Apabetalone, a Clinical-Stage, Selective BET Inhibitor, Opposes DUX4 Target Gene Expression in Primary Human FSHD Muscle Cells

Author:

Sarsons Christopher D.1,Gilham Dean1ORCID,Tsujikawa Laura M.1,Wasiak Sylwia1,Fu Li1,Rakai Brooke D.1,Stotz Stephanie C.1,Carestia Agostina1,Sweeney Michael2,Kulikowski Ewelina1ORCID

Affiliation:

1. Resverlogix Corp., 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, Canada

2. Resverlogix Corp., 535 Mission St., 14th Floor, San Francisco, CA 94105, USA

Abstract

Facioscapulohumeral dystrophy (FSHD) is a muscle disease caused by inappropriate expression of the double homeobox 4 (DUX4) gene in skeletal muscle, and its downstream activation of pro-apoptotic transcriptional programs. Inhibitors of DUX4 expression have the potential to treat FSHD. Apabetalone is a clinical-stage bromodomain and extra-terminal (BET) inhibitor, selective for the second bromodomain on BET proteins. Using primary human skeletal muscle cells from FSHD type 1 patients, we evaluated apabetalone for its ability to counter DUX4′s deleterious effects and compared it with the pan-BET inhibitor JQ1, and the p38 MAPK inhibitor—and DUX4 transcriptional repressor—losmapimod. We applied RNA-sequencing and bioinformatic analysis to detect treatment-associated impacts on the transcriptome of these cells. Apabetalone inhibited the expression of DUX4 downstream markers, reversing hallmarks of FSHD gene expression in differentiated muscle cells. JQ1, but not apabetalone, was found to induce apoptosis. While both BET inhibitors modestly impacted differentiation marker expression, they did not affect myotube fusion. Losmapimod also reduced expression of DUX4 target genes but differed in its impact on FSHD-associated pathways. These findings demonstrate that apabetalone inhibits DUX4 target gene expression and reverses transcriptional programs that contribute to FSHD pathology, making this drug a promising candidate therapeutic for FSHD.

Funder

Resverlogix Corp.

Publisher

MDPI AG

Subject

General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)

Reference57 articles.

1. Facioscapulohumeral dystrophy and scapuloperoneal syndromes;Orrell;Handb. Clin. Neurol.,2011

2. Population-based incidence and prevalence of facioscapulohumeral dystrophy;Deenen;Neurology,2014

3. A unifying genetic model for facioscapulohumeral muscular dystrophy;Lemmers;Science,2010

4. Physical mapping evidence for a duplicated region on chromosome 10qter showing high homology with the facioscapulohumeral muscular dystrophy locus on chromosome 4qter;Deidda;Eur. J. Hum. Genet.,1995

5. Genetic linkage map of facioscapulohumeral muscular dystrophy and five polymorphic loci on chromosome 4q35-qter;Wijmenga;Am. J. Hum. Genet.,1992

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3