The Translational Landscape of the Human Heart

Sebastiaan van Heesch; Franziska Witte; Valentin Schneider-Lunitz; Jana F Schulz; Eleonora Adami; Allison B Faber; Marieluise Kirchner; Henrike Maatz; Susanne Blachut; Clara-Louisa Sandmann; Masatoshi Kanda; Catherine L Worth; Sebastian Schafer; Lorenzo Calviello; Rhys Merriott; Giannino Patone; Oliver Hummel; Emanuel Wyler; Benedikt Obermayer; Michael B Mücke; Eric L Lindberg; Franziska Trnka; Sebastian Memczak; Marcel Schilling; Leanne E Felkin; Paul J R Barton; Nicholas M Quaife; Konstantinos Vanezis; Sebastian Diecke; Masaya Mukai; Nancy Mah; Su-Jun Oh; Andreas Kurtz; Christoph Schramm; Dorothee Schwinge; Marcial Sebode; Magdalena Harakalova; Folkert W Asselbergs; Aryan Vink; Roel A de Weger; Sivakumar Viswanathan; Anissa A Widjaja; Anna Gärtner-Rommel; Hendrik Milting; Cris Dos Remedios; Christoph Knosalla; Philipp Mertins; Markus Landthaler; Martin Vingron; Wolfgang A Linke; Jonathan G Seidman; Christine E Seidman; Nikolaus Rajewsky; Uwe Ohler; Stuart A Cook; Norbert Hubner

doi:10.1016/j.cell.2019.05.010

The Translational Landscape of the Human Heart

Sebastiaan van Heesch, Franziska Witte, Valentin Schneider-Lunitz, Jana F Schulz, Eleonora Adami, Allison B Faber, Marieluise Kirchner, Henrike Maatz, Susanne Blachut, Clara-Louisa Sandmann, Masatoshi Kanda, Catherine L Worth, Sebastian Schafer, Lorenzo Calviello, Rhys Merriott, Giannino Patone, Oliver Hummel, Emanuel Wyler, Benedikt Obermayer, Michael B MückeEric L Lindberg, Franziska Trnka, Sebastian Memczak, Marcel Schilling, Leanne E Felkin, Paul J R Barton, Nicholas M Quaife, Konstantinos Vanezis, Sebastian Diecke, Masaya Mukai, Nancy Mah, Su-Jun Oh, Andreas Kurtz, Christoph Schramm, Dorothee Schwinge, Marcial Sebode, Magdalena Harakalova, Folkert W Asselbergs, Aryan Vink, Roel A de Weger, Sivakumar Viswanathan, Anissa A Widjaja, Anna Gärtner-Rommel, Hendrik Milting, Cris Dos Remedios, Christoph Knosalla, Philipp Mertins, Markus Landthaler, Martin Vingron, Wolfgang A Linke, Jonathan G Seidman, Christine E Seidman, Nikolaus Rajewsky, Uwe Ohler, Stuart A Cook, Norbert Hubner

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Gene expression in human tissue has primarily been studied on the transcriptional level, largely neglecting translational regulation. Here, we analyze the translatomes of 80 human hearts to identify new translation events and quantify the effect of translational regulation. We show extensive translational control of cardiac gene expression, which is orchestrated in a process-specific manner. Translation downstream of predicted disease-causing protein-truncating variants appears to be frequent, suggesting inefficient translation termination. We identify hundreds of previously undetected microproteins, expressed from lncRNAs and circRNAs, for which we validate the protein products in vivo. The translation of microproteins is not restricted to the heart and prominent in the translatomes of human kidney and liver. We associate these microproteins with diverse cellular processes and compartments and find that many locate to the mitochondria. Importantly, dozens of microproteins are translated from lncRNAs with well-characterized noncoding functions, indicating previously unrecognized biology. Translational profiling in a primary human tissue reveals frequent translation downstream of predicted disease-causing variants as well as translation of hundreds of microproteins from long noncoding RNAs and circular RNAs.

