Sweatt / Meaney / Nestler Epigenetic Regulation in the Nervous System

Basic Mechanisms and Clinical Impact
1. Auflage 2012
ISBN: 978-0-12-394405-4
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, 374 Seiten

Epigenetic Regulation in the Nervous System addresses current understanding of the roles of epigenetic processes at the molecular/cellular level, their impact on neural development and behavior, and the potential roles of these mechanisms in neurological and psychiatric disorders. This award-winning volume spans molecular epigenetics, development, cellular physiology and biochemistry, synaptic and neural plasticity, and behavioral models, and is unique in covering epigenetically based disorders of the central nervous system.Behavioral epigenetics is the study of how environmental factors alter behavior, addressing the fundamental mechanisms that shape development and individual vulnerability/resilience to adverse behavioral outcomes. By understanding the molecular mechanisms involved in epigenetic modulation, researchers may be able to develop targeted therapies for those individuals in whom it malfunctions.Edited by the most highly regarded leaders in the field, this book offers a comprehensive review of behavioral epigenetics and a balanced treatment of the strengths and weaknesses in experimentation in this area. Covering background material as well as topics of current interest, it serves both as a cutting-edge resource and a foundational reference. The book will benefit neuroscience researchers and graduate students with an interest in the links between gene regulation and behavior, as will clinicians dealing with disorders such as addiction, depression, and schizophrenia. - BMA Medical Book Awards 2014 - Highly Commended,ÿ Neurology, British Medical Association - BMA Medical Book Awards 2014 - First Prize, Neurology, British Medical Association - 2013 PROSE Award winner for Best in Reference Works and Best Single Volume Reference in Science from the Association of American Publishers - Presents a unified view of epigenetic mechanisms from behavior to genes and everything in between - Discusses clinically relevant disorders in the context of epigenetics research, making the volume appealing to clinicians as well as basic scientists - Provides numerous practical examples for the new investigator to facilitate implementation of research in neuroepigenetics

Autoren/Hrsg.

Sweatt, J. David

Meaney, Michael J.

Nestler, Eric J.

