Genome-Wide Polyadenylation Maps Reveal Dynamic mRNA 3'-End Formation in the Failing Human Heart.

Autor:	Creemers EE; From the Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (E.E.C., A.B., H.W.M.D., I.M., N.E.G., M.E.A., C.R.B., Y.M.P.); Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands (A.P.U., R.E., R.A.); National Heart and Lung Institute, Imperial College, London, United Kingdom (S.A.C.); Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany (N.H.); and Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands (J.V.). e.e.creemers@amc.uva.nl y.pinto@amc.uva.nl., Bawazeer A; From the Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (E.E.C., A.B., H.W.M.D., I.M., N.E.G., M.E.A., C.R.B., Y.M.P.); Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands (A.P.U., R.E., R.A.); National Heart and Lung Institute, Imperial College, London, United Kingdom (S.A.C.); Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany (N.H.); and Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands (J.V.)., Ugalde AP; From the Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (E.E.C., A.B., H.W.M.D., I.M., N.E.G., M.E.A., C.R.B., Y.M.P.); Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands (A.P.U., R.E., R.A.); National Heart and Lung Institute, Imperial College, London, United Kingdom (S.A.C.); Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany (N.H.); and Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands (J.V.)., van Deutekom HW; From the Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (E.E.C., A.B., H.W.M.D., I.M., N.E.G., M.E.A., C.R.B., Y.M.P.); Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands (A.P.U., R.E., R.A.); National Heart and Lung Institute, Imperial College, London, United Kingdom (S.A.C.); Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany (N.H.); and Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands (J.V.)., van der Made I; From the Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (E.E.C., A.B., H.W.M.D., I.M., N.E.G., M.E.A., C.R.B., Y.M.P.); Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands (A.P.U., R.E., R.A.); National Heart and Lung Institute, Imperial College, London, United Kingdom (S.A.C.); Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany (N.H.); and Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands (J.V.)., de Groot NE; From the Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (E.E.C., A.B., H.W.M.D., I.M., N.E.G., M.E.A., C.R.B., Y.M.P.); Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands (A.P.U., R.E., R.A.); National Heart and Lung Institute, Imperial College, London, United Kingdom (S.A.C.); Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany (N.H.); and Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands (J.V.)., Adriaens ME; From the Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (E.E.C., A.B., H.W.M.D., I.M., N.E.G., M.E.A., C.R.B., Y.M.P.); Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands (A.P.U., R.E., R.A.); National Heart and Lung Institute, Imperial College, London, United Kingdom (S.A.C.); Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany (N.H.); and Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands (J.V.)., Cook SA; From the Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (E.E.C., A.B., H.W.M.D., I.M., N.E.G., M.E.A., C.R.B., Y.M.P.); Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands (A.P.U., R.E., R.A.); National Heart and Lung Institute, Imperial College, London, United Kingdom (S.A.C.); Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany (N.H.); and Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands (J.V.)., Bezzina CR; From the Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (E.E.C., A.B., H.W.M.D., I.M., N.E.G., M.E.A., C.R.B., Y.M.P.); Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands (A.P.U., R.E., R.A.); National Heart and Lung Institute, Imperial College, London, United Kingdom (S.A.C.); Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany (N.H.); and Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands (J.V.)., Hubner N; From the Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (E.E.C., A.B., H.W.M.D., I.M., N.E.G., M.E.A., C.R.B., Y.M.P.); Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands (A.P.U., R.E., R.A.); National Heart and Lung Institute, Imperial College, London, United Kingdom (S.A.C.); Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany (N.H.); and Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands (J.V.)., van der Velden J; From the Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (E.E.C., A.B., H.W.M.D., I.M., N.E.G., M.E.A., C.R.B., Y.M.P.); Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands (A.P.U., R.E., R.A.); National Heart and Lung Institute, Imperial College, London, United Kingdom (S.A.C.); Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany (N.H.); and Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands (J.V.)., Elkon R; From the Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (E.E.C., A.B., H.W.M.D., I.M., N.E.G., M.E.A., C.R.B., Y.M.P.); Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands (A.P.U., R.E., R.A.); National Heart and Lung Institute, Imperial College, London, United Kingdom (S.A.C.); Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany (N.H.); and Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands (J.V.)., Agami R; From the Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (E.E.C., A.B., H.W.M.D., I.M., N.E.G., M.E.A., C.R.B., Y.M.P.); Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands (A.P.U., R.E., R.A.); National Heart and Lung Institute, Imperial College, London, United Kingdom (S.A.C.); Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany (N.H.); and Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands (J.V.)., Pinto YM; From the Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (E.E.C., A.B., H.W.M.D., I.M., N.E.G., M.E.A., C.R.B., Y.M.P.); Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands (A.P.U., R.E., R.A.); National Heart and Lung Institute, Imperial College, London, United Kingdom (S.A.C.); Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany (N.H.); and Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands (J.V.). e.e.creemers@amc.uva.nl y.pinto@amc.uva.nl.
Jazyk:	angličtina
Zdroj:	Circulation research [Circ Res] 2016 Feb 05; Vol. 118 (3), pp. 433-8. Date of Electronic Publication: 2015 Dec 15.
DOI:	10.1161/CIRCRESAHA.115.307082
Abstrakt:	Rationale: Alternative cleavage and polyadenylation (APA) of mRNA represents a layer of gene regulation that to date has remained unexplored in the heart. This phenomenon may be relevant, as the positioning of the poly(A) tail in mRNAs influences the length of the 3'-untranslated region (UTR), a critical determinant of gene expression. Objective: To investigate whether the 3'UTR length is regulated by APA in the human heart and whether this changes in the failing heart. Methods and Results: We used 3'end RNA sequencing (e3'-Seq) to directly measure global patterns of APA in healthy and failing human heart specimens. By monitoring polyadenylation profiles in these hearts, we identified disease-specific APA signatures in numerous genes. Interestingly, many of the genes with shortened 3'UTRs in heart failure were enriched for functional groups such as RNA binding, whereas genes with longer 3'UTRs were enriched for cytoskeletal organization and actin binding. RNA sequencing in a larger series of human hearts revealed that these APA candidates are often differentially expressed in failing hearts, with an inverse correlation between 3'UTR length and the level of gene expression. Protein levels of the APA regulator, poly(A)-binding protein nuclear-1 were substantially downregulated in failing hearts. Conclusions: We provide genome-wide, high-resolution polyadenylation maps of the human heart and show that the 3'end formation of mRNA is dynamic in heart failure, suggesting that APA-mediated 3'UTR length modulation represents an additional layer of gene regulation in failing hearts. (© 2015 American Heart Association, Inc.)
Databáze:	MEDLINE
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