Human β cell transcriptome analysis uncovers lncRNAs that are tissue-specific, dynamically regulated, and abnormally expressed in type 2 diabetes

Ignasi Morán; Ildem Akerman; Martijn Van De Bunt; Ruiyu Xie; Marion Benazra; Takao Nammo; Luis Arnes; Nikolina Nakić; Javier García-Hurtado; Santiago Rodríguez-Seguí; Lorenzo Pasquali; Claire Sauty-Colace; Anthony Beucher; Raphael Scharfmann; Joris Van Arensbergen; Paul R. Johnson; Andrew Berry; Clarence Lee; Timothy Harkins; Valery Gmyr; François Pattou; Julie Kerr-Conte; Lorenzo Piemonti; Thierry Berney; Neil Hanley; Anna L. Gloyn; Lori Sussel; Linda Langman; Kenneth L. Brayman; Maike Sander; Mark I. McCarthy; Philippe Ravassard; Jorge Ferrer

doi:10.1016/j.cmet.2012.08.010

Human β cell transcriptome analysis uncovers lncRNAs that are tissue-specific, dynamically regulated, and abnormally expressed in type 2 diabetes

Ignasi Morán, Ildem Akerman, Martijn Van De Bunt, Ruiyu Xie, Marion Benazra, Takao Nammo, Luis Arnes, Nikolina Nakić, Javier García-Hurtado, Santiago Rodríguez-Seguí, Lorenzo Pasquali, Claire Sauty-Colace, Anthony Beucher, Raphael Scharfmann, Joris Van Arensbergen, Paul R. Johnson, Andrew Berry, Clarence Lee, Timothy Harkins, Valery GmyrFrançois Pattou, Julie Kerr-Conte, Lorenzo Piemonti, Thierry Berney, Neil Hanley, Anna L. Gloyn, Lori Sussel, Linda Langman, Kenneth L. Brayman, Maike Sander, Mark I. McCarthy, Philippe Ravassard, Jorge Ferrer^*

^*Corresponding author for this work

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

376 Citations (Scopus)

Abstract

A significant portion of the genome is transcribed as long noncoding RNAs (lncRNAs), several of which are known to control gene expression. The repertoire and regulation of lncRNAs in disease-relevant tissues, however, has not been systematically explored. We report a comprehensive strand-specific transcriptome map of human pancreatic islets and β cells, and uncover >1100 intergenic and antisense islet-cell lncRNA genes. We find islet lncRNAs that are dynamically regulated and show that they are an integral component of the β cell differentiation and maturation program. We sequenced the mouse islet transcriptome and identify lncRNA orthologs that are regulated like their human counterparts. Depletion of HI-LNC25, a β cell-specific lncRNA, downregulated GLIS3 mRNA, thus exemplifying a gene regulatory function of islet lncRNAs. Finally, selected islet lncRNAs were dysregulated in type 2 diabetes or mapped to genetic loci underlying diabetes susceptibility. These findings reveal a new class of islet-cell genes relevant to β cell programming and diabetes pathophysiology.

Original language	English
Pages (from-to)	435-448
Number of pages	14
Journal	Cell Metabolism
Volume	16
Issue number	4
DOIs	https://doi.org/10.1016/j.cmet.2012.08.010
Publication status	Published - 3 Oct 2012

Bibliographical note

Funding Information:
This work was funded by grants from the NIH-BCBC (2U01 DK072473-06 to J.F., P.R., and L.S.; U01-DK089567 to M.S. and J.F.), the Juvenile Diabetes Research Foundation (26-2008-633 to J.F. and 31-2008-416 to T.B., F.P., and L.P. to support human islet isolation), Ministerio de Economía y Competitividad (SAF2008-03116 to J.F. and a Ph.D. fellowship to Ignasi Morán). A.L.G. is a Wellcome Trust Senior Fellow in Basic Biomedical Research (WT 09510/Z/10/Z). We thank Rudolph Leibel (University of Columbia) for providing B6.V-Lepob/J mice, Bing Ren (Ludwig Institute for Cancer Research) for generating the ENCODE mouse tissue RNA-seq data, Kelli Bramlett (Genome Sequencing Collaborations Group) for her help in generation of SOLiD data and Viacyte, Inc. for performing implantations of hES cell derivatives. We are also grateful to Ayellet Segrè (Broad Institute) for helpful discussion on MAGENTA, and to Chris Stoeckert and Elisabetta Manduchi (University of Pennsylvania) for help with the online submission.

