Epigenetics in Organ Specific Disorders

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Epigenetics in Organ Specific Disorders
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Contents
Contributors
Chapter 1 Introduction—Epigenetics regulations in organ specific disorders
	1 Overview of epigenetics in organ-specific disorders
	2 Epigenetics in human diseases/disorders
		2.1 Epigenetic influences on cellular functions
			2.1.1 Tissue fibrosis
			2.1.2 Vascular stenosis
			2.1.3 Tumor metastasis
		2.2 Epigenetic mechanisms in cellular dedifferentiation
		2.3 Epigenetic mechanisms in autophagy-mediated cell survival
	3 Current progress on “epigenetic drugs”
	4 About the chapters described in this book
	References
Section: 1 Molecular and structural epigenetics
	Chapter 2 Higher-order chromatin structure and gene regulation
		1 Introduction
		2 Chromatin structure
			2.1 Nucleosomes and the factors that regulate their dynamics
			2.2 How the nucleosomes are (not) organized
			2.3 Chromatin loops
			2.4 Chromatin remodelers
			2.5 Chromosome compartmentalization
		3 Roles of enhancers in cell type-specific gene expression
			3.1 General features
			3.2 Classification of enhancer states
			3.3 Enhancer grammar
			3.4 Evolution of enhancers
			3.5 Enhancer-promoter interactions
			3.6 Super-enhancers
			3.7 Insulated neighborhoods
			3.8 Cell type-specific variation of chromatin structure
		4 Concluding remarks
		References
	Chapter 3 Molecular and structural interactions between epigenetic regulators
		1 Introduction
		2 DNMTs as epigenetic regulators
			2.1 Protein-interacting domains of DNMT1
			2.2 Interactions between DNMT1 and UHRF1
			2.3 Indirect regulatory functions of UHRF1 on DNA methylation
			2.4 Molecular interactions between DNMT1 and other cellular proteins
			2.5 Functions of structural domains in de novo methyltransferases
			2.6 Functional significance and molecular interactions of DNMT3A and DNMT3B
			2.7 Mutations affecting molecular interactions of DNMT3A and DNMT3B
		3 Unique role of UHRF1 in directing DNMT1
		4 HDACs as epigenetic gene regulators
		5 Conclusions
		References
Section  2: Epigenetic effects on cell fate
	Chapter 4 Epigenetic regulation of necrosis and pyknosis
		1 Introduction
		2 DNA methylation and necrosis
		3 Histone modification and higher order chromatin remodeling in necrosis
		4 The role of noncoding RNA in necrosis
		5 Pyknosis: Nuclear morphological changes in cell death
			5.1 Apoptotic pyknosis
			5.2 Necrotic pyknosis
			5.3 Epigenetic regulation of pyknosis
		6 Conclusion
		References
	Chapter 5 HDAC inhibition in cancer
		1 Epigenetics and major epigenetic alterations
			1.1 Introduction to epigenetics
				1.1.1 Histones in epigenetics
				1.1.2 Types of chromatin modifications
				1.1.3 DNA methylation
				1.1.4 Methylations and acetylations of histones
				1.1.5 Phosphorylation of histones
				1.1.6 Histone acetyl transferase (HAT)
				1.1.7 HAT inhibitors
			1.2 Histone deacetylases
				1.2.1 Histone deacetylation by histone deacetylases (HDACs)
		2 HDACs, HDACIs, and cell cycle regulation
			2.1 HDACs and cell cycle
				2.1.1 Modulation of cell cycle by HDACs
				2.1.2 HDACs and p53
				2.1.3 HDACs and p21
			2.2 Inhibition of histone deacetylases
				2.2.1 HDAC inhibition and cellular mechanisms
			2.3 Histone deacetylase inhibitors (HDACIs)
				2.3.1 Suberoylanilide hydroxamic acid
				2.3.2 Trichostatin A
				2.3.3 Valproic acid
				2.3.4 Suberic bis-hydroxamic acid
				2.3.5 Panobinostat
				2.3.6 Sodium butyrate
				2.3.7 Cell cycle arrest by HDACIs
				2.3.8 HDACI induction of p21WAF1/CIP1
				2.3.9 HDACI treatment disrupts mitosis and the mitotic checkpoint
			2.4 HDACIs and cell death
				2.4.1 Sensitivity for HDACIs and correlation to apoptosis
