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Animal Models of Epigenetic Regulation in Neuropsychiatric Disorders

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Molecular and Functional Models in Neuropsychiatry

Part of the book series: Current Topics in Behavioral Neurosciences ((CTBN,volume 7))

Abstract

Epigenetics describes the phenomenon of heritable changes in gene regulation that are governed by non-Mendelian processes, primarily through biochemical modifications to chromatin structure that occur during cell development and differentiation. Numerous lines of evidence link abnormal levels of chromatin modifications (either to DNA, histones, or both) in patients with a wide variety of diseases including cancer, psychiatry, neurodegeneration, metabolic and inflammatory disorders. Drugs that target the proteins controlling chromatin modifications can modulate the expression of clusters of genes, potentially offering higher therapeutic efficacy than classical agents with single target pharmacologies that are susceptible to biochemical pathway degeneracy. Here, we summarize recent research linking epigenetic dysregulation with diseases in neurosciences, the application of relevant animal models, and the potential for small molecule modulator development to facilitate target discovery, validation and translation into clinical treatments.

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Abbreviations

2-OG:

2-Oxo-glutarate

AAV:

Adeno-associated virus

BDNF:

Brain-derived neurotrophic factor

BET:

Bromodomain and extra C-terminal domain protein

CaMK:

Ca2+/calmodulin-dependent protein kinase

CDK5:

Cyclin-dependent kinase 5

ChIP:

Chromatin immunoprecipitation

CoA:

Coenzyme A

CpG:

Short stretches of DNA in which the frequency of C and G base pairs are higher than other regions

CREB:

cAMP response element binding protein

CRH:

Corticotrophin releasing hormone

CTCL:

Cutaneous T-cell lymphoma

DNMT:

DNA methyltransferase

FAD:

Flavin adenine dinucleotide

FPC:

Frontopolar cortex

FRET:

Forster resonance energy transfer

GABA:

Gamma-aminobutyric acid

GR:

Glucocorticoid receptor

H3K9Me2:

Histone H3 dimethylated at lysine-9 ε-nitrogen

HAT:

Histone acetyl transferase

HDAC:

Histone deacetylase

HSV:

Herpes simplex virus

IKB:

IκB transcription factor

IKK:

IκB kinase

JMJD:

Jumonji (demethylase) domain

KDM:

Lysine demethylase

KO:

Knockout

LG:

Licking and grooming

LSL:

Lox P-stop-Lox P cassette

LTP:

Long-term potentiation

MAOI:

Monoamine oxidase inhibitor

MBD:

Methyl-CpG-binding domain protein

MBT:

Maligant brain tumour domain

MeCP2:

Methyl CpG binding protein 2

miRNA:

MicroRNA

NAc:

Nucleus accumbens

NFκB:

Nuclear factor-kappaB

NGFIA:

Nerve growth factor inducible protein A

PHD:

Plant homeodomain

PRMT:

Arginine methyltransferase

PTGS:

Post-transcriptional gene silencing

SAHA:

Suberoyl-aniline hydroxamic acid

SirT:

Sirtuin (NAD+-dependent histone deacetylase)

SUMO:

Small ubiquitin-like modifier

TSA:

Trichostatin A

TSS:

Transcription start site

WT:

Wild-type

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Acknowledgments

The Structural Genomics Consortium (a registered charity; number 1097737) receives funds from the Canadian Institutes for Health Research, the Canadian Foundation for Innovation, Genome Canada through the Ontario Genomics Institute, GlaxoSmithKline, Karolinska Institutet, the Knut and Alice Wallenberg Foundation, the Ontario Innovation Trust, the Ontario Ministry for Research and Innovation, Merck and Co., Inc., the Novartis Research Foundation, the Swedish Agency for Innovation Systems, the Swedish Foundation for Strategic Research and the Wellcome Trust. The work was supported by the NIHR Biomedical Research Unit Oxford. We gratefully acknowledge the assistance of Ms J. Zapisek and Ms. M. Kalinowska in the preparation of this article.

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  1. Structural Genomics Consortium, University of Oxford, Oxford, OX3 7DQ, UK

    Chas Bountra, Udo Oppermann & Tom D. Heightman

  2. Botnar Research Centre, Oxford Biomedical Research Unit, University of Oxford, Oxford, OX3 7LD, UK

    Udo Oppermann

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  1. Chas Bountra
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  2. Udo Oppermann
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Correspondence to Chas Bountra .

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  1. Global Medical Excellence Cluster (GMEC), King's College London, London, SE1 1UL, United Kingdom

    Jim J. Hagan

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Bountra, C., Oppermann, U., Heightman, T.D. (2011). Animal Models of Epigenetic Regulation in Neuropsychiatric Disorders. In: Hagan, J. (eds) Molecular and Functional Models in Neuropsychiatry. Current Topics in Behavioral Neurosciences, vol 7. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7854_2010_104

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