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

Abstract 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 b...

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Autores principales: Tim-Michael Decker, Michael Kluge, Stefan Krebs, Nilay Shah, Helmut Blum, Caroline C. Friedel, Dirk Eick
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Publicado: Nature Portfolio 2017
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spelling oai:doaj.org-article:ba77fcb301da4351a857a418f3d765e02021-12-02T11:52:27ZTranscriptome analysis of dominant-negative Brd4 mutants identifies Brd4-specific target genes of small molecule inhibitor JQ110.1038/s41598-017-01943-62045-2322https://doaj.org/article/ba77fcb301da4351a857a418f3d765e02017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01943-6https://doaj.org/toc/2045-2322Abstract 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.Tim-Michael DeckerMichael KlugeStefan KrebsNilay ShahHelmut BlumCaroline C. FriedelDirk EickNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Tim-Michael Decker
Michael Kluge
Stefan Krebs
Nilay Shah
Helmut Blum
Caroline C. Friedel
Dirk Eick
Transcriptome analysis of dominant-negative Brd4 mutants identifies Brd4-specific target genes of small molecule inhibitor JQ1
description Abstract 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.
format article
author Tim-Michael Decker
Michael Kluge
Stefan Krebs
Nilay Shah
Helmut Blum
Caroline C. Friedel
Dirk Eick
author_facet Tim-Michael Decker
Michael Kluge
Stefan Krebs
Nilay Shah
Helmut Blum
Caroline C. Friedel
Dirk Eick
author_sort Tim-Michael Decker
title Transcriptome analysis of dominant-negative Brd4 mutants identifies Brd4-specific target genes of small molecule inhibitor JQ1
title_short Transcriptome analysis of dominant-negative Brd4 mutants identifies Brd4-specific target genes of small molecule inhibitor JQ1
title_full Transcriptome analysis of dominant-negative Brd4 mutants identifies Brd4-specific target genes of small molecule inhibitor JQ1
title_fullStr Transcriptome analysis of dominant-negative Brd4 mutants identifies Brd4-specific target genes of small molecule inhibitor JQ1
title_full_unstemmed Transcriptome analysis of dominant-negative Brd4 mutants identifies Brd4-specific target genes of small molecule inhibitor JQ1
title_sort transcriptome analysis of dominant-negative brd4 mutants identifies brd4-specific target genes of small molecule inhibitor jq1
publisher Nature Portfolio
publishDate 2017
url https://doaj.org/article/ba77fcb301da4351a857a418f3d765e0
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AT stefankrebs transcriptomeanalysisofdominantnegativebrd4mutantsidentifiesbrd4specifictargetgenesofsmallmoleculeinhibitorjq1
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