Inhibition of the acetyl lysine-binding pocket of bromodomain and extraterminal domain proteins interferes with adipogenesis
| Autor: | Zahra Kadri, Stéphane Prost, Olivier Goupille, Suthat Fucharoen, Philippe Leboulch, Leila Maouche-Chretien, Tipparat Penglong, Stany Chrétien, Marine Granger-Locatelli |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Chromosomal Proteins Non-Histone Biophysics Adipose tissue Down-Regulation 030209 endocrinology & metabolism White adipose tissue Biochemistry 03 medical and health sciences Mice 0302 clinical medicine 3T3-L1 Cells Brown adipose tissue medicine Adipocytes STAT5 Transcription Factor Animals Humans Molecular Biology Transcription factor STAT5 Histone Acetyltransferases Adipogenesis Binding Sites biology Lysine Cell Biology Azepines Triazoles Lipid Metabolism Chromatin Bromodomain 030104 developmental biology medicine.anatomical_structure biology.protein Transcription Factors |
| Zdroj: | Biochemical and biophysical research communications. 472(4) |
| ISSN: | 1090-2104 |
| Popis: | The bromodomain and extraterminal (BET) domain family proteins are epigenetic modulators involved in the reading of acetylated lysine residues. The first BET protein inhibitor to be identified, (+)-JQ1, a thienotriazolo-1, 4-diazapine, binds selectively to the acetyl lysine-binding pocket of BET proteins. We evaluated the impact on adipogenesis of this druggable targeting of chromatin epigenetic readers, by investigating the physiological consequences of epigenetic modifications through targeting proteins binding to chromatin. JQ1 significantly inhibited the differentiation of 3T3-L1 preadipocytes into white and brown adipocytes by down-regulating the expression of genes involved in adipogenesis, particularly those encoding the peroxisome proliferator-activated receptor (PPAR-γ), the CCAAT/enhancer-binding protein (C/EBPα) and, STAT5A and B. The expression of a constitutively activated STAT5B mutant did not prevent inhibition by JQ1. Thus, the association of BET/STAT5 is required for adipogenesis but STAT5 transcription activity is not the only target of JQ1. Treatment with JQ1 did not lead to the conversion of white adipose tissue into brown adipose tissue (BAT). BET protein inhibition thus interferes with generation of adipose tissue from progenitors, confirming the importance of the connections between epigenetic mechanisms and specific adipogenic transcription factors. |
| Databáze: | OpenAIRE |
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