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dc.contributor.author
Mirtschink, Peter
dc.contributor.author
Bischof, Corinne
dc.contributor.author
Pham, Minh-Duc
dc.contributor.author
Sharma, Rahul
dc.contributor.author
Khadayate, Sanjay
dc.contributor.author
Rossi, Geetha
dc.contributor.author
Fankhauser, Niklaus
dc.contributor.author
Traub, Shuyang
dc.contributor.author
Sossalla, Samuel
dc.contributor.author
Hagag, Eman
dc.contributor.author
Berthonneche, Corinne
dc.contributor.author
Sarre, Alexandre
dc.contributor.author
Stehr, Sebastian N.
dc.contributor.author
Grote, Phillip
dc.contributor.author
Pedrazzini, Thierry
dc.contributor.author
Dimmeler, Stefanie
dc.contributor.author
Krek, Wilhelm
dc.contributor.author
Krishnan, Jaya
dc.date.accessioned
2019-06-25T09:26:58Z
dc.date.available
2019-06-25T02:08:23Z
dc.date.available
2019-06-25T09:26:58Z
dc.date.issued
2019-06-11
dc.identifier.issn
0009-7322
dc.identifier.issn
1524-4539
dc.identifier.other
10.1161/CIRCULATIONAHA.118.036769
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/349500
dc.identifier.doi
10.3929/ethz-b-000349500
dc.description.abstract
Background: Enhancers are genomic regulatory elements conferring spatiotemporal and signal-dependent control of gene expression. Recent evidence suggests that enhancers can generate noncoding enhancer RNAs, but their (patho)biological functions remain largely elusive. Methods: We performed chromatin immunoprecipitation–coupled sequencing of histone marks combined with RNA sequencing of left ventricular biopsies from experimental and genetic mouse models of human cardiac hypertrophy to identify transcripts revealing enhancer localization, conservation with the human genome, and hypoxia-inducible factor 1α dependence. The most promising candidate, hypoxia-inducible enhancer RNA (HERNA)1, was further examined by investigating its capacity to modulate neighboring coding gene expression by binding to their gene promoters by using chromatin isolation by RNA purification and λN–BoxB tethering–based reporter assays. The role of HERNA1 and its neighboring genes for pathological stress–induced growth and contractile dysfunction, and the therapeutic potential of HERNA1 inhibition was studied in gapmer-mediated loss-of-function studies in vitro using human induced pluripotent stem cell–derived cardiomyocytes and various in vivo models of human pathological cardiac hypertrophy. Results: HERNA1 is robustly induced on pathological stress. Production of HERNA1 is initiated by direct hypoxia-inducible factor 1α binding to a hypoxia-response element in the histoneH3-lysine27acetylation marks–enriched promoter of the enhancer and confers hypoxia responsiveness to nearby genes including synaptotagmin XVII, a member of the family of membrane-trafficking and Ca2+-sensing proteins and SMG1, encoding a phosphatidylinositol 3-kinase–related kinase. Consequently, a substrate of SMG1, ATP-dependent RNA helicase upframeshift 1, is hyperphoshorylated in a HERNA1- and SMG1-dependent manner. In vitro and in vivo inactivation of SMG1 and SYT17 revealed overlapping and distinct roles in modulating cardiac hypertrophy. Finally, in vivo administration of antisense oligonucleotides targeting HERNA1 protected mice from stress-induced pathological hypertrophy. The inhibition of HERNA1 postdisease development reversed left ventricular growth and dysfunction, resulting in increased overall survival. Conclusions: HERNA1 is a novel heart-specific noncoding RNA with key regulatory functions in modulating the growth, metabolic, and contractile gene program in disease, and reveals a molecular target amenable to therapeutic exploitation.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
Lippincott Williams & Wilkins
en_US
dc.rights.uri
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject
heart failure
en_US
dc.subject
hypoxia
en_US
dc.subject
RNA
en_US
dc.title
Inhibition of the Hypoxia-Inducible Factor 1 alpha-Induced Cardiospecific HERNA1 Enhance-Templated RNA Protects From Heart Disease
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
ethz.journal.title
Circulation
ethz.journal.volume
139
en_US
ethz.journal.issue
24
en_US
ethz.journal.abbreviated
Circulation (N.Y.N.Y.)
ethz.pages.start
2778
en_US
ethz.pages.end
2792
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
Philadelphia, PA
en_US
ethz.publication.status
published
en_US
ethz.date.deposited
2019-06-25T02:08:25Z
ethz.source
WOS
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2019-06-25T09:27:56Z
ethz.rosetta.lastUpdated
2020-02-15T19:49:47Z
ethz.rosetta.versionExported
true
ethz.COinS
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