				2.4.2 HDACI-induced necroptosis
				2.4.3 Cell differentiation induced by HDACIs
				2.4.4 Inhibition of DNA repair
		3 Epigenetics and cancer
			3.1 Epigenetic modifications in cancer and cancer growth
			3.2 Epigenetic changes in prostate cancer
			3.3 Histone acetylation and deacetylation in breast cancer
		References
	Chapter 6 Epigenetic signatures that maintain stemness in pluripotent and mesenchymal stem cells
		1 Introduction
		2 Chromatin reorganization
			2.1 Polycomb and Trithorax complexes
			2.2 ATP-based chromatin remodeling
				2.2.1 SWI/SNF
				2.2.2 ISWI
				2.2.3 CHD
				2.2.4 INO80
		3 DNA methylation
		4 TET proteins
		5 Histone variants
		6 Histone modifications
			6.1 Histone methylation
			6.2 Histone acetylation
			6.3 Histone phosphorylation
		7 Conclusion
		References
	Chapter 7 Epigenetic modifications and alternative pre-mRNA splicing in cancer
		1 Introduction
		2 Alternative splicing: An overview
			2.1 The history of alternative splicing
			2.2 The types and mechanisms of alternatively spliced events
		3 A simplistic overview on epigenetics
			3.1 DNA methylation
			3.2 Posttranslational histone modifications
			3.3 Nucleosome remodeling
			3.4 Noncoding RNAs
		4 The epigenetics whereabouts in cancer
		5 The epigenetically controlled alternative splicing in cancer
			5.1 Cotranscriptional coupling of alternative splicing events
			5.2 Reorganized chromatin promotes cancer-specific splicing
			5.3 Reformed nucleosome positioning
			5.4 DNA methylation in tumorigenesis
			5.5 Tailored histone modifications promote cancer
		6 Implications of epigenetics in anticancer therapy
		7 Conclusions
		References
Section 3: Epigenetic regulations in infections and immune responses
	Chapter 8 Epigenetics of T cell - mediated immunological responses
		1 Introduction
		2 Epigenetics of T cell immunity
			2.1 Epigenetic factors and T cell development
			2.2 Epigenetics of T cell plasticity
			2.3 miRNAs in T cell development
		3 Epigenetics in allergy and inflammatory diseases
			3.1 Epigenetics in asthma
				3.1.1 Childhood asthma
				3.1.2 Adult asthma
				3.1.3 Histone modifications in asthma
				3.1.4 Role of miRNAs in asthma
			3.2 Epigenetics in atopic dermatitis
			3.3 Other allergies
		4 Epigenetics in autoimmunity
			4.1 DNA methylation
			4.2 DNA hydroxymethylation
			4.3 Histone modifications
			4.4 Methylation of retroelements
		5 Conclusion
		References
	Chapter 9 Epigenetic modifications and regulation in infection
		1 Introduction
		2 Viral infections
			2.1 DNA hypomethylation
			2.2 Histone mimicry
			2.3 Epigenetic modifications of host antiviral responses
			2.4 Epigenetics and latency
			2.5 Epigenetic regulation of ACE2 in SARS-CoV-2 infection
			2.6 Epigenetics and viral oncogenesis
		3 Bacterial infections
			3.1 Methylation of bacterial genes
			3.2 Methylation and acetylation of host genes in bacterial infection
		4 Trained immunity and epigenetics
			4.1 Trained innate immunity
			4.2 Epigenetic changes associated with trained immunity
			4.3 Role of vaccinations in trained immunity
			4.4 Epigentic regulation via metabolic pathways in infections
		References
Section  4: Epigenetic influences on aging, diseases, and diet
	Chapter 10 Epigenetics of aging
		1 Introduction
		2 Epigenetics, disease, and aging
			2.1 DNA modifications
			2.2 Histone modifications
			2.3 Chromatin remodeling
			2.4 Noncoding RNAs
			2.5 RNA methylation
		3 Cancer
		4 Neurodegeneration
		5 Cardiovascular disease
		6 Conclusions and future perspectives
		References
	Chapter 11 Epigenetic regulation mediated by diets
		1 Introduction
			1.1 Effects of diet on epigenetics and health
				1.1.1 Effects of specific nutrients on specific epigenetic mechanisms
			1.2 Impact of diet on fetal epigenetics
