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

Scientific Reports
Tim-Michael DeckerDirk Eick


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. I...Continue Reading


Jan 5, 2001·Nucleic Acids Research·Marino SchuhmacherDirk Eick
Mar 26, 2002·FEBS Letters·Lei Zeng, Ming Ming Zhou
Sep 9, 2005·Nucleic Acids Research·Georg BornkammJean Feuillard
Oct 4, 2005·Proceedings of the National Academy of Sciences of the United States of America·Aravind SubramanianJill P Mesirov
Dec 31, 2005·Annals of the New York Academy of Sciences·Duonan YuAndrei Thomas-Tikhonenko
Mar 2, 2006·Molecular and Cellular Biology·Kathryn A O'DonnellChi V Dang
Dec 16, 2006·Nucleic Acids Research·Michael HölzelDirk Eick
Mar 3, 2007·The Journal of Biological Chemistry·Shwu-Yuan Wu, Cheng-Ming Chiang
Aug 11, 2007·Proceedings of the National Academy of Sciences of the United States of America·Dwayne A BisgroveEric Verdin
Sep 28, 2010·Nature·Panagis FilippakopoulosJames E Bradner
Nov 12, 2010·Nature·Edwige NicodemeAlexander Tarakhovsky
May 7, 2011·Bioinformatics·Arthur LiberzonJill P Mesirov
Jul 23, 2011·Genes & Cancer·Barbara Herkert, Martin Eilers
Aug 5, 2011·Nature·Johannes ZuberChristopher R Vakoc
Sep 6, 2011·Cell·Jake E DelmoreConstantine S Mitsiades
Sep 29, 2011·Proceedings of the National Academy of Sciences of the United States of America·Jennifer A MertzRobert J Sims
Jun 23, 2012·Nature Reviews. Cancer·Anna C Belkina, Gerald V Denis
Jul 10, 2012·Cell·Mark A Dawson, Tony Kouzarides
Feb 20, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Anna C BelkinaGerald V Denis
Oct 15, 2013·Cell·Denes HniszRichard A Young
Dec 18, 2014·Genome Biology·Michael I LoveSimon Anders
Jan 1, 2015·Nature Reviews. Molecular Cell Biology·Eric Verdin, Melanie Ott
May 1, 2015·BMC Bioinformatics·Thomas BonfertCaroline C Friedel
Oct 9, 2016·Biochimica Et Biophysica Acta·Qiong DuanTianlun Yang
Oct 23, 2016·Drug Discovery Today. Technologies·Guillaume AndrieuGerald V Denis

Methods Mentioned

histone acetylation
flow cytometry
restriction digest

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