Abstract
RE-1 Silencing Transcription factor (REST) is a key repressor of neural genes. REST is upregulated under stress signals, aging and neurodegenerative diseases, but although it is upregulated, it loses its function in Alzheimer's Disease. However, why it becomes inactive remains unclear. Here, we show that the NAD-dependent deacetylase SIRT6 regulates REST expression, location and activity. In SIRT6 absence, REST is overexpressed but mislocalized, and loses part of its activity, becoming toxic. SIRT6 deficiency abrogates REST and EZH2 interaction, perturbs its location to heterochromatin Lamin B ring, and leads to REST target gene overexpression. SIRT6 reintroduction or REST methyl-mimic K494M expression rescues this phenotype, while an acetyl-mimic mutant loses its function even in WT cells. Our studies define a novel regulatory switch, where the function of a critical repressor is regulated by post-translational modifications on K494, depending on SIRT6 existence and, in turn, modulating neuronal gene expression.