				1.2.1 Early-life nutritional exposures impact later-life phenotypes
				1.2.2 Specific diets can influence outcomes in both the mother and offspring
			1.3 Transmissibility of dietary effects to offspring
				1.3.1 The adverse effects of maternal overnutrition on offspring
				1.3.2 The effects of maternal undernutrition on offspring
			1.4 Exploiting knowledge about maternal diet and epigenetics to improve parental and child health
				1.4.1 Fatty acids in the maternal diet
				1.4.2 Vitamins in the maternal diet
				1.4.3 Other beneficial maternal diets
			1.5 Implications and applications of dietary changes associated with epigenetics
				1.5.1 Modifying in patients with cancer
				1.5.2 Diet and systemic inflammation
				1.5.3 Diet in age-related conditions and viral infections
				1.5.4 Diet and personality
			1.6 Plant dietary compounds in gastroenterological disorders
				1.6.1 Curcumin
				1.6.2 Flavonoids
			1.7 Impact of diet on metabolic disease and diabetes
			1.8 The impact of diet on carcinogenesis
			1.9 The impact of diet on aging and aging-related disease
		2 Conclusions
		References
Section 5: Epigenetic alterations in organ specific diseases
	Chapter 12 Epigenetic regulations in neurological disorders
		1 Introduction
		2 Epigenetic modifications implicated in neurological disorders
			2.1 DNA methylation
			2.2 Histone modifications
			2.3 Chromatin remodeling
			2.4 Histone variants
			2.5 Noncoding RNAs
		3 Epigenetic links of neurodevelopmental disorders
			3.1 Rett syndrome
			3.2 Attention-deficit hyperactivity disorder
			3.3 Autism spectrum disorder
		4 Psychological disorders with epigenetic link
			4.1 Fragile X syndrome
			4.2 Schizophrenia
			4.3 Bipolar disorder
			4.4 Depression
			4.5 Anxiety disorders
			4.6 Epilepsy
			4.7 Obsessive-compulsive disorder
			4.8 Drug abuse and addiction
			4.9 Stress, early-life trauma, and PTSD
		5 Epigenetics of neurodegenerative disorders
			5.1 Alzheimer’s disease
			5.2 Parkinson’s disease
			5.3 Amyotrophic lateral sclerosis
			5.4 Huntington’s disease
		6 Imprinting disorders
			6.1 Angelman syndrome and Prader-Willi syndrome
			6.2 Rubinstein-Taybi syndrome
		7 Concluding remarks
		Funding
		References
	Chapter 13 Epigenetic disorders in the anterior segment of the eyes
		1 Molecular mechanisms of epigenetics
			1.1 DNA methylation
			1.2 Acetylation/deacetylation
			1.3 Noncoding RNAs
		2 Basic anatomy of anterior segment of eye
		3 Role of epigenetics in anterior segment ocular disorders
			3.1 Corneal wound healing
			3.2 Fuchs’ corneal dystrophy
			3.3 Pterygium
			3.4 Glaucoma
			3.5 Cataract
		4 Conclusion and future directions
		References
	Chapter 14 Epigenetic regulations in fat depots
		1 Introduction
		2 Physiological role of fat
		3 Fat depots and fat deposits on visceral organs
			3.1 Adipose tissue on heart
				3.1.1 Epicardial and pericardial adipose tissue
				3.1.2 EAT quantification and disease correlations
				3.1.3 Pathological role of EAT in heart diseases
					Atherosclerosis
					Metabolic syndrome and EAT
					Atrial fibrillation and heart failure
		4 Clinical interventions to reduce fat depots
		5 Molecular and epigenetic mechanisms of fat
		6 Adipokines and epigenetic modulations in fat metabolism
			6.1 Adiponectin
			6.2 Adrenomedullin
			6.3 Omentin
		7 Conclusions
		References
	Chapter 15 Epigenetic changes in periodontal tissues
		1 Introduction
		2 Periodontal diseases
			2.1 Bacterial infections and inflammation in periodontitis
			2.2 Immunological and tissue characteristics in periodontitis
		3 Periodontitis and allied diseases
		4 Epigenetic mechanisms in periodontal diseases
			4.1 Methylation-mediated initiation of inflammation in periodontitis
			4.2 Histone modifications in periodontitis
