REST, a master transcriptional regulator in neurodegenerative disease

• Published in: Current opinion in neurobiology 2018-02, Vol.48, p.193-200
• Main Authors: Hwang, Jee-Yeon, Zukin, R Suzanne
• Format: Article
• Language: English
• Subjects: Animals; Epigenomics; Gene Expression Regulation - physiology; Humans; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; Repressor Proteins - physiology
• ISSN: 0959-4388; 1873-6882
• DOI: 10.1016/j.conb.2017.12.008

•Identified as a master regulator of neuronal genes in embryogenesis, REST is a common theme in neurodegeneration.•Whereas bioinformatics predicts ∼2000 REST targets, a small subset are transcriptionally responsive.•The gene silencing transcription factor REST not only silences, but also activates gene transcription.•Whereas REST orchestrates fine-tuning of plasticity genes during development, it represses stress genes in aging neurons.•Whereas REST promotes death of insulted adult neurons, it protects aged neurons. The restrictive element-1 silencing transcription factor)/NRSF (neuron-restrictive silencing factor (NRSF) is a transcriptional repressor which acts via epigenetic remodeling to silence target genes. Emerging evidence indicates that REST is a master transcriptional regulator of neuron-specific genes not only in neurogenesis and neuronal differentiation, but also in differentiated neurons during the critical period in postnatal brain development, where it plays a role in fine-tuning of genes involved in synaptic plasticity, and in normal aging, where it promotes neuroprotection by repressing genes involved in oxidative stress and β-amyloid toxicity. This review focuses on recent findings that dysregulation of REST and REST-dependent epigenetic remodeling provide a central mechanism critical to the progressive neurodegeneration associated with neurologic disorders and diseases including global ischemia, stroke, epilepsy, Alzheimer's and Huntington's disease.