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Epigenetic regulation in psychiatric disorders

Nature Reviews Neuroscience volume 8, pages 355–367 (2007)Cite this article

An Author Correction to this article was published on 13 December 2018

This article has been updated

Key Points

  • Epigenetic regulation of a gene is the process by which the activity of a particular gene is controlled by the structure of nearby chromatin.

  • Chromatin remodelling is complex and involves covalent modification of histones (for example, acetylation, methylation and phosphorylation), ATPase-containing protein complexes that move histone oligomers along a strand of DNA, direct methylation of DNA, and the binding of numerous transcription factors and transcriptional co-activators and co-repressors, all of which act in a concerted fashion to determine the activity of a given gene.

  • Epigenetic regulation is crucial for nervous system development, and several common mental retardation syndromes and related neurodevelopmental disorders are caused by abnormalities in chromatin remodelling mechanisms.

  • Epigenetic regulation also occurs in the mature brain, and may underlie stable changes in gene expression both under normal conditions (for example, learning and memory) and in several neuropathological states.

  • Long-lasting changes in histone acetylation, histone methylation and DNA methylation have been demonstrated in rodent models of depression. Drugs that increase histone acetylation exert antidepressant-like effects in these models.

  • Some of the lasting effects on the brain of drugs of abuse such as cocaine have been related to the drug's regulation of histone acetylation. Agents that increase histone acetylation enhance biochemical and behavioural responses to cocaine, and mice lacking certain enzymes that mediate histone deacetylation show similar increases in cocaine responsiveness.

  • Rett syndrome, an autism spectrum disorder, is caused by loss of function mutations in the gene that encodes a protein that binds to methylated sites in DNA and acts to repress the associated genes.

  • Recent work has implicated abnormalities in DNA methylation and histone acetylation in schizophrenia.

  • Work on epigenetic mechanisms of psychiatric disorders is in its early stages, but promises to improve our understanding of disease pathophysiology and might lead to the development of fundamentally new treatments for these conditions.

Abstract

Many neurological and most psychiatric disorders are not due to mutations in a single gene; rather, they involve molecular disturbances entailing multiple genes and signals that control their expression. Recent research has demonstrated that complex 'epigenetic' mechanisms, which regulate gene activity without altering the DNA code, have long-lasting effects within mature neurons. This review summarizes recent evidence for the existence of sustained epigenetic mechanisms of gene regulation in neurons that have been implicated in the regulation of complex behaviour, including abnormalities in several psychiatric disorders such as depression, drug addiction and schizophrenia.

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Figure 1: General scheme of chromatin remodelling.
Figure 2: Regulation of chromatin remodelling via intracellular signalling cascades.
Figure 3: Regulation of the Bdnf gene by social defeat.
Figure 4: Proposed chromatin remodelling events at a cocaine-activated gene.

Change history

  • 14 December 2018

    In part c of Figure 1 in this article, the orientation of the tail of histone 3 with respect to the core region of this molecule was incorrect, and the amino acid residue K79 should not have been depicted in the tail. The corrected figure is shown below. The authors and editors thank T. Brown, R. Lober and C. Waker for bringing this error to our attention. Note that the present affiliation of the corresponding author and their current email address have been added to the correction notice.

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Acknowledgements

Preparation of this review was supported by grants from the National Institute on Drug Abuse and the National Institute of Mental Health.

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Authors and Affiliations

  1. Department of Psychiatry and Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Nadia Tsankova, William Renthal, Arvind Kumar & Eric J. Nestler

Authors
  1. Nadia Tsankova
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  2. William Renthal
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  3. Arvind Kumar
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  4. Eric J. Nestler
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Corresponding author

Correspondence to Eric J. Nestler.

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Supplementary information S1 (table)

Tsankova et al., Epigenetic Regulation in Psychiatric Disorders (PDF 215 kb)

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DATABASES

OMIM

Rett syndrome

Rubinstein–Taybi syndrome

schizophrenia

FURTHER INFORMATION

Nestler's laboratory

Glossary

Histones

Highly basic proteins that comprise the major protein constituents of the nucleus. Octomeric complexes of histones, around which DNA is wrapped, form the nucleosome, the basic building block of chromatin.

Nucleosome

The basic building block of chromatin in which 147 base pairs of DNA are wrapped (∼1.65 turns) around a core histone octamer.

Heterochromatin

The inactivated state of chromatin, in which DNA is not accessible for transcription due to covalent modifications of histones, methylation of the DNA and the binding of numerous repressor proteins.

Euchromatin

The activated state of chromatin, in which sections of DNA are accessible to the transcriptional machinery.

Ubiquitylation

Covalent addition of a small protein, called ubiquitin, to many types of proteins. Addition of multiple ubiquitin groups, polyubiquitylation, targets proteins for degradation in the proteasome. By contrast, monoubiquitylation of histones and other regulatory proteins alters their functional properties.

SUMOylation

Covalent addition of SUMO, which are small ubiquitin-related modifier proteins, to histones and many other types of regulatory proteins, which alters those proteins' function.

Nucleosome sliding

The movement of the core histone octamer relative to the DNA, which allows that DNA to be progressively transcribed into RNA.

SWI/SNF

Protein complex that partly mediates nucleosome sliding in an ATP-dependent manner. The name comes from genetic screens of yeast which identified proteins implicated in mating switching and sucrose non-fermentation. The proteins were later found to regulate nucleosome sliding.

Histone substitution

A type of chromatin remodelling where histone constituents of the nucleosome can be replaced by other naturally occurring histone variants.

X-chromosome inactivation

Chromatin remodelling on a very large scale, whereby one of two X chromosomes in all cells of a female organism are inactivated by DNA hypermethylation. Once that chromosome is silenced, it remains inactive for the life of the organism.

Genetic imprinting

A process where only the maternal or paternal allele of a gene is expressed in the offspring. The other, inactivated allele is transcriptionally silenced through DNA methylation at CpG-rich domains.

Chromatin immunoprecipitation

(ChIP). A method that enables the identification of histone modifications or transcriptional regulatory proteins at a given gene promoter. In the assay, DNA is crosslinked to nearby proteins by light fixation, the material is sheared, then immunoprecipitated with an antibody to a particular protein of interest, and genes in the final immunoprecipitate are quantified by polymerase chain reaction.

Immediate-early genes

Genes that are induced rapidly and transiently without the need for new protein synthesis. Many immediate-early genes, such as c-Fos, control the transcription of other genes, and thereby provide the early stages in the control of the production of specific proteins.

DNA demethylases

Enzymes, not yet molecularly characterized, that demethylate CpG residues in DNA. Active DNA demethylation may also occur through alternative mechanisms such as DNA repair and deamination.

ChIP on chip

A method that enables a global analysis of genes associated with a particular histone modification or transcriptional regulatory protein. Immunoprecipitated chromatin is analysed on a microarray gene chip, enriched in promoter regions.

SACO

Serial analysis of chromatin occupancy, an alternative method to ChIP on chip, is used to obtain a genome-wide appreciation of the genes that bind a particular histone modification or transcriptional regulatory protein. Instead of hybridizing the immunoprecipitated DNA to a microarray, the DNA is directly sequenced.

Circular dichroism

A form of spectroscopy, involving the differential absorption of left- and right-handed polarized light, used to study the structure of complex molecules.

Valproate

A commonly used anticonvulsant and antimanic medication. Among many other actions (for example, direct effects on the brains GABA pathways), valproate is a nonspecific inhibitor of class I and class II HDACs.

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Tsankova, N., Renthal, W., Kumar, A. et al. Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci 8, 355–367 (2007). https://doi.org/10.1038/nrn2132

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