Original language	English
Pages (from-to)	242-260.e29
Journal	Cell
Volume	178
Issue number	1
Early online date	29 May 2019
DOIs	https://doi.org/10.1016/j.cell.2019.05.010
Publication status	Published - 27 Jun 2019

Keywords

circRNAs
dilated cardiomyopathy
heart failure
human heart
lncRNAs
microproteins
ORF detection
protein-truncating variants
ribosome profiling
short ORFs
titin
translational regulation
translatome

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10.1016/j.cell.2019.05.010

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van Heesch, S., Witte, F., Schneider-Lunitz, V., Schulz, J. F., Adami, E., Faber, A. B., Kirchner, M., Maatz, H., Blachut, S., Sandmann, C.-L., Kanda, M., Worth, C. L., Schafer, S., Calviello, L., Merriott, R., Patone, G., Hummel, O., Wyler, E., Obermayer, B., ... Hubner, N. (2019). The Translational Landscape of the Human Heart. Cell, 178(1), 242-260.e29. https://doi.org/10.1016/j.cell.2019.05.010

@article{f41fcf977d5046a68b9900a578a1a28c,

title = "The Translational Landscape of the Human Heart",

abstract = "Gene expression in human tissue has primarily been studied on the transcriptional level, largely neglecting translational regulation. Here, we analyze the translatomes of 80 human hearts to identify new translation events and quantify the effect of translational regulation. We show extensive translational control of cardiac gene expression, which is orchestrated in a process-specific manner. Translation downstream of predicted disease-causing protein-truncating variants appears to be frequent, suggesting inefficient translation termination. We identify hundreds of previously undetected microproteins, expressed from lncRNAs and circRNAs, for which we validate the protein products in vivo. The translation of microproteins is not restricted to the heart and prominent in the translatomes of human kidney and liver. We associate these microproteins with diverse cellular processes and compartments and find that many locate to the mitochondria. Importantly, dozens of microproteins are translated from lncRNAs with well-characterized noncoding functions, indicating previously unrecognized biology. Translational profiling in a primary human tissue reveals frequent translation downstream of predicted disease-causing variants as well as translation of hundreds of microproteins from long noncoding RNAs and circular RNAs.",

keywords = "circRNAs, dilated cardiomyopathy, heart failure, human heart, lncRNAs, microproteins, ORF detection, protein-truncating variants, ribosome profiling, short ORFs, titin, translational regulation, translatome",

author = "{van Heesch}, Sebastiaan and Franziska Witte and Valentin Schneider-Lunitz and Schulz, {Jana F} and Eleonora Adami and Faber, {Allison B} and Marieluise Kirchner and Henrike Maatz and Susanne Blachut and Clara-Louisa Sandmann and Masatoshi Kanda and Worth, {Catherine L} and Sebastian Schafer and Lorenzo Calviello and Rhys Merriott and Giannino Patone and Oliver Hummel and Emanuel Wyler and Benedikt Obermayer and M{\"u}cke, {Michael B} and Lindberg, {Eric L} and Franziska Trnka and Sebastian Memczak and Marcel Schilling and Felkin, {Leanne E} and Barton, {Paul J R} and Quaife, {Nicholas M} and Konstantinos Vanezis and Sebastian Diecke and Masaya Mukai and Nancy Mah and Su-Jun Oh and Andreas Kurtz and Christoph Schramm and Dorothee Schwinge and Marcial Sebode and Magdalena Harakalova and Asselbergs, {Folkert W} and Aryan Vink and {de Weger}, {Roel A} and Sivakumar Viswanathan and Widjaja, {Anissa A} and Anna G{\"a}rtner-Rommel and Hendrik Milting and {Dos Remedios}, Cris and Christoph Knosalla and Philipp Mertins and Markus Landthaler and Martin Vingron and Linke, {Wolfgang A} and Seidman, {Jonathan G} and Seidman, {Christine E} and Nikolaus Rajewsky and Uwe Ohler and Cook, {Stuart A} and Norbert Hubner",

