Clinical Epigenetics

1. Auflage 2019
ISBN: 978-981-1389-60-3
Verlag: Springer Nature Singapore

Buch, Englisch, 265 Seiten, Paperback, Format (B × H): 155 mm x 235 mm, Gewicht: 488 g

In genetic pathology, epigenetic testing is rare and under utilised. In this book, we introduce epigenetics to a non-expert scientific audience and describe current and future clinical utility of epigenetic testing. By focussing on epigenetics in human disease this book will guide professionals (scientists and clinicians) to understand how epigenetics is relevant in a clinical context, and to implement epigenetic testing in diagnostic laboratories.

The book begins with a historical perspective of genetics and epigenetics and describes the work of pioneers who have helped shape these fields. The various mechanisms by which epigenetics can regulate the function of the genome is described. These include DNA methylation, histone modifications, histone variants, nucleosome positioning, cis-regulatory elements, non-coding RNAs and the three-dimensional organisation of chromatin in the nucleus. These are discussed in the context of embryological development, cancer and imprinting disorders, and include examples of epigenetic changes that can be used in diagnosis, prediction of therapeutic response, prognostication or disease monitoring. Finally, for those wishing to implement epigenetic testing in a diagnostic setting, the book includes a case study that illustrates the clinical utility of epigenetic testing.

Zielgruppe

Research

Autoren/Hrsg.

Pritchard, Antonia L.

Hesson, Luke B.

Fachgebiete

• Medizin | Veterinärmedizin Medizin | Public Health | Pharmazie | Zahnmedizin Vorklinische Medizin: Grundlagenfächer Humangenetik
• Medizin | Veterinärmedizin Medizin | Public Health | Pharmazie | Zahnmedizin Vorklinische Medizin: Grundlagenfächer Molekulare Medizin, Zellbiologie
• Medizin | Veterinärmedizin Medizin | Public Health | Pharmazie | Zahnmedizin Klinische und Innere Medizin Gentherapie

Inhaltsverzeichnis

Chapter 1 - Introduction

The Introduction chapter will highlight the broad scope of the book. It will define the term epigenetics and provide an historical perspective of the development of the field through the research of early pioneers who helped to shape our current understanding of epigenetics.

Chapter 2 - Chromatin and gene regulation



In this chapter I will describe the composition of chromatin (the combination of DNA and protein within the nucleus of a cell) and detail the various chemical modifications to DNA, histones, nucleosome asymmetry and positioning that regulate DNA function. The way these different epigenetic modifications interact cooperatively to alter DNA function will be discussed. A description of epigenetic changes during early development will be followed by the phenomenon of X chromosome inactivation and then by examples of physiological epigenetic regulation at specific chromosomal regions and genes. Higher order chromatin structure, the organisation of chromatin in the nucleus and the relatively recent explosion in our understanding of the function of non-coding DNA, non-coding RNA, enhancers and long-range chromatin interactions will also be covered.

Chapter 3 - Epigenetics and human disease



This chapter will describe the clinical relevance of epigenetics by providing examples of epigenetic changes associated with disease and will constitute the largest chapter in the book. The reader will gain an appreciation of the different types of epigenetic alterations that can occur in pathological states and the molecular mechanisms involved. The concepts that will be covered in detail will include transgenerational epigenetic inheritance, imprinting (including disorders of imprinting), epimutations and epigenetic alterations that accumulate over the lifetime of an individual, such as those found in cancer.

Chapter 4 - Epigenetic alterations: cause or consequence



For many years epigeneticists have debated whether epigenetic changes are a cause or consequence of pathology. Whether epigenetic changes precede or follow altered states of gene activity remains an active area of research. It now appears that epigenetic modifications such as DNA hypermethylation are a consequence of gene silencing rather than a cause, but this does not necessarily preclude a role in disease nor impact on the clinical utility of assaying or therapeutically targeting epigenetic alterations. In this chapter, I will describe the studies that have dissected how and why epigenetic alterations arise and the evidence that epigenetic alterations can be driven by local cis-acting mechanisms such as sequence context, enhancer activity and nucleosome occupancy.

Chapter 5 - Methods for detecting and quantitating epigenetic modifications.



This chapter will be a thorough review of the methodological and technical aspects of detecting and quantitating epigenetic modifications. Site-specific and genome-wide methodologies for assaying DNA methylation, histone modifications and nucleosome positioning will be considered and compared. The interpretation of information from each of these approaches will be discussed. Those wishing to profile epigenetic changes will find this chapter informative for choosing an appropriate methodology for a particular application.

Chapter 6 - The clinical utility of epigenetic markers.



In this chapter I will show that altered epigenetic states represent a rich source of biomarkers with the potential to inform patient management and clinical decision-making. This includes the detection of aberrant epigenetic states in normal specimens from patients for diagnostic purposes, early diagnosis of sporadic conditions such as cancer, monitoring of disease stage or progression, or for predicting the response of patients to specific therapies.

Chapter 7 - Therapeutic targeting of epigenetic modifications.



To convey the molecular mechanism of action of drugs that target epigenetic modifications this chapter will describe the proteins and complexes that function to modify chromatin in different ways. The concept of epigenetic writers, readers and erasers, which modify chromatin, interpret chromatin modifications or remove chromatin modifications, respectively, will be covered. The various drugs in clinical trials that target these proteins will be described, as will their mechanism of action. The focus will be on drugs that have proven efficacy and the conditions they are indicated for.
Chapter 8 - Implementing epigenetic assays in a diagnostic laboratory.


In this chapter, I will describe the barriers that must be overcome in designing, interpreting and implementing epigenetic assays within a diagnostic environment. Special considerations regarding epigenetic analysis will be covered including specimen requirements, collection, storage, processing, confirming analytical validity and reflex assays that can complement the different types of epigenetic tests currently possible. This chapter will be informative for the scientist, clinician or genetic pathologist wishing to incorporate and validate epigenetic testing in a diagnostic laboratory.

Über Autor(innen)

Associate Professor Luke B. Hesson is a Clinical Scientist who has studied the genetic and epigenetic causes of cancer for more than 18 years. He holds a doctorate in Clinical Genetics from The University of Birmingham UK and is a former Director for the Australian Society for Medical Research (2012-2015). In 2016 he was admitted as a Fellow of the Faculty of Science of the Royal College of Pathologists of Australasia. He has lectured at the University of New South Wales, Sydney in genetics, epigenetics, cancer, pathology and personalised medicine. Luke is currently the Head of Cancer Diagnostics and Laboratory Director at the Garvan Institute of Medical Research DNA sequencing facility in Sydney, which provides clinically accredited genome sequencing.

Dr. Antonia L. Pritchard is currently a Senior Lecturer at the University of the Highlands and Islands, Scotland, UK and a visiting scientist at QIMR Berghofer Medical Research Institute, Brisbane, Australia. She gained her Ph.D in Psychiatric Genetics from the University of Birmingham in 2005. Her research interests have centred around the genetic influence on disease (including Alzheimer’s disease, asthma and cancer) and on the human immune system. Dr Pritchard has published over 60 peer reviewed articles on these themes and continues to work on the interaction of genetics, genomics and immunology in cancer, particularly focused on melanoma. She is a member of the British Society of Immunology (BSI), the American Association for Cancer Research (AACR), the Association of Cancer Immuotherapy (CIMT) and the Society for Melanoma Research (SMR). Dr Pritchard’s research group is a member of the GenoMEL Consortium and the BAP1 Interest Group (BIG) Consortium, both of which are highly productive, collaborative and multidisciplinary groups which comprise researchers from across the World.