Histone Deacetylases and Mood Disorders: Epigenetic Programming in Gene‐Environment Interactions

• Published in: CNS neuroscience & therapeutics 2011-12, Vol.17 (6), p.699-704
• Main Authors: Machado‐Vieira, Rodrigo, Ibrahim, Lobna, Zarate, Jr, Carlos A.
• Format: Article
• Language: English
• Subjects: Acetylation; Adaptations; Animals; Antidepressants; Antimanic Agents - therapeutic use; Biological and medical sciences; Bipolar disorder; Central nervous system; Chemical and industrial products toxicology. Toxic occupational diseases; Chromatin remodeling; Cognition; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Depression; Disorders of higher nervous function. Focal brain diseases. Central vestibular syndrome and deafness. Brain stem syndromes; Epigenesis, Genetic; Epigenetics; Gene expression; Gene-Environment Interaction; Histone deacetylase; Histone Deacetylase Inhibitors - therapeutic use; Histone Deacetylases - genetics; Histone Deacetylases - physiology; Histones; Histones - metabolism; Histones - physiology; Humans; Medical sciences; Metals and various inorganic compounds; Molecular modelling; Mood; Mood Disorders - enzymology; Mood Disorders - genetics; Mood Disorders - physiopathology; Nervous system; Nervous system (semeiology, syndromes); Neurology; Nucleotide sequence; Pathophysiology; Promoters; Review; Reviews; Side effects; Toxicology; Transcription factors; Treatment; Valproate; Valproic acid; Valproic Acid - therapeutic use
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/j.1755-5949.2010.00203.x

SUMMARY Epigenetics involves molecular mechanisms related to gene expression independent of DNA sequence, mostly mediated by modification of chromatin histones. It has recently been suggested that these transcriptional changes may be implicated in the pathophysiology of mood disorders. In addition, histone deacetylase (HDAC) inhibitors have been shown to control epigenetic programming associated with the regulation of cognition and behavior, and may reverse dysfunctional epigenetic regulation associated with early life events in preclinical models. In this context, the active and continuous adaptation of chromatin, and the access of gene promoters to transcription factor mechanisms may represent a potential therapeutic target in the treatment of mood disorders such as bipolar disorder (BD) and major depressive disorder (MDD). Notably, the standard mood stabilizer valproate (VPA) has been shown to modulate the epigenome by inhibiting HDACs. However, several potential limitations are associated with this class of agents, including lack of selectivity for specific HDAC isoforms as well as risk of potentially serious side effects. Further studies regarding the potential role of chromatin remodeling in the mechanism of action of antidepressants and mood stabilizers are necessary to clarify the potential role of this class of agents as therapeutics for mood disorders.