title: 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.
abstract: 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.
authors.affiliation: Inserm U861, AFM Evry Cedex, France; UEVE U861, AFM Evry Cedex, France.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Charbord
authors.forename: Pauline
authors.initials: P
authors.lastname: Poydenot
authors.forename: Caroline
authors.initials: C
authors.lastname: Bonnefond
authors.forename: Maxime
authors.initials: M
authors.lastname: Feyeux
authors.forename: Fabrice
authors.initials: F
authors.lastname: Casagrande
authors.forename: Benjamin
authors.initials: B
authors.lastname: Brinon
authors.forename: Laetitia
authors.initials: L
authors.lastname: Francelle
authors.forename: Gwenaelle
authors.initials: G
authors.lastname: Aurégan
authors.forename: Martine
authors.initials: M
authors.lastname: Guillermier
authors.forename: Michel
authors.initials: M
authors.lastname: Cailleret
authors.forename: Pedro
authors.initials: P
authors.lastname: Viegas
authors.forename: Camille
authors.initials: C
authors.lastname: Nicoleau
authors.forename: Cécile
authors.initials: C
authors.lastname: Martinat
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Brouillet
authors.forename: Elena
authors.initials: E
authors.lastname: Cattaneo
authors.forename: Marc
authors.initials: M
authors.lastname: Peschanski
authors.forename: Marc
authors.initials: M
authors.lastname: Lechuga
authors.forename: Anselme L
authors.initials: AL
authors.lastname: Perrier
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D006816:Huntington Disease / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology*; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D000099229:RE1-Silencing Transcription Factor
chemical_list: D008156:Luciferases; D012097:Repressor Proteins; D054852:Small Molecule Libraries; D000099229:RE1-Silencing Transcription Factor
keywords: High throughput screening; Human embryonic stem cells; Neural stem cells; Neuron restrictive silencer factor; Repressor element-1 silencing transcription factor