modifiers 7.4 Gene Regulation via Chromatin Modifiers Additional Reading 8 Chromatin Remodeling and Organization 8.1 Nucleosome Positioning at Promoters 8.2 Chromatin Remodeling 8.3 Organization of Chromatin in the Nucleus Additional Reading 9 Regulatory Impact of Non-coding RNA 9.1 Non-Coding RNAs 9.2 miRNAs and Their Regulatory Potential 9.3 Long ncRNAs 9.4 Enhancer RNAs Additional Reading 10 Genome-Wide Principles of Gene Regulation 10.1 Gene Regulation in the Context of Big Biology 10.2 Epigenetic Methods 10.3 Integrating Epigenome-Wide Datasets 10.4 Genome-Wide Understanding of Epigenetics Additional Reading 11 Epigenetics in Development 11.1 Epigenetic Changes During Early Human Development 11.2 The Epigenetic Landscape 11.3 Epigenetic Dynamics During Differentiation 11.4 Epigenetics of Blood Cell Differentiation 11.5 Neuronal Development: The Role of Epigenetics 11.6 Epigenetic Basis of Memory Additional Reading 12 Epigenetics and Aging 12.1 Transgenerational Epigenetic Inheritance 12.2 Population Epigenetics 12.3 Epigenetics of Aging 12.4 Epigenetics of the Circadian Clock Additional Reading 13 Epigenetics and Disease 13.1 Epigenetic Reprograming in Cancer 13.2 Epigenetic Basis of Neurological Diseases 13.3 Epigenetic Therapy of Diseases Additional Reading 14 Cells and Tissues of the Immune System 14.1 Global Burden of Infectious Diseases 14.2 Innate and Adaptive Immunity 14.3 Hematopoiesis 14.4 Primary and Secondary Structures of the Immune System Additional Reading 15 Innate Immunity and Inflammation 15.1 Receptors for PAMPs and DAMPs 15.2 Myeloid and Lymphoid Cells of Innate Immunity 15.3 Role of Epigenetics in Immune Responses 15.4 Mechanisms of Phagocytosis and Inflammation Additional Reading 16 Adaptive Immunity and Antigen Receptor Diversity 16.1 Classes and Responses of Adaptive Immune Cells 16.2 Lymphocyte Maturation 16.3 Mechanisms of Antigen Receptor Diversity Additional Reading 17 B Cell Immunity: BCRs, Antibodies and Their Effector Functions 17.1 Structure and Diversity of Antibodies and BCRs 17.2 BCR Signaling 17.3 Humoral Adaptive Immune Response Additional Reading 18 Antigen-Presenting Cells and MHCs 18.1 Antigen-Presenting Cells 18.2 MHC Proteins and the HLA Locus 18.3 MHC Pathways Additional Reading 19 T Cell Immunity: TCRs and Their Effector Functions 19.1 TCR Signaling 19.2 T Cell Effector Functions 19.3 TH Cells 19.4 Cytotoxic T Cells Additional Reading 20 Immunity to Bacterial Pathogens and the Microbiome 20.1 Principles of Immune Responses to Infections 20.2 Immune Responses to Bacteria 20.3 Emerging Microbial Pathogens 20.4 Immunity to the Microbiome Additional Reading 21 Immunity to Viral Pathogens and the Virome 21.1 Principles of Immune Responses to Viruses 21.2 Chronic Virus Infections and Emerging Viral Pathogens 21.3 Influenza 21.4 COVID-19 Additional Reading 22 Tolerance and Transplantation Immunology 22.1 Central and Peripheral Tolerance 22.2 Graft Rejection 22.3 Immunosuppression Additional Reading 23 Immunological Hypersensitivities: Allergy and Autoimmunity 23.1 Classification of Hypersensitivities 23.2 Immunity of Allergies 23.3 Type 2 and 3 Hypersensitivities 23.4 T Cell-Mediated Autoimmunity 23.5 The Equilibrium Model of Immunity Additional Reading 24 Introduction to Cancer 24.1 The Global Burden of Cancer 24.2 Categorization and Diagnosis of Tumors 24.3 Crucial Transitions in Cancer 24.4 Causes of Cancer 24.5 Cancer Prevention Additional Reading 25 Oncogenes, Signal Transduction and the Hallmarks of Cancer 25.1 Cellular Transformation 25.2 Activating Oncogenes in Signal Transduction Pathways 25.3 Oncogenic Translocations and Amplifications 25.4 