Inhibition of the Hypoxia-Inducible Factor 1α-Induced Cardiospecific HERNA1 Enhance-Templated RNA Protects From Heart Disease.

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Serval ID
serval:BIB_BAE7C7F2C66F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Inhibition of the Hypoxia-Inducible Factor 1α-Induced Cardiospecific HERNA1 Enhance-Templated RNA Protects From Heart Disease.
Journal
Circulation
Author(s)
Mirtschink P., Bischof C., Pham M.D., Sharma R., Khadayate S., Rossi G., Fankhauser N., Traub S., Sossalla S., Hagag E., Berthonneche C., Sarre A., Stehr S.N., Grote P., Pedrazzini T., Dimmeler S., Krek W., Krishnan J.
ISSN
1524-4539 (Electronic)
ISSN-L
0009-7322
Publication state
Published
Issued date
11/06/2019
Peer-reviewed
Oui
Volume
139
Number
24
Pages
2778-2792
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
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.
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.
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 Ca <sup>2+</sup> -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.
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.
Keywords
Animals, Binding Sites, Cardiomyopathy, Dilated/genetics, Cardiomyopathy, Dilated/metabolism, Cardiomyopathy, Dilated/pathology, Cardiomyopathy, Dilated/prevention & control, Cardiomyopathy, Hypertrophic/genetics, Cardiomyopathy, Hypertrophic/metabolism, Cardiomyopathy, Hypertrophic/pathology, Cardiomyopathy, Hypertrophic/prevention & control, Case-Control Studies, Disease Models, Animal, HEK293 Cells, Humans, Hypoxia-Inducible Factor 1, alpha Subunit/deficiency, Hypoxia-Inducible Factor 1, alpha Subunit/genetics, Hypoxia-Inducible Factor 1, alpha Subunit/metabolism, Male, Mice, Inbred C57BL, Mice, Knockout, Myocytes, Cardiac/metabolism, Myocytes, Cardiac/pathology, Oligonucleotides, Antisense/administration & dosage, Promoter Regions, Genetic, RNA, Untranslated/genetics, RNA, Untranslated/metabolism, Signal Transduction, Von Hippel-Lindau Tumor Suppressor Protein/genetics, Von Hippel-Lindau Tumor Suppressor Protein/metabolism, RNA, heart failure, hypoxia
Pubmed
Web of science
Open Access
Yes
Create date
15/04/2019 9:39
Last modification date
15/01/2021 7:11
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