Inhibition of the Hypoxia-Inducible Factor 1α-Induced Cardiospecific HERNA1 Enhance-Templated RNA Protects From Heart Disease
| Autor: | Peter Mirtschink, Rahul Sharma, Geetha Rossi, Sanjay Khadayate, Corinne Berthonneche, Eman Hagag, Wilhelm Krek, Corinne Bischof, Jaya Krishnan, Thierry Pedrazzini, Samuel Sossalla, Phillip Grote, Shuyang Traub, Niklaus Fankhauser, Alexandre Sarre, Sebastian Stehr, Stefanie Dimmeler, Minh Duc Pham |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
RNA Untranslated heart failure 0302 clinical medicine Original Research Articles Gene expression Myocytes Cardiac Promoter Regions Genetic Mice Knockout 0303 health sciences RNA hypoxia 3. Good health Cell biology Hypoxia-inducible factors Von Hippel-Lindau Tumor Suppressor Protein 030220 oncology & carcinogenesis ComputingMethodologies_DOCUMENTANDTEXTPROCESSING medicine.symptom Signal transduction Cardiology and Cardiovascular Medicine Signal Transduction Cardiomyopathy Dilated 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 Mice Inbred C57BL Myocytes Cardiac/metabolism Myocytes Cardiac/pathology Oligonucleotides Antisense/administration & dosage RNA Untranslated/genetics RNA Untranslated/metabolism Von Hippel-Lindau Tumor Suppressor Protein/genetics Von Hippel-Lindau Tumor Suppressor Protein/metabolism 03 medical and health sciences Physiology (medical) medicine Binding site Enhancer 030304 developmental biology business.industry HEK 293 cells Cardiomyopathy Hypertrophic Oligonucleotides Antisense Hypoxia (medical) Hypoxia-Inducible Factor 1 alpha Subunit business |
| Zdroj: | Circulation, vol. 139, no. 24, pp. 2778-2792 Circulation Circulation, 139 (24) |
| Popis: | Supplemental Digital Content is available in the text. 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. |
| Databáze: | OpenAIRE |
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