title: Genome-Wide Polyadenylation Maps Reveal Dynamic mRNA 3'-End Formation in the Failing Human Heart.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: 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.
authors.forename: Esther E
authors.initials: EE
authors.lastname: Creemers
authors.affiliation: 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.).
authors.forename: Amira
authors.initials: A
authors.lastname: Bawazeer
authors.affiliation: 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.).
authors.forename: Alejandro P
authors.initials: AP
authors.lastname: Ugalde
authors.affiliation: 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.).
authors.forename: Hanneke W M
authors.initials: HW
authors.lastname: van Deutekom
authors.affiliation: 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.).
authors.forename: Ingeborg
authors.initials: I
authors.lastname: van der Made
authors.affiliation: 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.).
authors.forename: Nina E
authors.initials: NE
authors.lastname: de Groot
authors.affiliation: 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.).
authors.forename: Michiel E
authors.initials: ME
authors.lastname: Adriaens
authors.affiliation: 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.).
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Cook
authors.affiliation: 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.).
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
authors.affiliation: 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.).
authors.forename: Norbert
authors.initials: N
authors.lastname: Hubner
authors.affiliation: 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.).
authors.forename: Jolanda
authors.initials: J
authors.lastname: van der Velden
authors.affiliation: 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.).
authors.forename: Ran
authors.initials: R
authors.lastname: Elkon
authors.affiliation: 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.).
authors.forename: Reuven
authors.initials: R
authors.lastname: Agami
authors.affiliation: 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.
authors.forename: Yigal M
authors.initials: YM
authors.lastname: Pinto
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000368:Aged; D001483:Base Sequence; D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006333:Heart Failure / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D039122:Poly(A)-Binding Protein I / Q000378:metabolism; D026723:Polyadenylation; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C576588:PABPN1 protein, human; D039122:Poly(A)-Binding Protein I; D012333:RNA, Messenger
keywords: cardiomyopathies; gene expression regulation; heart failure; humans; polyadenylation; untranslated regions