A novel P300 inhibitor reverses DUX4-mediated global histone H3 hyperacetylation, target gene expression, and cell death

被引：49

作者：

Bosnakovski, Darko ^{[1
,2
,3
]}

da Silva, Meiricris T. ^{[1
,2
,7
]}

Sunny, Sithara T. ^{[1
,2
]}

Ener, Elizabeth T. ^{[1
,2
]}

Toso, Erik A. ^{[1
,2
]}

Yuan, Ce ^{[4
]}

Cui, Ziyou ^{[1
,2
]}

Walters, Michael A. ^{[5
]}

Jadhav, Ajit ^{[6
]}

Kyba, Michael ^{[1
,2
]}

机构：

[1] Univ Minnesota, Lillehei Heart Inst, Minneapolis, MN 55455 USA

[2] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA

[3] Univ Goce Delcev Stip, Fac Med Sci, Stip 2000, Macedonia

[4] Univ Minnesota, Bioinformat & Computat Biol Program, Minneapolis, MN 55455 USA

[5] Univ Minnesota, Inst Therapeut Discovery & Dev, Minneapolis, MN 55455 USA

[6] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA

[7] Univ Sao Paulo, Lab Skeletal Muscle Plast, Dept Anat, Inst Biomed Sci, Sao Paulo, Brazil

来源：

SCIENCE ADVANCES | 2019年 / 5卷 / 09期

关键词：

DUX4; D4Z4; SEQUENCE; MUSCLE; CONSERVATION; PROGENITORS; PATIENT; LOCUS; MODEL;

D O I：

10.1126/sciadv.aaw7781

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Facioscapulohumeral muscular dystrophy (FSHD) results from mutations causing overexpression of the transcription factor, DUX4, which interacts with the histone acetyltransferases, EP300 and CBP. We describe the activity of a new spirocyclic EP300/CBP inhibitor, iP300w, which inhibits the cytotoxicity of the DUX4 protein and reverses the overexpression of most DUX4 target genes, in engineered cell lines and FSHD myoblasts, as well as in an FSHD animal model. In evaluating the effect of iP300w on global histone H3 acetylation, we discovered that DUX4 overexpression leads to a dramatic global increase in the total amount of acetylated histone H3. This unexpected effect requires the C-terminus of DUX4, is conserved with mouse Dux, and may facilitate zygotic genome activation. This global increase in histone H3 acetylation is reversed by iP300w, highlighting the central role of EP300 and CBP in the transcriptional mechanism underlying DUX4 cytotoxicity and the translational potential of blocking this interaction.

引用

页数：9

共 38 条

[1] Trimmomatic: a flexible trimmer for Illumina sequence data [J].

Bolger, Anthony M. ;

Lohse, Marc ;

Usadel, Bjoern .

BIOINFORMATICS, 2014, 30 (15) :2114-2120

[2] An isogenetic myoblast expression screen identifies DUX4-mediated FSHD-associated molecular pathologies [J].

Bosnakovski, Darko ;

Xu, Zhaohui ;

Gang, Eun Ji ;

Galindo, Cristi L. ;

Liu, Mingju ;

Simsek, Tugba ;

Garner, Harold R. ;

Agha-Mohammadi, Siamak ;

Tassin, Alexandra ;

Coppee, Frederique ;

Belayew, Alexandra ;

Perlingeiro, Rita R. ;

Kyba, Michael .

EMBO JOURNAL, 2008, 27 (20) :2766-2779

[3] Low level DUX4 expression disrupts myogenesis through deregulation of myogenic gene expression [J].

Bosnakovski, Darko ;

Gearhart, Micah D. ;

Toso, Erik A. ;

Ener, Elizabeth T. ;

Choi, Si Ho ;

Kyba, Michael .

SCIENTIFIC REPORTS, 2018, 8

[4] The DUX4 homeodomains mediate inhibition of myogenesis and are functionally exchangeable with the Pax7 homeodomain [J].

Bosnakovski, Darko ;

Toso, Erik A. ;

Hartweck, Lynn M. ;

Magli, Alessandro ;

Lee, Heather A. ;

Thompson, Eliza R. ;

Dandapat, Abhijit ;

Perlingeiro, Rita C. R. ;

Kyba, Michael .

JOURNAL OF CELL SCIENCE, 2017, 130 (21) :3685-3697

[5] Muscle pathology from stochastic low level DUX4 expression in an FSHD mouse model [J].

Bosnakovski, Darko ;

Chan, Sunny S. K. ;

Recht, Olivia O. ;

Hartweck, Lynn M. ;

Gustafson, Collin J. ;

Athman, Laura L. ;

Lowe, Dawn A. ;

Kyba, Michael .

NATURE COMMUNICATIONS, 2017, 8

[6] High-throughput screening identifies inhibitors of DUX4-induced myoblast toxicity [J].

Bosnakovski, Darko ;

Choi, Si Ho ;

Strasser, Jessica M. ;

Toso, Erik A. ;

Walters, Michael A. ;

Kyba, Michael .

SKELETAL MUSCLE, 2014, 4

[7] Biphasic Myopathic Phenotype of Mouse DUX, an ORF within Conserved FSHD-Related Repeats [J].

Bosnakovski, Darko ;

Daughters, Randy S. ;

Xu, Zhaohui ;

Slack, Jonathan M. W. ;

Kyba, Michael .

PLOS ONE, 2009, 4 (09)

[8] Virtual Ligand Screening of the p300/CBP Histone Acetyltransferase: Identification of a Selective Small Molecule Inhibitor [J].

Bowers, Erin M. ;

Yan, Gai ;

Mukherjee, Chandrani ;

Orry, Andrew ;

Wang, Ling ;

Holbert, Marc A. ;

Crump, Nicholas T. ;

Hazzalin, Catherine A. ;

Liszczak, Glen ;

Yuan, Hua ;

Larocca, Cecilia ;

Saldanha, S. Adrian ;

Abagyan, Ruben ;

Sun, Yan ;

Meyers, David J. ;

Marmorstein, Ronen ;

Mahadevan, Louis C. ;

Alani, Rhoda M. ;

Cole, Philip A. .

CHEMISTRY & BIOLOGY, 2010, 17 (05) :471-482

[9] Runx1 is required for the endothelial to haematopoietic cell transition but not thereafter [J].

Chen, Michael J. ;

Yokomizo, Tomomasa ;

Zeigler, Brandon M. ;

Dzierzak, Elaine ;

Speck, Nancy A. .

NATURE, 2009, 457 (7231) :887-891

[10] Transcriptional Inhibitors Identified in a 160,000-Compound Small-Molecule DUX4 Viability Screen [J].

Choi, Si Ho ;

Bosnakovski, Darko ;

Strasser, Jessica M. ;

Toso, Erik A. ;

Walters, Michael A. ;

Kyba, Michael .

JOURNAL OF BIOMOLECULAR SCREENING, 2016, 21 (07) :680-688

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