SIRT6-dependent functional switch via K494 modifications of RE-1 Silencing Transcription factor [REST_experiment_1]

RE-1 Silencing Transcription factor (REST) is a key repressor of neural genesREST functions as a key factor for cell differentiation, repressing neural genes in non-neural somatic tissues. REST is upregulated under stress signals, aging, and neurodegenerative diseases, but 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 mis localized and inactive. 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, in turn modulating neuronal gene expression.