학술논문
Genome-Wide Dynamics of Nascent Noncoding RNA Transcription in Porcine Heart After Myocardial Infarction.
Document Type
Academic Journal
Author
Kaikkonen MU; From the Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio (M.U.K., P.H., O.H.-F.L., T.T., J.P., P.M., I.S., T.T., E.A., P.T., S.Y.-H.); and Heart Center and Gene Therapy Unit, Kuopio University Hospital, Finland (S.Y.-H.). minna.kaikkonen@uef.fi.; Halonen P; From the Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio (M.U.K., P.H., O.H.-F.L., T.T., J.P., P.M., I.S., T.T., E.A., P.T., S.Y.-H.); and Heart Center and Gene Therapy Unit, Kuopio University Hospital, Finland (S.Y.-H.).; Liu OH; From the Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio (M.U.K., P.H., O.H.-F.L., T.T., J.P., P.M., I.S., T.T., E.A., P.T., S.Y.-H.); and Heart Center and Gene Therapy Unit, Kuopio University Hospital, Finland (S.Y.-H.).; Turunen TA; From the Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio (M.U.K., P.H., O.H.-F.L., T.T., J.P., P.M., I.S., T.T., E.A., P.T., S.Y.-H.); and Heart Center and Gene Therapy Unit, Kuopio University Hospital, Finland (S.Y.-H.).; Pajula J; From the Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio (M.U.K., P.H., O.H.-F.L., T.T., J.P., P.M., I.S., T.T., E.A., P.T., S.Y.-H.); and Heart Center and Gene Therapy Unit, Kuopio University Hospital, Finland (S.Y.-H.).; Moreau P; From the Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio (M.U.K., P.H., O.H.-F.L., T.T., J.P., P.M., I.S., T.T., E.A., P.T., S.Y.-H.); and Heart Center and Gene Therapy Unit, Kuopio University Hospital, Finland (S.Y.-H.).; Selvarajan I; From the Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio (M.U.K., P.H., O.H.-F.L., T.T., J.P., P.M., I.S., T.T., E.A., P.T., S.Y.-H.); and Heart Center and Gene Therapy Unit, Kuopio University Hospital, Finland (S.Y.-H.).; Tuomainen T; From the Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio (M.U.K., P.H., O.H.-F.L., T.T., J.P., P.M., I.S., T.T., E.A., P.T., S.Y.-H.); and Heart Center and Gene Therapy Unit, Kuopio University Hospital, Finland (S.Y.-H.).; Aavik E; From the Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio (M.U.K., P.H., O.H.-F.L., T.T., J.P., P.M., I.S., T.T., E.A., P.T., S.Y.-H.); and Heart Center and Gene Therapy Unit, Kuopio University Hospital, Finland (S.Y.-H.).; Tavi P; From the Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio (M.U.K., P.H., O.H.-F.L., T.T., J.P., P.M., I.S., T.T., E.A., P.T., S.Y.-H.); and Heart Center and Gene Therapy Unit, Kuopio University Hospital, Finland (S.Y.-H.).; Ylä-Herttuala S; From the Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio (M.U.K., P.H., O.H.-F.L., T.T., J.P., P.M., I.S., T.T., E.A., P.T., S.Y.-H.); and Heart Center and Gene Therapy Unit, Kuopio University Hospital, Finland (S.Y.-H.).
Source
Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 101489144 Publication Model: Print Cited Medium: Internet ISSN: 1942-3268 (Electronic) Linking ISSN: 19423268 NLM ISO Abbreviation: Circ Cardiovasc Genet Subsets: MEDLINE
Subject
Language
English
Abstract
Background: Microarrays and RNA sequencing are widely used to profile transcriptome remodeling during myocardial ischemia. However, the steady-state RNA analysis lacks in sensitivity to detect all noncoding RNA species and does not provide separation between transcriptional and post-transcriptional regulations. Here, we provide the first comprehensive analysis of nascent RNA profiles of mRNAs, primary micro-RNAs, long noncoding RNAs, and enhancer RNAs in a large animal model of acute infarction.
Methods and Results: Acute infarction was induced by cardiac catheterization of domestic swine. Nuclei isolated from healthy, border zone, and ischemic regions of the affected heart were subjected to global run-on sequencing. Global run-on sequencing analysis indicated that half of affected genes are regulated at the level of transcriptional pausing. A gradient of induction of inflammatory mediators and repression of peroxisome proliferator-activated receptor signaling and oxidative phosphorylation was detected when moving from healthy toward infarcted area. In addition, we interrogated the transcriptional regulation of primary micro-RNAs and provide evidence that several arrhythmia-related target genes exhibit repression at post-transcriptional level. We identified 450 long noncoding RNAs differently regulated by ischemia, including novel conserved long noncoding RNAs expressed in antisense orientation to myocardial transcription factors GATA-binding protein 4, GATA-binding protein 6, and Krüppel-like factor 6. Finally, characterization of enhancers exhibiting differential expression of enhancer RNAs pointed a central role for Krüppel-like factor, MEF2C, ETS, NFY, ATF, E2F2, and NRF1 transcription factors in determining transcriptional responses to ischemia.
Conclusions: Global run-on sequencing allowed us to follow the gradient of gene expression occurring in the ischemic heart and identify novel noncoding RNAs regulated by oxygen deprivation. These findings highlight potential new targets for diagnosis and treatment of myocardial ischemia.
(© 2017 American Heart Association, Inc.)
Methods and Results: Acute infarction was induced by cardiac catheterization of domestic swine. Nuclei isolated from healthy, border zone, and ischemic regions of the affected heart were subjected to global run-on sequencing. Global run-on sequencing analysis indicated that half of affected genes are regulated at the level of transcriptional pausing. A gradient of induction of inflammatory mediators and repression of peroxisome proliferator-activated receptor signaling and oxidative phosphorylation was detected when moving from healthy toward infarcted area. In addition, we interrogated the transcriptional regulation of primary micro-RNAs and provide evidence that several arrhythmia-related target genes exhibit repression at post-transcriptional level. We identified 450 long noncoding RNAs differently regulated by ischemia, including novel conserved long noncoding RNAs expressed in antisense orientation to myocardial transcription factors GATA-binding protein 4, GATA-binding protein 6, and Krüppel-like factor 6. Finally, characterization of enhancers exhibiting differential expression of enhancer RNAs pointed a central role for Krüppel-like factor, MEF2C, ETS, NFY, ATF, E2F2, and NRF1 transcription factors in determining transcriptional responses to ischemia.
Conclusions: Global run-on sequencing allowed us to follow the gradient of gene expression occurring in the ischemic heart and identify novel noncoding RNAs regulated by oxygen deprivation. These findings highlight potential new targets for diagnosis and treatment of myocardial ischemia.
(© 2017 American Heart Association, Inc.)