Open AccessHigh throughput screening for inhibitors of REST in neural derivatives of human embryonic stem cells reveals a chemical compound that promotes expression of neuronal genes
Author(s) -
Charbord Jérémie,
Poydenot Pauline,
Bonnefond Caroline,
Feyeux Maxime,
Casagrande Fabrice,
Bri Benjamin,
Francelle Laetitia,
Aurégan Gwenaelle,
Guillermier Martine,
Cailleret Michel,
Viegas Pedro,
Nicoleau Camille,
Martinat Cécile,
Brouillet Emmanuel,
Cattaneo Elena,
Peschanski Marc,
Lechuga Marc,
Perrier Anselme L.
Publication year - 2013
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.1430
Subject(s) - biology , induced pluripotent stem cell , neural stem cell , embryonic stem cell , gene silencing , transcriptome , huntington's disease , microbiology and biotechnology , stem cell , gene expression , gene , genetics , medicine , disease
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. S tem C ells 2013;31:1816‐1828