Epigenetic therapeutic strategies for the treatment of neuropsychiatric disorders: ready for prime time?
Chromatin remodeling is recognized as a major regulator of gene expression that can be influenced by inhibition of epigenetic mechanisms that result in stable, heritable, covalent modifications of histone proteins and their associated DNA. Epigenetically regulated covalent modifications are implicated in the pathogenesis of some forms of cancer and stimulated clinical trials of compounds selected for their ability to arrest cell division and promote differentiation of malignantly transformed cells. Chromatin remodeling may also be considered as a therapeutic target in diverse neuropsychiatric disorders such as Huntington disease and other neurodegenerative disorders characterized by expression of mutant proteins with expanded tracts of polyglutamine repeats, schizophrenia, and major depression. Ideally, these strategies will be relatively selective because epigenetic abnormalities may be most pronounced in specific cell types, and tissues and transcriptional dysregulation due to pathological covalent modifications involve only a small percentage of all the expressed genes in the human genome. To date, beneficial effects of epigenetic therapeutic interventions such as administration of histone deacetylase inhibitors have been observed in transgenic mice expressing mutant human DNA constructs of proteins with expanded polyglutamine repeats and other rodent models of neuropsychiatric disorders. The epigenetic therapeutic strategy has much promise, and its development will foster collaboration and cross fertilization between molecular and cell biologists, oncologists, psychiatrists, and neurologists.
Deutsch
Stephen I
SI
Mental Health Service Line (116A), Department of Veterans Affairs Medical Center, Washington, DC 20422, USA. Stephen.Deutsch@med.va.gov
Rosse
Richard B
RB
Mastropaolo
John
J
Long
Katrice D
KD
Gaskins
Brooke L
BL
D000818:Animals; D042002:Chromatin Assembly and Disassembly; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000502:physiology*; D006801:Humans; D001523:Mental Disorders / Q000235:genetics* / Q000628:therapy*; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000628:therapy*