Prognostic Epigenetics

,

• Publisher: Academic Press
• Year: 2019
• Print ISBN: 9780128142592
• eBook ISBN: 9780128142608
• Topic: Medicine
• Subtopic: Genetics in Medicine

This volume provides comprehensive information on how mapping an individual's epigenome can be medically relevant and holds the potential to improve preventive medicine and precision therapeutics at an early-stage (prior to disease onset). In order to advance clinical adoption of the recently developed epigenetic approaches, it is necessary for translational scientists, clinicians, and students to gain a better understanding about epigenetic mechanisms that are associated with a particular disorder; and to be able to effectively identify biomarkers that can be applied in drug development and for better diagnosis and prognosis of diseases.Prognostic Epigenetics is the most-inclusive volume to-date specifically dedicated to epigenetic markers that have been developed for prognosis of diseases, recent advances in this field, the clinical implementation of this research, and the future outlook.- Compiles all known information on prognostic epigenetics and its role in preventive medicine and drug discovery- Covers the basic functionality of epigenetic mechanisms involved in early disease prognosis and diagnosis, and provides tools for the identification and development of these biomarkers for a wide range of diseases- Enables clinicians, researchers, and pharmacologists to improve preventive medicine and precision therapeutics throughout a person's lifetime- Features chapter contributions from leading international researchers

Chapter 1

Basics of epigenetics: It is more than simple changes in sequence that govern gene expression

Shilpy Sharma; Osama Aazmi Department of Biotechnology, Savitribai Phule Pune University (Formerly University of Pune), Pune, India

Abstract

It is a widely accepted fact that distinction between species is defined not only by the ensemble of its genes but also more critically by how these genes are regulated such that the expression profiles change over space and time. Two major factors that determine gene expression and, in fact, a particular state of a functional cell, include genetics, the study of heritable changes in the nucleotide sequences, and epigenetics, the study of mitotically and/or meiotically heritable alterations in gene expression that are not associated with changes in the underlying DNA sequences. Here, we provide an overview about the major epigenetic mechanisms including DNA methylation, histone posttranslational modifications, chromatin modifications, and noncoding RNAs (including miRNAs and lncRNAs) that govern changes in gene expression that are actually dependent on the environment and not on the underlying gene sequence. These mechanisms are potentially reversible and play crucial roles in regulating normal growth and differentiation. Alteration in the epigenetic marks have often been linked with different disease processes; and several attempts have been made to use these epigenetic modifications as a biomarker for the identification of individuals at risk and/or suffering from a disease condition using minimally invasive techniques. Additionally, the reversible nature of these epigenetic marks offers an attractive target for therapy, and hence, several drugs that target epigenetic factors and/or the linked pathways are currently being developed and/or tested in clinical trials. These topics have been extensively discussed through the length of this chapter.

Keywords

Histone modifications; DNA methylation; Noncoding RNAs; miRNAs; Long noncoding RNAs

Acknowledgments

SS acknowledges the funding from Ramalingaswami fellowship (BT/RLF/Re-entry/11/2012; Department of Biotechnology—DBT, Government of India) and University Grants Commission (UGC, Government of India F.4-5(18-FRP)(IV-Cycle)/2017(BSR)). SS lab has been generously supported by Research and Development grant and DST-Purse grant to the Department of Biotechnology, SPPU and Board of College and University Development (BCUD) grant (SPPU) to SS and UPE Phase II grant to SPPU. OA acknowledges DBT, GOI for his Masters in Biotechnology fellowship.

