Chromatin Signaling and Neurological Disorders

,

• Publisher: Academic Press
• Year: 2019
• Print ISBN: 9780128137963
• eBook ISBN: 9780128137970
• Topic: Medicine
• Subtopic: Genetics in Medicine

Chromatin Signaling and Neurological Disorders, Volume Seven, explores our current understanding of how chromatin signaling regulates access to genetic information, and how their aberrant regulation can contribute to neurological disorders. Researchers, students and clinicians will not only gain a strong grounding on the relationship between chromatin signaling and neurological disorders, but they'll also discover approaches to better interpret and employ new diagnostic studies and epigenetic-based therapies. A diverse range of chapters from international experts speaks to the basis of chromatin and epigenetic signaling pathways and specific chromatin signaling factors that regulate a range of diseases.In addition to the basic science of chromatin signaling factors, each disease-specific chapter speaks to the translational or clinical significance of recent findings, along with important implications for the development of epigenetics-based therapeutics. Common themes of translational significance are also identified across disease types, as well as the future potential of chromatin signaling research.- Examines specific chromatin signaling factors that regulate spinal muscular atrophy, ulbospinal muscular atrophy, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, multiple sclerosis, Angelman syndrome, Rader-Willi syndrome, and more- Contains chapter contributions from international experts who speak to the clinical significance of recent findings and the implications for the development of epigenetics-based therapeutics- Provides researchers, students and clinicians with approaches to better interpret and employ new diagnostic studies for treating neurological disorders

Chapter 1

Chromatin and epigenetic signaling pathways

Catherine A. Musselman University of Iowa Carver College of Medicine, Iowa City, IA United States

Abstract

The eukaryotic genome is packaged into the nucleus in the form of chromatin. Beyond a mechanism for packaging, chromatin has evolved as a means for dynamically regulating the genome. At its most basic description, chromatin consists of histone proteins in complex with DNA. Modification of the histone proteins and DNA plays a major role in regulating chromatin structure, and together they form an extensive signaling network. The modification state of chromatin has been found to be responsive to the environment and the metabolic state of the cell, and there is now evidence that some histone and DNA modifications are heritable. Moreover, dysregulation of chromatin signaling pathways underlies a wide range of diseases and disorders, providing a link between the environment and nutrition, gene regulation, and human health and susceptibility to diseases. In this chapter the basics of chromatin signaling pathways are outlined.

Keywords

Chromatin; DNA; Histone; Inheritance; Metabolism; Modification; Nucleosome

1. 1.1 Chromatin signaling and epigenetics
2. 1.2 Chromatin organization
3. 1.3 Histone posttranslational modifications and the histone code
4. 1.4 Functions of histone posttranslational modifications
5. 1.5 DNA methylation
6. 1.6 Writers, erasers, and readers
   1. 1.6.1 Histone writers
   2. 1.6.2 DNA writers
   3. 1.6.3 Histone erasers
   4. 1.6.4 DNA erasers
   5. 1.6.5 Histone readers
   6. 1.6.6 DNA readers

1. 1.7 Modification cross talk
2. 1.8 Effects of metabolism on histone and DNA modifications
3. 1.9 Epigenetic inheritance
4. 1.10 Summary
5. References

1.1. Chromatin signaling and epigenetics

The term chromatin was coined around the year 1880 by Walther Flemming. Flemming noted that “The word chromatin may stand until its chemical nature is known, and meanwhile stands for that substance in the cell nucleus which is readily stained” [1,2]. Today we know that chromatin is composed of genomic DNA in complex with histone proteins, but the original name still holds. Beyond packaging the genome into the nucleus, chromatin provides an elegant mechanism for regulating all DNA-templated processes. There are a large number of factors that go into defining and regulating chromatin structure, including the extensive modification of the histones and DNA.