Akbarian, Schahram

Leseproben

Chapter 2 Histone Modifications in the Nervous System and Neuropsychiatric Disorders Morgan Bridi1 and Ted Abel2, 1Department of Neuroscience, Perelman School of Medicine, 2Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA Introduction
The previous chapter dealt with the “nuts-and-bolts” issues of chromatin biology and the histone code: the ways in which post-translational modification of the core histone proteins can contribute to higher-order chromatin structure and differential patterns of gene expression, a concept referred to broadly as epigenetics. This term was coined by Conrad Waddington, a developmental biologist, who referred to an “epigenetic landscape” to explain the observation that cells sharing the same origin and genotype display different phenotypes over the course of development.1,2 This concept was updated in the decades to follow as our understanding of genetics grew, and epigenetics came to refer to “potentially heritable changes in gene expression that do not involve changes in DNA sequence”.3,4 Epigenetics was first conceived as a way to explain developmental phenomena and, indeed, epigenetic modifications are heritable through cell division, influencing the transcriptome and phenotype of subsequent generations of cells. Epigenetic changes are also mitotically stable enough to be heritable transgenerationally and passed on from parent to offspring and influence behavioral and genetic phenotypes.5,6 However, epigenetic modifications are not limited to developmental contexts and it is now clear that such mechanisms are at work even in terminally differentiated cells such as neurons. The modern understanding of epigenetics reflects this, and we now define epigenetics as “the sum of the alterations to the chromatin template that collectively establish and propagate different patterns of gene expression and silencing from the same genome”.7 Changes to the epigenome can be stable and long lasting. They are also dynamic and can be recruited in response to external stimuli in non-dividing cells, such as neurons.8 Research into the various epigenetic systems at work in the central nervous system (CNS) is a burgeoning field, and investigators have begun to reveal essential roles for post-translational histone modifications in a diverse array of neuronal systems. In this chapter, we explore some of the implications of histone modifications in central nervous system function, as well as the relationship between histone modifications and neuropsychiatric and neurological disorders. The Histone Code: Complex and Combinatorial
Chromatin is the tightly packaged complex of DNA and proteins that facilitates the proper organization, storage, and transcription of the genome within the nucleus. The basic unit of chromatin is the nucleosome core particle, 147 base pairs of DNA wrapped around an octamer composed of two copies each of the canonical core histone proteins H2A, H2B, H3, and H4.9 A number of post-translational modifications can be made to the histones, altering the structure of nucleosomes and chromatin and thereby potentially altering patterns of gene expression.10,11 The histone code hypothesis was first proposed by David Allis and colleagues over a decade ago.12 At its most basic, this idea was that histone modifications act in combination to effect downstream changes in gene expression in response to external stimuli. The histone code has served the field well as a general hypothesis and framework for experimental design. As our knowledge of chromatin biology has expanded and matured, so too has the formulation of the histone code hypothesis changed to keep pace with current research.8,13,14 A more current view of the histone code is that of an “epigenetic index”8 in which the different combinations of histone modifications correspond to particular transcriptional and epigenomic states. This idea is taken further with the concept of a “histone language”,14 in which the downstream effects of histone modifications are context-sensitive and cross-talk between modifications influences the addition, removal and, ultimately, the readout of epigenetic histone marks. There are at least 14 distinct modifications that have been identified in the literature, occurring at over 100 sites on the N-terminal tails and the globular bodies of histone proteins (Figure 2.1).15,16 Histone modifications regulate various processes including activation or inactivation of transcription, DNA repair, replication, and chromatin condensation.11,17 Histone acetylation occurs at lysine residues on all of the core histone proteins, and is usually associated with active transcription.18 Phosphorylation at serine, threonine, and tyrosine residues is also correlated with actively-transcribed genes, and it is frequently found to co-occur with histone acetylation, although some uncertainty surrounds the nature of this relationship.19,20 Histone methylation is a more complicated modification. Methyl groups are added to both lysine and arginine residues. Lysines can be mono-, di-, or trimethylated, while arginine residues can only have one or two methyl groups added. Histone methylation is an uncharged modification and is associated with both activation and inactivation of transcription, depending on the site modified and the number of methyl groups added.22 Figure 2.1 Post-translational histone modifications.
(A) Histone marks are added and removed by particular classes of enzymes. Histone methylation occurs on lysine and arginine residues. Methyl groups are added by histone methyltransferase enzymes, and are removed by histone demethylase enzymes. Acetyl groups are added to lysine residues by the histone acetyltransferase enzymes; histone deacetylase enzymes remove them. Histone kinases phosphorylate serine, tyrosine, and threonine residues; histone phosphatase enzymes erase these marks.10,11,17,19 (B) Multiple histone modifications of different types can occur together on the same histone protein.21 The other histone modifications are generally not as well understood, especially as they relate to brain function. Ubiquitination is a very large modification, associated with repression, and it may interfere with histone acetylation. Sumoylation is related to ubiquitination, though it is smaller and antagonizes both acetylation and ubiquitination.11,17 Deimination, or citrullination, is the conversion of an arginine residue to citrulline, which possibly interferes with transcriptional activation by arginine methylation,23,24 although this relationship may also go the other way.25 There are still other histone modifications: proprionylation, formylation, butyrylation, ADP ribosylation, and proline isomerization have all been reported, but it is not yet known what role they play in CNS function. Novel histone modifications and modification sites are still being discovered. The addition of beta-N-acetylglucosamine (O-GlcNAc) to serine and threonine on histones H2A, H2B, and H4 was first described in 2010. Histone O-GlcNAcylation was found to be responsive to heat shock and mitotic cell division, and may be involved in chromatin remodeling.26 Crotonylation is a recently described modification, discovered in 2011.27 Histone crotonylation was observed at lysine residues and is associated with the promoters of actively transcribed genes in male germ cells. The same study that identified crotonylation also found another novel, as-yet-uncharacterized mark, histone tyrosine hydroxylation.27 Clearly, future research is needed to define these histone modifications and what roles they play in neurons. A rough, back-of-the-envelope calculation can give us a feel for the complexity of the histone code by estimating how many potential epigenetic states histone modification could establish at the promoter of any particular gene. To begin, consider the number of modifications that are possible on the nucleosome core proteins: approximately 100 modifications between histones H3 and H4 and another 10 between histones H2A and H2B. If all the different combinations are taken into account, this gives a possible 106 states. Some redundancy may be involved, because not all modifications make unique contributions and not all possible combinations are observed in vivo. In that case, we can trim the number down to a more conservative 103 possible combinations per gene. Multiply that figure by the approximately 30 000 genes identified in the human genome, and we could estimate that there are 30 000 000 possible histone modification states that could be established in the nucleus. The potential number of epigenetic states created by histone modifications is large and the cross-talk between histone modifications is complex, but the histone code seems to follow particular rules that could make understanding it more tractable. Genome-wide studies in yeast, Drosophila, and mammalian cells have mapped histone modifications and found that not all of the possible histone modification patterns actually occur in vivo.30–32 Smaller-scale experiments have also found some of the relationships and rules that dictate the histone code. For example, not all histone modifications make unique contributions, and the addition of some histone modifications is...