The Hallmarks of Cancer Concept Additional Reading 26 Tumor Suppressor Genes and Cell Fate Control 26.1 p53—A Master Example Tumor Suppressor 26.2 Tumor Suppressors and Oncogenes in Cell Cycle Control 26.3 Tumor Suppressor Inhibition and Cancer Onset Additional Reading 27 Multistep Tumorigenesis and Genome Instability 27.1 Characteristics of Tumor Growth 27.2 Multistep Tumorigenesis 27.3 Genome Instability 27.4 Cancer Driver Mutations and Genes Additional Reading 28 Cancer Genomics 28.1 Human Genetic Variation and Cancer Susceptibility 28.2 The Cancer Genome 28.3 Cancer Genome Projects Additional Reading 29 Cancer Epigenomics 29.1 Epigenetic Mechanisms of Cancer 29.2 DNA Methylation and Cancer 29.3 Chromatin Changes and Cancer Additional Reading 30 Aging and Cancer 30.1 Central Role of Aging During Chronic Diseases 30.2 The Hallmarks of Aging 30.3 Telomeres and Replicative Immortality Additional Reading 31 Tumor Microenvironment 31.1 The Impact of the Wound Healing Program for Cancer 31.2 Cell Types of the Tumor Microenvironment 31.3 Inducing Angiogenesis 31.4 Tumor-Promoting Inflammation 31.5 Deregulating Cellular Energetics Additional Reading 32 Metastasis and Cachexia 32.1 The Metastatic Cascade 32.2 Epithelial-Mesenchymal Transition 32.3 Metastatic Colonization 32.4 Cachexia Additional Reading 33 Cancer Immunology 33.1 Outline of Cancer Immunity 33.2 Recognition of Cancer Antigens 33.3 Monoclonal Antibodies in Cancer Immunotherapy 33.4 Immune Cell Therapies Additional Reading 34 Architecture of Cancer Therapies 34.1 Classical Cancer Treatments 34.2 Targeted Therapies 34.3 Precision Oncology Additional Reading 35 Nutrition and Common Diseases 35.1 Evolution of Human Nutrition 35.2 Principles of Metabolism 35.3 Dietary Molecules and Their Sensing 35.4 Nutrition and Metabolic Diseases 35.5 Impact of Physical Activity Additional Reading 36 Interference of the Human Genome with Nutrients 36.1 Human Genetic Adaptions 36.2 Genetic Adaption to Dietary Changes 36.3 Regulatory SNPs and Quantitative Traits 36.4 Definition of Nutrigenomics 36.5 Personal Omics Profiles Additional Reading 37 Nutritional Epigenetics, Signaling and Aging 37.1 Intermediary Metabolism and Epigenetic Signaling 37.2 Aging and Conserved Nutrient-Sensing Pathways 37.3 Neuroendocrine Regulation of Aging 37.4 Principles of Insulin Signaling 37.5 Central Role of FOXO Transcription Factors 37.6 Calorie Restriction from Yeast to Mammals 37.7 Cellular Energy Status Sensing by SIRTs and AMPK Additional Reading 38 Chronic Inflammation and Metabolic Stress 38.1 Acute and Chronic Inflammation 38.2 Reverse Cholesterol Transport and Inflammation 38.3 Sensing Metabolic Stress via the ER Additional Reading 39 Obesity 39.1 Definition of Obesity 39.2 Adipogenesis 39.3 Inflammation in Adipose Tissue 39.4 Energy Homeostasis and Hormonal Regulation of Food Uptake 39.5 Genetics of Obesity Additional Reading 40 Insulin Resistance and Diabetes 40.1 Glucose Homeostasis 40.2 Insulin Resistance in Skeletal Muscle and Liver 40.3 β Cell Failure 40.4 Definition of Diabetes 40.5 Failure of Glucose Homeostasis in T2D and Its Treatment 40.6 Genetics and Epigenetics of T2D Additional Reading 41 Heart Disease and the Metabolic Syndrome 41.1 Hypertension 41.2 Mechanisms of Atherosclerosis 41.3 Lipoproteins and Dyslipidemias 41.4 Whole Body’s Perspective of the Metabolic Syndrome 41.5 Metabolic Syndrome in Key Metabolic Organs 41.6 Genetics and Epigenetics of the Metabolic Syndrome Additional Reading 42 Epigenetics, Inflammation and Disease 42.1 Genetics, Epigenetics and Environment 42.2 Central Relation of Epigenetics and Immunity Additional Reading Glossary