PMID- 23712629 OWN - NLM STAT- MEDLINE DCOM- 20140507 LR - 20131007 IS - 1549-4918 (Electronic) IS - 1066-5099 (Linking) VI - 31 IP - 9 DP - 2013 Sep TI - High throughput screening for inhibitors of REST in neural derivatives of human embryonic stem cells reveals a chemical compound that promotes expression of neuronal genes. PG - 1816-28 LID - 10.1002/stem.1430 [doi] AB - Decreased expression of neuronal genes such as brain-derived neurotrophic factor (BDNF) is associated with several neurological disorders. One molecular mechanism associated with Huntington disease (HD) is a discrete increase in the nuclear activity of the transcriptional repressor REST/NRSF binding to repressor element-1 (RE1) sequences. High-throughput screening of a library of 6,984 compounds with luciferase-assay measuring REST activity in neural derivatives of human embryonic stem cells led to identify two benzoimidazole-5-carboxamide derivatives that inhibited REST silencing in a RE1-dependent manner. The most potent compound, X5050, targeted REST degradation, but neither REST expression, RNA splicing nor binding to RE1 sequence. Differential transcriptomic analysis revealed the upregulation of neuronal genes targeted by REST in wild-type neural cells treated with X5050. This activity was confirmed in neural cells produced from human induced pluripotent stem cells derived from a HD patient. Acute intraventricular delivery of X5050 increased the expressions of BDNF and several other REST-regulated genes in the prefrontal cortex of mice with quinolinate-induced striatal lesions. This study demonstrates that the use of pluripotent stem cell derivatives can represent a crucial step toward the identification of pharmacological compounds with therapeutic potential in neurological affections involving decreased expression of neuronal genes associated to increased REST activity, such as Huntington disease. CI - (c) AlphaMed Press. FAU - Charbord, Jeremie AU - Charbord J AD - Inserm U861, AFM Evry Cedex, France; UEVE U861, AFM Evry Cedex, France. FAU - Poydenot, Pauline AU - Poydenot P FAU - Bonnefond, Caroline AU - Bonnefond C FAU - Feyeux, Maxime AU - Feyeux M FAU - Casagrande, Fabrice AU - Casagrande F FAU - Brinon, Benjamin AU - Brinon B FAU - Francelle, Laetitia AU - Francelle L FAU - Auregan, Gwenaelle AU - Auregan G FAU - Guillermier, Martine AU - Guillermier M FAU - Cailleret, Michel AU - Cailleret M FAU - Viegas, Pedro AU - Viegas P FAU - Nicoleau, Camille AU - Nicoleau C FAU - Martinat, Cecile AU - Martinat C FAU - Brouillet, Emmanuel AU - Brouillet E FAU - Cattaneo, Elena AU - Cattaneo E FAU - Peschanski, Marc AU - Peschanski M FAU - Lechuga, Marc AU - Lechuga M FAU - Perrier, Anselme L AU - Perrier AL LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - Stem Cells JT - Stem cells (Dayton, Ohio) JID - 9304532 RN - 0 (RE1-silencing transcription factor) RN - 0 (Repressor Proteins) RN - 0 (Small Molecule Libraries) RN - EC 1.13.12.- (Luciferases) SB - IM MH - Animals MH - Cell Line MH - Disease Models, Animal MH - Embryonic Stem Cells/cytology/drug effects/*metabolism MH - Gene Expression Regulation/*drug effects MH - Genes, Reporter MH - High-Throughput Screening Assays/*methods MH - Humans MH - Huntington Disease/pathology MH - Luciferases/metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Neural Stem Cells/cytology/drug effects/*metabolism MH - Neurons/drug effects/*metabolism MH - Repressor Proteins/*antagonists & inhibitors/metabolism MH - Small Molecule Libraries/*pharmacology MH - Transcriptome/drug effects/genetics OTO - NOTNLM OT - High throughput screening OT - Human embryonic stem cells OT - Neural stem cells OT - Neuron restrictive silencer factor OT - Repressor element-1 silencing transcription factor EDAT- 2013/05/29 06:00 MHDA- 2014/05/08 06:00 CRDT- 2013/05/29 06:00 PHST- 2012/10/11 00:00 [received] PHST- 2013/04/05 00:00 [revised] PHST- 2013/04/09 00:00 [accepted] PHST- 2013/05/29 06:00 [entrez] PHST- 2013/05/29 06:00 [pubmed] PHST- 2014/05/08 06:00 [medline] AID - 10.1002/stem.1430 [doi] PST - ppublish SO - Stem Cells. 2013 Sep;31(9):1816-28. doi: 10.1002/stem.1430.