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Decker, T.-M. ; Kluge, M.* ; Krebs, S.* ; Shah, N. ; Blum, H.* ; Friedel, C.C.* ; Eick, D.

Transcriptome analysis of dominant-negative Brd4 mutants identifies Brd4-specific target genes of small molecule inhibitor JQ1.

Sci. Rep. 7:1684 (2017)
Verlagsversion DOI
Open Access Gold
Creative Commons Lizenzvertrag
The bromodomain protein Brd4 is an epigenetic reader and plays a critical role in the development and maintenance of leukemia. Brd4 binds to acetylated histone tails and activates transcription by recruiting the positive elongation factor P-TEFb. Small molecule inhibitor JQ1 competitively binds the bromodomains of Brd4 and displaces the protein from acetylated histones. However, it remains unclear whether genes targeted by JQ1 are mainly regulated by Brd4 or by other bromodomain proteins such as Brd2 and Brd3. Here, we describe anti-proliferative dominant-negative Brd4 mutants that compete with the function of distinct Brd4 domains. We used these Brd4 mutants to compare the Brd4-specific transcriptome with the transcriptome of JQ1-treated cells. We found that most JQ1-regulated genes are also regulated by dominant-negative Brd4 mutants, including the mutant that competes with the P-TEFb recruitment function of Brd4. Importantly, JQ1 and dominant-negative Brd4 mutants regulated the same set of target genes of c-Myc, a key regulator of the JQ1 response in leukemia cells. Our results suggest that Brd4 mediates most of the anti-cancer effects of JQ1 and that the major function of Brd4 in this process is the recruitment of P-TEFb. In summary, our studies define the molecular targets of JQ1 in more detail.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Bromodomain Protein Brd4; B-cell Line; C-myc; Selective-inhibition; Bet Bromodomains; Super-enhancers; P-tefb; Chromatin; Leukemia; Cancer
ISSN (print) / ISBN 2045-2322
e-ISSN 2045-2322
Zeitschrift Scientific Reports
Quellenangaben Band: 7, Heft: 1, Seiten: , Artikelnummer: 1684 Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Begutachtungsstatus