note = "Funding Information: S.v.H. was supported by an EMBO long-term fellowship ( ALTF 186-2015 , LTFCOFUND2013 , GA-2013-609409 ). N.H. is the recipient of an ERC advanced grant under the European Union Horizon 2020 Research and Innovation Program (grant agreement AdG788970 ). C.E.S., J.G.S., S.A.C., and N.H. are supported by a grant from the Leducq Foundation ( 16CVD03 ). N.H., M.L. and U.O. were supported by the Federal Ministry of Education and Research of Germany in the framework of CaRNAtion ( 031L0075A ). W.A.L. was supported by the German Research Foundation ( SFB1002 and TPA08 ). S.A.C., P.J.R.B., and L.E.F. received support from the British Heart Foundation , the Medical Research Council (UK), the NIHR Imperial College Biomedical Research Centre , the NIHR Cardiovascular BRU of Royal Brompton & Harefield NHS Foundation Trust UK , the Imperial College Academic Health Science Centre , and Heart Research UK . N.M.Q. is funded by the Imperial College Academic Health Science Centre . M. Kanda received funding provided by the Alexander von Humboldt Foundation . L.C. and U.O. were supported by the German Federal Ministry of Education and Research in the framework of RNA Bioinformatics Center of the German Network for Bioinformatics Infrastructure (de.NBI; BMBF 031 A538C ). Funding Information: S.v.H. was supported by an EMBO long-term fellowship (ALTF 186-2015, LTFCOFUND2013, GA-2013-609409). N.H. is the recipient of an ERC advanced grant under the European Union Horizon 2020 Research and Innovation Program (grant agreement AdG788970). C.E.S. J.G.S. S.A.C. and N.H. are supported by a grant from the Leducq Foundation (16CVD03). N.H. M.L. and U.O. were supported by the Federal Ministry of Education and Research of Germany in the framework of CaRNAtion (031L0075A). W.A.L. was supported by the German Research Foundation (SFB1002 and TPA08). S.A.C. P.J.R.B. and L.E.F. received support from the British Heart Foundation, the Medical Research Council (UK), the NIHR Imperial College Biomedical Research Centre, the NIHR Cardiovascular BRU of Royal Brompton & Harefield NHS Foundation Trust UK, the Imperial College Academic Health Science Centre, and Heart Research UK. N.M.Q. is funded by the Imperial College Academic Health Science Centre. M. Kanda received funding provided by the Alexander von Humboldt Foundation. L.C. and U.O. were supported by the German Federal Ministry of Education and Research in the framework of RNA Bioinformatics Center of the German Network for Bioinformatics Infrastructure (de.NBI; BMBF 031 A538C). Conceptualization, S.v.H. and N.H.; Methodology, S.v.H. F.W. V.S.-L. J.F.S. E.A. L.C. U.O. and N.H.; Software, F.W. V.S.-L. A.B.F. C.L.W. B.O. M. Schilling, L.C. and U.O.; Validation, J.F.S. C.-L.S. S.B. S.v.H. E.W. R.M. M. Kirchner, S.M. E.L.-H.L. F.T. and P.M.; Formal Analysis, F.W. V.S.-L. A.B.F. C.L.W. G.P. M.V. and O.H.; Investigation, S.v.H. J.F.S. E.A. S.B. M. Kirchner, M. Kanda, N.M.Q. K.V. M.B.M. Y.K. M.L. N.R. F.W. and V.S.-L.; Resources, M.H. F.W.A. A.V. R.A.d.W. C.K. W.A.L. C.d.R. H. Milting, A.G.-R. P.J.R.B. L.E.F. J.G.S. C.E.S. M. Kanda, M.M. N.M. S.-J.O. A.K. M. Sebode, C.S. D.S. S.D. S.S. S.V. A.A.W. and S.A.C.; Data Curation, F.W. V.S.-L. C.L.W. A.B.F. and S.v.H.; Writing – Original Draft, S.v.H.; Writing – Review & Editing, S.v.H. H. Maatz, C.-L.S. J.F.S. F.W. V.S.-L. A.B.F. C.L.W. S.A.C. and N.H. with input from all authors; Visualization, S.v.H. F.W. V.S.-L. A.B.F. J.F.S. C.L.W. and E.A.; Supervision, S.v.H. and N.H.; Project Administration, S.v.H. and N.H.; Funding Acquisition, S.v.H. and N.H. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = jun,

day = "27",

doi = "10.1016/j.cell.2019.05.010",

language = "English",

volume = "178",

pages = "242--260.e29",

number = "1",

}

van Heesch, S, Witte, F, Schneider-Lunitz, V, Schulz, JF, Adami, E, Faber, AB, Kirchner, M, Maatz, H, Blachut, S, Sandmann, C-L, Kanda, M, Worth, CL, Schafer, S, Calviello, L, Merriott, R, Patone, G, Hummel, O, Wyler, E, Obermayer, B, Mücke, MB, Lindberg, EL, Trnka, F, Memczak, S, Schilling, M, Felkin, LE, Barton, PJR, Quaife, NM, Vanezis, K, Diecke, S, Mukai, M, Mah, N, Oh, S-J, Kurtz, A, Schramm, C, Schwinge, D, Sebode, M, Harakalova, M , Asselbergs, FW, Vink, A, de Weger, RA, Viswanathan, S, Widjaja, AA, Gärtner-Rommel, A, Milting, H, Dos Remedios, C, Knosalla, C, Mertins, P, Landthaler, M, Vingron, M, Linke, WA, Seidman, JG, Seidman, CE, Rajewsky, N, Ohler, U, Cook, SA & Hubner, N 2019, 'The Translational Landscape of the Human Heart', Cell, vol. 178, no. 1, pp. 242-260.e29. https://doi.org/10.1016/j.cell.2019.05.010