1 Introduction

1.1 Genetics versus epigenetics

It is a widely accepted fact that distinction between species is defined not only by the ensemble of its genes but also more critically by how these genes are regulated such that the expression profiles change over space and time [1]. Two major factors that determine gene expression and, in fact, a particular state of a functional cell include genetics and epigenetics. Genetics has been classically defined as the study of heritable changes in the nucleotide sequences [2]. With the recent advances in the knowledge of the human genome sequence, a detailed description of mutations and polymorphisms present in the human genome is available [3, 4]. Most human traits and diseases have been associated with a genetic component and have been enlisted in the OMIM database (https://www.omim.org/) [4]. In the case of simple disorders involving a single gene (i.e., monogenic disorders), the variations that lead to the disease phenotype have been discovered and have been traditionally used for disease diagnosis and/or prognosis [5]. For example, the A → T transition in the sixth codon of the β-globin gene has been widely used for the diagnosis of sickle cell anemia [6]. However, this is an exception, and in most cases, either a limited number of point mutations (e.g., α1-antitrypsin deficiency) [7, 8]; a diverse array of variations, including point and frameshift mutations, insertions, and deletions across the human gene (e.g., β-thalassemia [9, 10], muscular dystrophy [11, 12]); or repeat number variations (e.g., triplet repeat expansion in case of fragile X syndrome [13, 14] and Huntington’s disease [15, 16]) have been used for the diagnosis of monogenic diseases [5]. However, the occurrence of such diseases is rare.

Most common chronic diseases are usually complex in nature and do not follow Mendelian inheritance patterns. These complex diseases (e.g., diabetes, cancer, coronary heart disease, hypertension, obesity, Alzheimer’s disease, and Parkinson’s disease, to name a few) appear to be associated with an unknown number of genes, with lifestyle, and environmental factors playing a key role in governing their onset/development [17, 18]. Even though several technologies and strategies have been developed to detect the genetic factors that influence the development of such multigenic disorders, the process has suffered from limitations including complexity at the individual and at the population levels [18]. For example, several genome-wide association studies (GWAS) have been conducted in populations of distinct origins that have led to the discovery of genetic loci linked with different diseases. Between the years 2007 and 2015, > 260 genetic loci have been identified through different GWAS studies that show association with obesity and type 2 diabetes alone [19]. A representation of the results obtained from GWAS studies conducted in different populations for a few major complex diseases has been represented in Table 1. However, the lack of reproducibility in different populations, population biases, gene × gene interactions, gene × environment interaction, and phenotypic heterogeneity in the samples used for the studies have laid obstacles in the identification of a set of genes/alleles for disease prediction [37, 38]. For example, the prediction of risk on the basis of genetic variants has been limited to a factor of not > 0.6 for type 2 diabetes [37, 39]. Therefore, there exists a need to find better markers that can be used for disease diagnosis/prediction.

Table 1

Representation of genes identified by GWAS studies performed in different populations that have been linked with different diseases

S. No.	Disease	Gene(s) identified	Population studied	Reference
1.	Diabetes	ADAMTS9, CDKAL1, CDKN2A/B, FTO, IGF...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• Chapter 1: Basics of epigenetics: It is more than simple changes in sequence that govern gene expression
• Chapter 2: Epigenetic biomarkers for disease diagnosis
• Chapter 3: Technological advances in studying epigenetics biomarkers of prognostic potential for clinical research
• Chapter 4: Use of circulating nucleic acids, metabolites, and proteins as clinical biomarkers for earlier prognosis and diagnosis of disease
• Chapter 5: Deciphering ocular diseases on an epigenetic platform
• Chapter 6: Epigenetic biomarkers of asthma and allergic disorders
• Chapter 7: Epigenetics in infectious disease
• Chapter 8: Epigenetics of autoimmune diseases
• Chapter 9: Epigenetic mechanisms underlying the pathogenesis of osteoarthritis and their clinical relevance
• Chapter 10: Epigenetic biomarkers in metabolic syndrome and obesity
• Chapter 11: Chromatin landscape and epigenetic biomarkers for clinical diagnosis and prognosis of type 2 diabetes mellitus
• Chapter 12: Epigenetic landscape of infertility
• Chapter 13: Histone posttranslational modifications: Potential role in diagnosis, prognosis, and therapeutics of cancer
• Chapter 14: Epigenetic biomarkers in personalized medicine
• Chapter 15: Conclusions and perspectives: Major challenges and future prospects for prognostic epigenetics
• Index