title: Inhibition of the acetyl lysine-binding pocket of bromodomain and extraterminal domain proteins interferes with adipogenesis.
abstract: 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.
authors.affiliation: CEA, Institute of Emerging Diseases and Innovative Therapies (IMETI), Fontenay-aux-Roses and Université Paris-Saclay, UMR-E 007, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Goupille
authors.affiliation: CEA, Institute of Emerging Diseases and Innovative Therapies (IMETI), Fontenay-aux-Roses and Université Paris-Saclay, UMR-E 007, France; Thalassemia Research Center, Mahidol University, Thailand.
authors.forename: Tipparat
authors.initials: T
authors.lastname: Penglong
authors.affiliation: CEA, Institute of Emerging Diseases and Innovative Therapies (IMETI), Fontenay-aux-Roses and Université Paris-Saclay, UMR-E 007, France.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Kadri
authors.affiliation: CEA, Institute of Emerging Diseases and Innovative Therapies (IMETI), Fontenay-aux-Roses and Université Paris-Saclay, UMR-E 007, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Granger-Locatelli
authors.affiliation: Thalassemia Research Center, Mahidol University, Thailand.
authors.forename: Suthat
authors.initials: S
authors.lastname: Fucharoen
authors.affiliation: CEA, Institute of Emerging Diseases and Innovative Therapies (IMETI), Fontenay-aux-Roses and Université Paris-Saclay, UMR-E 007, France; INSERM, Paris, France.
authors.forename: Leila
authors.initials: L
authors.lastname: Maouche-Chrétien
authors.affiliation: CEA, Institute of Emerging Diseases and Innovative Therapies (IMETI), Fontenay-aux-Roses and Université Paris-Saclay, UMR-E 007, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Prost
authors.affiliation: CEA, Institute of Emerging Diseases and Innovative Therapies (IMETI), Fontenay-aux-Roses and Université Paris-Saclay, UMR-E 007, France; Thalassemia Research Center, Mahidol University, Thailand.
authors.forename: Philippe
authors.initials: P
authors.lastname: Leboulch
authors.affiliation: CEA, Institute of Emerging Diseases and Innovative Therapies (IMETI), Fontenay-aux-Roses and Université Paris-Saclay, UMR-E 007, France; INSERM, Paris, France. Electronic address: stany.chretien@cea.fr.
authors.forename: Stany
authors.initials: S
authors.lastname: Chrétien
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D014230:Triazoles / Q000494:pharmacology*; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D002868:Chromosomal Proteins, Non-Histone; D051548:Histone Acetyltransferases; D008239:Lysine; D050799:STAT5 Transcription Factor; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C562256:BRD1 protein, mouse; D000092468:Bromodomain Containing Proteins; C490844:Brd2 protein, mouse
keywords: BET protein inhibitor; Epigenetic modulators; STAT5; White and brown adipose tissues