TY - JOUR

T1 - The Translational Landscape of the Human Heart

AU - van Heesch, Sebastiaan

AU - Witte, Franziska

AU - Schneider-Lunitz, Valentin

AU - Schulz, Jana F

AU - Adami, Eleonora

AU - Faber, Allison B

AU - Kirchner, Marieluise

AU - Maatz, Henrike

AU - Blachut, Susanne

AU - Sandmann, Clara-Louisa

AU - Kanda, Masatoshi

AU - Worth, Catherine L

AU - Schafer, Sebastian

AU - Calviello, Lorenzo

AU - Merriott, Rhys

AU - Patone, Giannino

AU - Hummel, Oliver

AU - Wyler, Emanuel

AU - Obermayer, Benedikt

AU - Mücke, Michael B

AU - Lindberg, Eric L

AU - Trnka, Franziska

AU - Memczak, Sebastian

AU - Schilling, Marcel

AU - Felkin, Leanne E

AU - Barton, Paul J R

AU - Quaife, Nicholas M

AU - Vanezis, Konstantinos

AU - Diecke, Sebastian

AU - Mukai, Masaya

AU - Mah, Nancy

AU - Oh, Su-Jun

AU - Kurtz, Andreas

AU - Schramm, Christoph

AU - Schwinge, Dorothee

AU - Sebode, Marcial

AU - Harakalova, Magdalena

AU - Asselbergs, Folkert W

AU - Vink, Aryan

AU - de Weger, Roel A

AU - Viswanathan, Sivakumar

AU - Widjaja, Anissa A

AU - Gärtner-Rommel, Anna

AU - Milting, Hendrik

AU - Dos Remedios, Cris

AU - Knosalla, Christoph

AU - Mertins, Philipp

AU - Landthaler, Markus

AU - Vingron, Martin

AU - Linke, Wolfgang A

AU - Seidman, Jonathan G

AU - Seidman, Christine E

AU - Rajewsky, Nikolaus

AU - Ohler, Uwe

AU - Cook, Stuart A

AU - Hubner, Norbert

N1 - Funding Information: S.v.H. was supported by an EMBO long-term fellowship ( ALTF 186-2015 , LTFCOFUND2013 , GA-2013-609409 ). N.H. is the recipient of an ERC advanced grant under the European Union Horizon 2020 Research and Innovation Program (grant agreement AdG788970 ). C.E.S., J.G.S., S.A.C., and N.H. are supported by a grant from the Leducq Foundation ( 16CVD03 ). N.H., M.L. and U.O. were supported by the Federal Ministry of Education and Research of Germany in the framework of CaRNAtion ( 031L0075A ). W.A.L. was supported by the German Research Foundation ( SFB1002 and TPA08 ). S.A.C., P.J.R.B., and L.E.F. received support from the British Heart Foundation , the Medical Research Council (UK), the NIHR Imperial College Biomedical Research Centre , the NIHR Cardiovascular BRU of Royal Brompton & Harefield NHS Foundation Trust UK , the Imperial College Academic Health Science Centre , and Heart Research UK . N.M.Q. is funded by the Imperial College Academic Health Science Centre . M. Kanda received funding provided by the Alexander von Humboldt Foundation . L.C. and U.O. were supported by the German Federal Ministry of Education and Research in the framework of RNA Bioinformatics Center of the German Network for Bioinformatics Infrastructure (de.NBI; BMBF 031 A538C ). Funding Information: S.v.H. was supported by an EMBO long-term fellowship (ALTF 186-2015, LTFCOFUND2013, GA-2013-609409). N.H. is the recipient of an ERC advanced grant under the European Union Horizon 2020 Research and Innovation Program (grant agreement AdG788970). C.E.S. J.G.S. S.A.C. and N.H. are supported by a grant from the Leducq Foundation (16CVD03). N.H. M.L. and U.O. were supported by the Federal Ministry of Education and Research of Germany in the framework of CaRNAtion (031L0075A). W.A.L. was supported by the German Research Foundation (SFB1002 and TPA08). S.A.C. P.J.R.B. and L.E.F. received support from the British Heart Foundation, the Medical Research Council (UK), the NIHR Imperial College Biomedical Research Centre, the NIHR Cardiovascular BRU of Royal Brompton & Harefield NHS Foundation Trust UK, the Imperial College Academic Health Science Centre, and Heart Research UK. N.M.Q. is funded by the Imperial College Academic Health Science Centre. M. Kanda received funding provided by the Alexander von Humboldt Foundation. L.C. and U.O. were supported by the German Federal Ministry of Education and Research in the framework of RNA Bioinformatics Center of the German Network for Bioinformatics Infrastructure (de.NBI; BMBF 031 A538C). Conceptualization, S.v.H. and N.H.; Methodology, S.v.H. F.W. V.S.-L. J.F.S. E.A. L.C. U.O. and N.H.; Software, F.W. V.S.-L. A.B.F. C.L.W. B.O. M. Schilling, L.C. and U.O.; Validation, J.F.S. C.-L.S. S.B. S.v.H. E.W. R.M. M. Kirchner, S.M. E.L.-H.L. F.T. and P.M.; Formal Analysis, F.W. V.S.-L. A.B.F. C.L.W. G.P. M.V. and O.H.; Investigation, S.v.H. J.F.S. E.A. S.B. M. Kirchner, M. Kanda, N.M.Q. K.V. M.B.M. Y.K. M.L. N.R. F.W. and V.S.-L.; Resources, M.H. F.W.A. A.V. R.A.d.W. C.K. W.A.L. C.d.R. H. Milting, A.G.-R. P.J.R.B. L.E.F. J.G.S. C.E.S. M. Kanda, M.M. N.M. S.-J.O. A.K. M. Sebode, C.S. D.S. S.D. S.S. S.V. A.A.W. and S.A.C.; Data Curation, F.W. V.S.-L. C.L.W. A.B.F. and S.v.H.; Writing – Original Draft, S.v.H.; Writing – Review & Editing, S.v.H. H. Maatz, C.-L.S. J.F.S. F.W. V.S.-L. A.B.F. C.L.W. S.A.C. and N.H. with input from all authors; Visualization, S.v.H. F.W. V.S.-L. A.B.F. J.F.S. C.L.W. and E.A.; Supervision, S.v.H. and N.H.; Project Administration, S.v.H. and N.H.; Funding Acquisition, S.v.H. and N.H. The authors declare no competing interests. Publisher Copyright: © 2019 Elsevier Inc.

