Toxicoepigenetics

Core Principles and Applications

Shaun D. McCullough, Dana Dolinoy

• Publisher: Academic Press
• Year: 2018
• ISBN:
  9780128124345
• Topic: Medicine
• Subtopic: Toxicology

Toxicoepigenetics: Core Principles and Applications examines the core aspects of epigenetics, including chromatin biology, DNA methylation, and non-coding RNA, as well as fundamental techniques and considerations for studying each of these mechanisms of epigenetic regulation. Although its integration into the field of toxicology is in its infancy, epigenetics have taken center stage in the study of diseases such as cancer, diabetes, and neurodegeneration. Increasing the presence of epigenetics in toxicological research allows for a more in-depth understanding of important aspects of toxicology such as the role of the environment and lifestyle influencing the individual susceptibility to these effects and the trans-generational transmission of these health effects and susceptibilities. Methods chapters are included to help improve efficacy and efficiency of protocols in both the laboratory and the classroom. Toxicoepigenetics: Core Principles and Applications is an essential book for researchers and academics using epigenetics in toxicology research and study.

• Introduces the fundamental principles and practices for understanding the role of the epigenome in toxicology
• Presents the foundation of epigenetics for toxicologists with a broad range of backgrounds
• Discusses the incorporation of epigenetics and epigenomics into current toxicological studies and interpretation of epigenetic data in toxicological applications

Section 1

Histone Modifications and Chromatin Structure

Chapter 1-1

Role of Histone Acetylation and Acetyltransferases in Gene Regulation

Christina Y. Lee; Patrick A. Grant Department of Biochemistry and Molecular Genetics, University of Virginia Medical School, Charlottesville, VA, United States

Abstract

The compaction of DNA into chromatin poses a significant obstacle to DNA-templated events such as transcription, replication, and DNA repair. Importantly, chromatin structure is dynamically regulated, and one mechanism that facilitates this process is the posttranslational modification of histone proteins within nucleosomes. This is mediated by the action of chromatin-modifying activities, such as histone acetyltransferases. The acetyltransferases and deacetylases that regulate histone acetylation and chromatin function are arguably the most well-studied group of chromatin protein modifiers. Here, we provide an overview of this field and particularly draw insights from studies in yeast where many archetypal acetyltransferases and deacetylases have been found, along with their regulatory mechanisms. We provide an account of the families of histone acetyltransferases and their diverse roles in gene expression. We also give examples of diseases and environmental exposures that influence histone acetylation.

Keywords

Histone acetylation; Acetyltransferase; Deacetylase; SAGA; NuA4; MYST; GNAT; p300; CBP

Outline

• Introduction
  • History and Overview
  • Nucleosome Assembly
  • Chromatin Folding
  • Gene Expression
  • DNA Damage Repair
  • Toxicoepigenetic Relevance
• Histone Acetyltransferases
  • Families and Structures
  • Regulation of HATs
• Transcriptional Activation
  • Hat Complexes
  • SAGA Transcription Regulatory Complex
  • NuA4 Transcription Regulatory Complex
  • Elongator Complex
  • Chromatin Remodeling Complexes
• Global Histone Acetylation
• Role of Histone Acetyltransferases in Gene Activation
  • Recruitment of Transcriptional Machinery
  • Active Genes
  • Inducible/Repressed Genes
• Environmental Exposure
• Histone Deacetylases
  • Families
  • Catalytic Mechanisms and Structures
  • Regulation of HDAC Activity
  • Role of HDACs at Active Genes
  • Deacetylation and Gene Repression
  • HDAC Complexes
• Conclusion and Perspectives
• References

Introduction

History and Overview

Within the eukaryotic nucleus, DNA is compacted 10,000–20,000-fold, in part by being wound around octamers of core histone proteins that form nucleosomes. Nucleosomes each consist of 147 bp of DNA wrapped approximately twice around the protein core that contains two copies of each histone, H2A, H2B, H3, and H4 (Luger et al., 1997). The interaction of DNA and histones is critical to regulating transcription, replication, and repair of the genome and is influenced by various chromatin-modifying enzymes. Over 100 distinct histone modifications have been discovered (Zhao and Garcia, 2015). Histone proteins, the sites of posttranslational modification and modifying enzymes, are highly conserved across species from yeast to humans. This level of conservation has allowed great insights into the functions of histone modifications being garnered from model organisms such as the budding yeast or fruit flies. The N-terminal tails of the eight core histones are exposed to the nucleosome surface, allowing them to be modified by various mechanisms such as phosphorylation, methylation, ubiquitination, and acetylation (see review, Suganuma and Workman, 2011). Histone acetylation is associated with a variety of functions including regulation of nucleosome assembly, folding and decondensation of chromatin, heterochromatin silencing, and gene transcription (Fig. 1). Histone acetylation is conducted by histone acetyltransferases (HATs) and deacetylation by histone deacetylases (HDACs). In addition to the direct structural changes that lead to reorganization of chromatin as a consequence of histone acetylation, the histone modifications are also involved in the recruitment of specific “reader” proteins with binding affinity for specific marks. Acetylated lysines are read primarily by bromodomains, discussed in more detail below.

Fig. 1 Overview of N-terminal histone tail acetylations in mammals. The known functionality of each acetylation is color coded above the acetylation mark. The majority of marks are associated with transcriptional activation, and other functions include histone deposition for chromatin remodeling, DNA repair, replication, telomere silencing, and modulating euchromatin structure for chromatin folding. Histone N-terminal tails are in green; DNA wrapping around the nucleosome is in blue. In general, the overall acetylation level of histone proteins is more important than acetylation at specific lysines as there is functional redundancy in transcription (Shia et al., 2006). Key acetylations not only are noted on the histone tails but also can appear in the globular domain such as H3K122ac and H364ac, which mark gene enhancers (Pradeepa et al., 2016).

Although protein phosphorylation and acetylation were discovered within 4 years of each other in the 1960s, the understanding of histone acetylation continued to be relatively unknown until the 1990s when Allis and coworkers purified a HAT from Tetrahymena thermophila. This led to a clear link between histone acetylation and transcription regulation when it was revealed to be an enzyme orthologous to a yeast transcription regulator, Gcn5 (Brownell et al., 1996). Concurrently, Schreiber and colleagues discovered a human HDAC orthologous to a yeast transcription regulator, Rpd3 (Taunton et al., 1996). These discoveries were followed by a flurry of identifications of additional HATs associated with transcriptional regulation like CREB...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• Editors' Biography
• Introduction to the Role of the Epigenome in Health and Disease
• Section 1: Histone Modifications and Chromatin Structure
• Section 2: DNA Methylation
• Section 3: Noncoding RNAs
• Section 4: Special Considerations in Toxicoepigenetics Research
• Section 5: Protocols for Toxicoepigenetics Research
• Index