			4.3 Role of noncoding RNAs in periodontitis
		5 Conclusions
		References
	Chapter 16 Epigenetics of the pathogenic myofibroblast in lung disease
		1 Introduction
		2 Origins of myofibroblasts
			2.1 Tissue-resident fibroblasts
			2.2 Epithelial-mesenchymal transition
			2.3 Fibrocytes
			2.4 Pericytes
			2.5 Additional contributors of myofibroblast population
		3 Myofibroblasts in lung disease
			3.1 Idiopathic pulmonary fibrosis
			3.2 Asthma
			3.3 Chronic obstructive pulmonary disease
			3.4 Lung cancer
		4 Epigenetic factors that regulate the myofibroblast phenotype
			4.1 DNA methylation and histone modification
			4.2 Noncoding RNAs
				4.2.1 MicroRNAs
				4.2.2 Long noncoding RNAs
		5 Validation of epigenetic regulators as potential targets for the treatment of myofibroblast-driven lung disease
			5.1 HDACs
			5.2 Histone acetyltransferases
			5.3 Atypical HATs: Bromodomain-containing protein 4
			5.4 Histone methyltransferases
			5.5 DNA methylation
			5.6 Oxidative DNA damage: An environmental epigenetic mark
			5.7 Pioneer transcription factors
		6 Summary and future areas for development
		References
	Chapter 17 Epigenetic mechanisms in cardiovascular diseases
		1 General background
		2 Epigenetic modification
			2.1 DNA methylation
			2.2 Posttranslational modification of histone
			2.3 Noncoding RNA (ncRNAs)
		3 Epigenetic mechanisms in cardiovascular disease
			3.1 Diabetes
			3.2 Atherosclerosis
			3.3 Hypertension
			3.4 Aortic aneurysm
			3.5 Aging
			3.6 Heart failure
		4 Potential epigenetic therapies in the cardiovascular disease
		5 Summary and conclusion
		References
	Chapter 18 Epigenetics of NAFLD and NASH
		1 Introduction
		2 Pathogenesis of NAFLD and NASH
		3 Epigenetic factors associated with NAFLD and NASH
			3.1 DNA methylation
			3.2 Histone modifications
			3.3 MicroRNAs
				3.3.1 Hepatic miRNA profiling
				3.3.2 Candidate miRNAs
		4 Implications for the prevention and treatment of NAFLD and NASH
		5 Conclusions
		References
	Chapter 19 Role of histone modifications in the development of acute kidney injury
		1 Introduction
		2 Acute kidney injury: A global concern
		3 Epidemiology of AKI
		4 Epigenetics in acute kidney injury
		5 Histone posttranslational modifications
			5.1 Histone Acetylation
			5.2 Histone acetylation in AKI
				5.2.1 HDAC inhibitors
			5.3 Histone methylation
			5.4 Histone methylation in AKI
			5.5 Histone phosphorylation
			5.6 Histone phosphorylation in AKI
			5.7 Histone crotonylation
			5.8 Histone crotonylation in AKI
		6 Conclusion and future perspective
		References
	Chapter 20 Epigenetic regulation of chronic kidney disease development following prenatal maternal stress
		1 Chronic kidney disease
		2 Fetal kidney development
		3 Genetic regulation of kidney development
		4 Epigenetic signature of the kidney development
		5 Growing epidemic of CKD
		6 DNA methylation in CKD progression
		7 Histone modifications and miRNA in CKD progression
		8 Attributable risk factors for CKD
		9 Prenatal maternal stress (PNMS) as potential risk for CKD
		10 Alteration in DNA methylation by prenatal maternal stress and CKD
		11 Epigenetic modifiers as potential remedial CKD targets
		12 Conclusion
		References
	Chapter 21 Epigenetic modifications and regulations in gastrointestinal diseases
		1 Introduction
		2 Different epigenetic modifications
			2.1 DNA methylation
			2.2 Histone methylation
			2.3 Histone acetylation
			2.4 Chromatin remodeling proteins
				2.4.1 Polycomb proteins
				2.4.2 Trithorax proteins
				2.4.3 ATP-dependent chromatin remodeling
			2.5 Noncoding RNAs
		3 Role of epigenetics in gastrointestinal diseases
			3.1 Esophagus
				3.1.1 Barrett’s esophagus
				3.1.2 Esophageal adenocarcinoma and esophageal squamous cell carcinoma