PY - 2019/6/27

Y1 - 2019/6/27

N2 - Gene expression in human tissue has primarily been studied on the transcriptional level, largely neglecting translational regulation. Here, we analyze the translatomes of 80 human hearts to identify new translation events and quantify the effect of translational regulation. We show extensive translational control of cardiac gene expression, which is orchestrated in a process-specific manner. Translation downstream of predicted disease-causing protein-truncating variants appears to be frequent, suggesting inefficient translation termination. We identify hundreds of previously undetected microproteins, expressed from lncRNAs and circRNAs, for which we validate the protein products in vivo. The translation of microproteins is not restricted to the heart and prominent in the translatomes of human kidney and liver. We associate these microproteins with diverse cellular processes and compartments and find that many locate to the mitochondria. Importantly, dozens of microproteins are translated from lncRNAs with well-characterized noncoding functions, indicating previously unrecognized biology. Translational profiling in a primary human tissue reveals frequent translation downstream of predicted disease-causing variants as well as translation of hundreds of microproteins from long noncoding RNAs and circular RNAs.

AB - Gene expression in human tissue has primarily been studied on the transcriptional level, largely neglecting translational regulation. Here, we analyze the translatomes of 80 human hearts to identify new translation events and quantify the effect of translational regulation. We show extensive translational control of cardiac gene expression, which is orchestrated in a process-specific manner. Translation downstream of predicted disease-causing protein-truncating variants appears to be frequent, suggesting inefficient translation termination. We identify hundreds of previously undetected microproteins, expressed from lncRNAs and circRNAs, for which we validate the protein products in vivo. The translation of microproteins is not restricted to the heart and prominent in the translatomes of human kidney and liver. We associate these microproteins with diverse cellular processes and compartments and find that many locate to the mitochondria. Importantly, dozens of microproteins are translated from lncRNAs with well-characterized noncoding functions, indicating previously unrecognized biology. Translational profiling in a primary human tissue reveals frequent translation downstream of predicted disease-causing variants as well as translation of hundreds of microproteins from long noncoding RNAs and circular RNAs.

KW - circRNAs

KW - dilated cardiomyopathy

KW - heart failure

KW - human heart

KW - lncRNAs

KW - microproteins

KW - ORF detection

KW - protein-truncating variants

KW - ribosome profiling

KW - short ORFs

KW - titin

KW - translational regulation

KW - translatome

UR - http://www.scopus.com/inward/record.url?scp=85067655981&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2019.05.010

DO - 10.1016/j.cell.2019.05.010

M3 - Article

C2 - 31155234

SN - 0092-8674

VL - 178

SP - 242-260.e29

JO - Cell

JF - Cell

IS - 1

ER -

The Translational Landscape of the Human Heart

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