title: Epigenomics of Neural Cells: REST-Induced Down- and Upregulation of Gene Expression in a Two-Clone PC12 Cell Model.
abstract: 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 upregulation, 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 nontarget, REST-dependent 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; upregulated genes were mostly governed indirectly. Among other factors, Polycomb complexes cooperated with REST for downregulation, and Smad3 and Myod1 participated in upregulation. In conclusion, we have highlighted that PC12 clones are a useful model to investigate REST, opening opportunities to development of epigenomic investigation.
authors.affiliation: Scientific Institute San Raffaele, Center for Translational Genomics and Bioinformatics, 20132 Milan, Italy.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Garcia-Manteiga
authors.affiliation: Scientific Institute San Raffaele, Center for Translational Genomics and Bioinformatics, 20132 Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bonfiglio
authors.affiliation: CNR Institute of Neuroscience, 20129 Milan, Italy ; Humanitas Research Center, Rozzano, 20089 Milan, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Malosio
authors.affiliation: Scientific Institute San Raffaele, Center for Translational Genomics and Bioinformatics, 20132 Milan, Italy.
authors.forename: Dejan
authors.initials: D
authors.lastname: Lazarevic
authors.affiliation: Scientific Institute San Raffaele, Center for Translational Genomics and Bioinformatics, 20132 Milan, Italy ; Boehringer Ingelheim, 88400 Biberach an der Riß, Germany.
authors.forename: Elia
authors.initials: E
authors.lastname: Stupka
authors.affiliation: Scientific Institute San Raffaele, Center for Translational Genomics and Bioinformatics, 20132 Milan, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Cittaro
authors.affiliation: Division of Neurosciences, San Raffaele Institute and Vita-Salute San Raffaele University, 20133 Milan, Italy.
authors.forename: Jacopo
authors.initials: J
authors.lastname: Meldolesi
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000235:genetics; D057890:Epigenomics; D015870:Gene Expression / Q000235:genetics*; D053263:Gene Regulatory Networks; D008957:Models, Genetic; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D000099229:RE1-Silencing Transcription Factor
chemical_list: D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor