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SIRT6-dependent functional switch via K494 modifications of RE-1 Silencing Transcription factor [REST_experiment_2]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261903 | GEO | 2025/03/19

REPOSITORIES: GEO

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

Project description: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.

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Epigenomics of neural cells: REST-induced down- and up-regulation of gene expression in a two clone PC12 cell model.

Project description:Cell epigenomics depends on the marks released by transcription factors operating via the assembly of complexes that induce focal changes of DNA and histone structure. Among these factors is REST, a repressor that, via its strong decrease, governs both neuronal and neural cell differentiation and specificity. REST operation on thousands of possible genes can occur directly or via indirect mechanisms including repression of other factors. In previous studies of gene down- and up-regulation, processes had been only partially investigated in neural cells. PC12 are well known neural cells sharing properties with neurons. In the widely used PC12 populations, low-REST cells coexist with few, spontaneous high-REST PC12 cells. High- and low-REST PC12 clones were employed to investigate the role and the mechanisms of the repressor action. Among 15,500 expressed genes we identified 1,770 target and non-target, RESTdependent genes. Functionally, these genes were found to operate in many pathways, from synaptic function to extracellular matrix. Mechanistically, downregulated genes were predominantly repressed directly by REST; up-regulated genes were mostly governed indirectly. Among other factors, Polycomb complexes cooperated with REST for down-regulation, Smad3 and Myod1 participated in up-regulation. In conclusion, we have highlighted that PC12 clones are a useful model to investigate REST, opening opportunities to development of epigenomic investigation. 4 samples have been analyzed: 2 replicates from wtPC12 clone and 2 replicates from the hrPC12 clones

2015-08-31 | E-GEOD-59946 | biostudies-arrayexpress

Epigenomics of neural cells: REST-induced down- and up-regulation of gene expression in a two clone PC12 cell model.

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ATRX mutant neuroblastoma is sensitive to EZH2 inhibition via modulation of neuronal differentiation

Project description:We report on the characterization of ATRX in-frame fusion neuroblastoma and identify that ATRX IFF proteins re-locate from H3K9me3 enriched regions to active chromatin, such as the promoter of neural repressor REST. We further identify that REST is upregulated in ATRX IFF NB and that several neurogenesis and REST target genes are transcriptionally downregulated. Through ChIP-seq analysis, we observe that REST is bound to ATRX IFF Down genes, which have higher levels of H3K27me3. We further show that ATRX in-frame fusion neuroblastoma cells are sensitive to EZH2 inhibitors through de-repression of H3K27me3 bound neuronal function genes, includiing a subset of REST targets.

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