			3.2 Stomach
				3.2.1 Gastric cancer
			3.3 Colon-rectum
				3.3.1 Inflammatory bowel disease
				3.3.2 Colorectal adenocarcinoma
			3.4 Liver and biliary system
				3.4.1 Alcoholic steatohepatitis
				3.4.2 Nonalcoholic steatohepatitis
				3.4.3 Viral hepatitis
				3.4.4 Hepatocellular carcinoma
			3.5 Pancreas
				3.5.1 Diabetes mellitus
				3.5.2 Pancreatic adenocarcinoma
		4 Conclusion
		References
	Chapter 22 Epigenetics of radiation-induced GI damage: Role of protein modifications
		1 Radiation-induced GI damages: The core of the problem
		2 Epigenetics
			2.1 DNA methylation
			2.2 Histone modifications
			2.3 RNA-associated silencing
		3 Approaches to use epigenetic tools as radiation countermeasures
		4 Protein acetylation: Gene regulation to epigenetics
		5 Development of drugs potentially targeting protein acetylation for the mitigation of radiation induced GI damage
		References
	Chapter 23 Epigenetic modulations in age-associated bone disorders
		1 Introduction
			1.1 Bone structure
				1.1.1 Cellular and molecular mechanisms of bone remodeling and age-associated changes leading to osteoporosis
			1.2 Epigenetic regulation of bone
				1.2.1 Effect on osteoblasts and osteoclasts
				1.2.2 DNA methylation
				1.2.3 Histone modifications
				1.2.4 miRNAs
			1.3 Effect on adipocytes
				1.3.1 Histone demethylation
				1.3.2 Noncoding RNAs
			1.4 Age-associated adipogenesis and hematopoiesis
			1.5 Bone marrow adipocytes and leukemia
			1.6 Bone marrow adipocytes and multiple myeloma
			1.7 Bone marrow adipocytes and aplastic anemia
		2 Conclusion
		References
Section 6: Epigenetics and drug development
	Chapter 24 Epigenetic regulations in inflammatory diseases
		1 General introduction
		2 Molecular basis of inflammation
			2.1 Stimuli recognition
			2.2 Activation of the inflammatory pathway
				2.2.1 Nuclear factor kappa-B (NF- κ B) pathway
				2.2.2 MAPK pathway
				2.2.3 JAK-STAT pathway
		3 Organ-specific inflammatory diseases
			3.1 Brain
				3.1.1 Treatment of brain disease
			3.2 Intestinal tract
				3.2.1 Treatment of intestinal tract disease
			3.3 Heart
				3.3.1 Treatment of cardiovascular diseases
			3.4 Liver
				3.4.1 Treatment of liver disease
			3.5 Lungs
				3.5.1 Treatment of lung disease
			3.6 Kidneys
				3.6.1 Treatment of kidney disease
			3.7 Pancreas
				3.7.1 Treatment of pancreatitis
			3.8 Reproductive system
				3.8.1 Treatment of inflammatory diseases in the reproductive system
		4 Mediators of inflammation
			4.1 Vasoactive amines
			4.2 Arachidonic acid metabolites
			4.3 Pharmacologic inhibitors of leukotrienes and prostaglandins
				4.3.1 Cyclooxygenase inhibitors
				4.3.2 Lipoxygenase inhibitors
				4.3.3 Corticosteroids
				4.3.4 Leukotriene receptor antagonists
			4.4 Cytokines and chemokines
			4.5 Complement system
			4.6 Other mediators of Inflammation
		5 Epigenetic drugs
			5.1 DNA methylation inhibitors (iDNMTs)
			5.2 Histone deacetylase inhibitors (iHDACs)
		6 Conclusion
		References
	Chapter 25 Epigenetic drug discovery: Recent advances through structure-activity relationships and phenotypic profiling studies
		1 Introduction
		2 Epigenetics and modular drug development
			2.1 Readers, writers, and erasers as epigenetic modifiers
		3 Inhibitors of epigenetic writers: Structure-activity relationship
			3.1 DNA methyltransferase inhibitors
			3.2 Histone methyltransferase inhibitors (HMT)
		4 Inhibitors of epigenetic readers: Structure-activity relationship
		5 Inhibitors of epigenetic erasers: Structure-activity relationship
		6 Phenotypic drug discovery tools for epigenetics
			6.1 Phenotypic profiling for epigenetics in cancers
		Author Contributions
		Funding
		Conflicts of Interest
		References
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