Schizophrenia, epigenetics and ligand-activated nuclear receptors: a framework for chromatin therapeutics

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Abstract

Covalent modifications of DNA and its surrounding chromatin constitute an essential and powerful regulatory mechanism for gene transcription. Epigenetics is the study of this regulatory system. There is now strong albeit indirect evidence that epigenetic mechanisms contribute to the pathophysiology of schizophrenia. Furthermore, the discovery that valproic acid, a widely used psychotropic, has powerful epigenetic effects in clinically relevant concentrations suggests new therapeutic possibilities, i.e., drugs that act on chromatin structure. Fortunately, many proteins engaged in these processes, particularly chromatin remodeling, are accessible to pharmacological agents that have a high likelihood of crossing the blood brain barrier. This review will first summarize the essentials of the epigenetic regulatory system, then address the molecular evidence for altered epigenetic mechanisms in schizophrenia, and finally focus on the retinoic acid family of ligand-activated nuclear transcription factors as a likely system for new drug development in the management of schizophrenia-related symptoms.

Introduction

Epigenetics is the study of the heritable and potentially reversible covalent modifications of DNA and its surrounding proteins. These modifications determine whether the DNA strand is tightly wound in nucleosomal arrays (heterochromatin) and consequently, poorly accessible to transcriptional proteins, or if the DNA strand resides in a more relaxed transcriptionally active state (euchromatin). Epigenetic modifications are demonstrably important in influencing the levels of gene expression and play a pivotal role in phenotypic variations (commonly ascribed to the effects of either quantitative trait loci (QTLs) or the environment). These modifications may also be the basis of complex diseases, especially psychosis (Petronis, 2001). Because epigenetic mechanisms, such as histone acetylation, are modifiable by pharmacological interventions, the therapeutic potential of epigenetic research is profound. Inhibitors of histone deacetylase (HDAC) enzymes are already being considered in the treatment of cancer (Blaheta and Cinatl, 2002), and Valproic acid (Depakote®) is an FDA-approved drug for bipolar disorder with recently discovered HDAC-inhibiting property at clinically relevant plasma levels Gottlicher et al., 2001, Phiel et al., 2001.

The purpose of this review is to (1) describe the essential features of the epigenetic machinery in the context of some recent finding relating to the pathophysiology of schizophrenia; (2) present retinoid transcription factors as an illustrative example of the ligand-activated nuclear receptors (LNR), a pharmacologically accessible superfamily of proteins with profound effects on epigenetic mechanisms; and (3) consider the implications of these systems for the research and development of novel pharmacotherapeutic agents.

Section snippets

Epigenetic control of transcription: a brief review

The “normal” ground state for eukaryotic chromatin is nonpermissive to transcription (Struhl, 1999). However, normal chromatin does allow penetration by a small subset of transcription factors, which in turn induce two types of progression (Struhl, 1999); the restrictive ground state can be modified such that chromatin can enter a highly repressed “silent” state or can be converted to a transcriptionally “competent” state. The main components of this regulatory process will be briefly described

Therapeutic approaches towards chromatin structure

In this genomic era, our ability to manipulate genomic sequences is realistically limited to indirectly targeting proteins, albeit those engaged in the most intimate interaction with the DNA strand. Two such pharmacological opportunities are evident. The first is the targeting of proteins involved in aspects of the epigenetic machinery, i.e., DNA methylation and chromatin modifications. The second is the targeting of ligand-activated nuclear transcription factors. While the first is a powerful

Retinoic acid and retinoic acid receptors

Bioactive “retinoids” such as vitamin A (retinal), beta-carotene, and retinyl are acquired from the environment and ultimately converted to retinoic acids (all-trans-retinoic acid [t-RA] and 9-cis-retinoic acid stereo isomers [9-cis RA]). Two families of nuclear receptors transduce the retinoid signal. Each family is comprised of three individual receptors coded by separate genes (RARα, RARβ, and RARγ, as well as RXRα, RXRβ, and RXRγ). RARs have affinity for either RA isomer while RXRs bind

Conclusion

Our ability to manipulate gene expression for therapeutic objectives will be significantly enhanced by our ability to influence chromatin structure. The resurgence of interest in epigenetics, particularly chromatin as a regulatory protein sheath rather than a passive packaging material, paves the way for a new era of innovative pharmacology. This review addresses two such possibilities, nonspecific HDAC inhibitors with genome-wide influence such as valproic acid, and retinoid receptors with

Acknowledgements

The author gratefully acknowledges the helpful comments of Dr. Erminio Costa and Dr. Dennis Grayson, both of the Department of Psychiatry and College of Medicine, University of Illinois at Chicago.

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