The modification of histones and the potential for effect on genome regulation was first recognized in 1964. In particular, Allfrey and Mirsky [3] noted that the posttranslational acetylation of histones led to changes in transcription. Some years later, it was proposed that DNA methylation may also affect gene regulation [4,5]. However, it was not until several years later that the study of chromatin modifications entered the spotlight. This coincided with three key discoveries. It was found that the activities of histone acetyltransferase and deacetylase (enzymes responsible for catalyzing the placement and removal of acetyl groups, respectively) were directly associated with changes in transcription, followed by the discovery that an acetyltransferase subdomain, known as the bromodomain, could specifically recognize this histone modification [6,7]. These discoveries definitively linked histone modification to gene regulation, confirmed the reversible nature of histone modifications, and demonstrated that these modifications could be functionally recognized. The parallel to classical signal transduction was evident and the defined field of chromatin signaling was born. In the 20 years since these landmark reports, a wealth of discoveries has been made regarding chromatin signaling pathways. In addition, it has been determined that dysregulation of chromatin modifications contributes to a wide range of diseases and disorders, including neurodegenerative, neurodevelopmental, and neuropsychiatric disorders.

The term epigenetics is often associated with chromatin signaling pathways. This term is usually credited to Waddington, who described it in 1942 as the complex process between genotype and phenotype, especially as it relates to development [8]. As it became apparent that DNA and histone modifications could alter gene expression and change phenotype, these pathways begun to be referred to as epigenetic pathways. Epigenetic processes have historically been discussed in the context of heritability and in terms of environmental influences on gene expression. However, there has been much debate over whether or not these are requirements for something to be considered truly epigenetic [9]. The plasticity of this term in the field has led to some consternation among researchers, and the debate over what makes something truly epigenetic continues to evolve. As the mechanisms of chromatin signaling, the influence of environment on these pathways, and the potential for heritability of chromatin states are uncovered, this term may be defined more concretely. In this chapter the basics of chromatin structure and signaling will be presented, as well as the most recent findings on the influence of environment and metabolism, and the potential for heritability, with an overall emphasis on mechanism.

1.2. Chromatin organization

The fundamental subunit of chromatin is the nucleosome (Fig. 1.1). The nucleosome was first identified through enzymatic digestion of chromatin and was characterized through microscopy and X-ray diffraction [10,11]. These studies were later followed by a high-resolution crystal structure of the nucleosome core particle (NCP) [12]. The NCP consists of an octamer of the histone proteins H2A, H2B, H3, and H4 that is wrapped by ∼147 base pairs of DNA, with the DNA that bridges adjacent nucleosomes referred to as the linker DNA. The N-terminus of each of the histone proteins and the C-terminus of H2A protrude from the core and are referred to as the histone tails. These tails do not resolve in the majority of crystal structures of the NCP and are sensitive to protease digestion [13,14], leading to the common model that they are largely disordered and flexible, although some reports suggest transient interaction of the tails with the linker DNA [15–17].

Although the whole of chromatin consists of repeats of nucleosomes, the local chromatin structure is actually quite diverse. This diversity arises from a variety of factors and includes DNA sequence, nucleosome density and positioning, the presence or absence of histone H1 (which binds to the linker DNA), incorporation of histone variants, and chemical modification of the histones and DNA. Chromatin can be classified into two general categories: euchromatin and heterochromatin. Euchromatin has a lower density of nucleosomes, adopts a more open structure, and is associated with transcriptionally active genes. In contrast, heterochromatin contains a higher density of nucleosomes, is substantially more compact, and is transcriptionally silent. Heterochromatin is also enriched in linker histone, which contributes to compaction. Heterochromatin can either be constitutive or facultative. Constitutive heterochromatin contains genes that are stably repressed, whereas facultative heterochromatin retains the ability to convert between states. In interphase and postmitotic nuclei, euchromatin and heterochromatin are spatially segregated, where the former resides away from the nuclear periphery and the latter associates with the nuclear lamina. It is thought that this organization contributes to gene regulation [18]. In fact the higher order or...

Table of contents

• Cover image
• Title page
• Table of Contents
• Translational Epigenetics Series
• Copyright
• Contributors
• Preface
• Chapter 1. Chromatin and epigenetic signaling pathways
• Section 1. Neurodegenerative disorders
• Section 2. Neurodevelopmental disorders
• Section 3. Neuropsychiatric disorders
• Index