Psychiatric Disorders: a Feat of Epigenetic Engineering

RESEARCH HIGHLIGHTS MACMILLAN AUSTRALIA

PSYCHIATRIC DISORDERS A feat of epigenetic engineering

Chronic exposure to stress or drugs and Fosb-TALE‑VP64) in the mouse expression blocked cocaine- of abuse causes widespread changes NAc increased levels of Fosb as well induced locomotor sensitization, single in the activity of chromatin remod- as the level of H3K9 acetylation (an whereas Fosb-ZFP‑p65 and epigenetic elling enzymes. However, it has been activating histone modification) Fosb-TALE‑VP64 enhanced this difficult to determine the relative at the Fosb promoter. Conversely, response. Susceptibility to depres- modifications functional importance of drug- or expression of a construct containing sion has been linked to reduced can modulate stress-induced epigenetic modifica- a transcriptionally repressive domain FOSB levels in humans and animal both Fosb tions of individual genes. Nestler (Fosb-ZFP‑G9a) decreased Fosb models. The authors showed here expression and and colleagues have now employed expression and increased the level of that expression of Fosb-ZFP‑G9a gene- and brain-region-specific the repressive histone modification increased depression-like behav- its behavioural chromatin remodelling to examine H3K9me2. Thus, the engineered iour in a chronic social defeat effects. the role of one particular gene, Fosb, transcription factors induced specific stress model, indicating that the in addiction- and depression-related histone modifications and regulated H3K9me2 modification mediates changes in the brain and behaviour. Fosb expression in vivo. this effect. Changes in Fosb expression in Cocaine exposure induces Fosb This study shows that single epi- the nucleus accumbens (NAc) via expression in the NAc, and the genetic modifications can modulate epigenetic remodelling have been con- authors showed that expression of both Fosb expression and its behav- nected to addiction- and depression- Fosb-ZFP‑G9a blocked this induc- ioural effects. A similar approach related behaviour. To examine this link tion. Furthermore, Fosb-ZFP‑G9a may be used to target other genes more precisely the authors generated expression blocked the cocaine- of interest and elucidate further the engineered transcription factors induced enrichment of phosphoryl- changes in molecular pathways that comprised of zinc-finger proteins ated CREB at the Fosb promoter. underlie psychiatric disorders. (ZFPs) or transcription-activator-like H3K9me2 therefore regulates Katherine Whalley effectors (TALEs) that were targeted cocaine-induced Fosb expression selectively to the Fosb promoter and by inhibiting transcription factor ORIGINAL RESEARCH PAPER Heller, E. A. et al. were fused to domains that promote binding. Locus-specific epigenetic remodeling controls transcriptional activation or repression Next, the authors examined addiction- and depression-related behaviors. via histone modification. the role of histone modification Nature Neurosci. http://dx.doi.org/10.1038/ nn.3871 (2014) The authors showed that expres- at Fosb on the behavioural effects FURTHER READING Robison, A. J. & Nestler, E. J. sion of constructs that promote tran- of exposure to cocaine or stress. Transcriptional and epigenetic mechanisms of scriptional activation (Fosb-ZFP‑p65 They found that Fosb-ZFP‑G9a addiction. Nature Rev. Neurosci. 12, 623–637 (2011)

NATURE REVIEWS | NEUROSCIENCE VOLUME 15 | DECEMBER 2014