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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Morán, I., Akerman, I., Van De Bunt, M., Xie, R., Benazra, M., Nammo, T., Arnes, L., Nakić, N., García-Hurtado, J., Rodríguez-Seguí, S., Pasquali, L., Sauty-Colace, C., Beucher, A., Scharfmann, R., Van Arensbergen, J., Johnson, P. R., Berry, A., Lee, C., Harkins, T., ... Ferrer, J. (2012). Human β cell transcriptome analysis uncovers lncRNAs that are tissue-specific, dynamically regulated, and abnormally expressed in type 2 diabetes. Cell Metabolism, 16(4), 435-448. https://doi.org/10.1016/j.cmet.2012.08.010

@article{06e6e98d337a4ca2b1fbecdadd3c4857,

title = "Human β cell transcriptome analysis uncovers lncRNAs that are tissue-specific, dynamically regulated, and abnormally expressed in type 2 diabetes",

abstract = "A significant portion of the genome is transcribed as long noncoding RNAs (lncRNAs), several of which are known to control gene expression. The repertoire and regulation of lncRNAs in disease-relevant tissues, however, has not been systematically explored. We report a comprehensive strand-specific transcriptome map of human pancreatic islets and β cells, and uncover >1100 intergenic and antisense islet-cell lncRNA genes. We find islet lncRNAs that are dynamically regulated and show that they are an integral component of the β cell differentiation and maturation program. We sequenced the mouse islet transcriptome and identify lncRNA orthologs that are regulated like their human counterparts. Depletion of HI-LNC25, a β cell-specific lncRNA, downregulated GLIS3 mRNA, thus exemplifying a gene regulatory function of islet lncRNAs. Finally, selected islet lncRNAs were dysregulated in type 2 diabetes or mapped to genetic loci underlying diabetes susceptibility. These findings reveal a new class of islet-cell genes relevant to β cell programming and diabetes pathophysiology.",

author = "Ignasi Mor{\'a}n and Ildem Akerman and {Van De Bunt}, Martijn and Ruiyu Xie and Marion Benazra and Takao Nammo and Luis Arnes and Nikolina Naki{\'c} and Javier Garc{\'i}a-Hurtado and Santiago Rodr{\'i}guez-Segu{\'i} and Lorenzo Pasquali and Claire Sauty-Colace and Anthony Beucher and Raphael Scharfmann and {Van Arensbergen}, Joris and Johnson, {Paul R.} and Andrew Berry and Clarence Lee and Timothy Harkins and Valery Gmyr and Fran{\c c}ois Pattou and Julie Kerr-Conte and Lorenzo Piemonti and Thierry Berney and Neil Hanley and Gloyn, {Anna L.} and Lori Sussel and Linda Langman and Brayman, {Kenneth L.} and Maike Sander and McCarthy, {Mark I.} and Philippe Ravassard and Jorge Ferrer",

note = "Funding Information: This work was funded by grants from the NIH-BCBC (2U01 DK072473-06 to J.F., P.R., and L.S.; U01-DK089567 to M.S. and J.F.), the Juvenile Diabetes Research Foundation (26-2008-633 to J.F. and 31-2008-416 to T.B., F.P., and L.P. to support human islet isolation), Ministerio de Econom{\'i}a y Competitividad (SAF2008-03116 to J.F. and a Ph.D. fellowship to Ignasi Mor{\'a}n). A.L.G. is a Wellcome Trust Senior Fellow in Basic Biomedical Research (WT 09510/Z/10/Z). We thank Rudolph Leibel (University of Columbia) for providing B6.V-Lepob/J mice, Bing Ren (Ludwig Institute for Cancer Research) for generating the ENCODE mouse tissue RNA-seq data, Kelli Bramlett (Genome Sequencing Collaborations Group) for her help in generation of SOLiD data and Viacyte, Inc. for performing implantations of hES cell derivatives. We are also grateful to Ayellet Segr{\`e} (Broad Institute) for helpful discussion on MAGENTA, and to Chris Stoeckert and Elisabetta Manduchi (University of Pennsylvania) for help with the online submission. ",

year = "2012",

month = oct,

day = "3",

doi = "10.1016/j.cmet.2012.08.010",

language = "English",

volume = "16",

pages = "435--448",

journal = "Cell Metabolism",

issn = "1550-4131",

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Morán, I, Akerman, I, Van De Bunt, M, Xie, R, Benazra, M, Nammo, T, Arnes, L, Nakić, N, García-Hurtado, J, Rodríguez-Seguí, S, Pasquali, L, Sauty-Colace, C, Beucher, A, Scharfmann, R, Van Arensbergen, J, Johnson, PR, Berry, A, Lee, C, Harkins, T, Gmyr, V, Pattou, F, Kerr-Conte, J, Piemonti, L, Berney, T, Hanley, N, Gloyn, AL, Sussel, L, Langman, L, Brayman, KL, Sander, M, McCarthy, MI, Ravassard, P & Ferrer, J 2012, 'Human β cell transcriptome analysis uncovers lncRNAs that are tissue-specific, dynamically regulated, and abnormally expressed in type 2 diabetes', Cell Metabolism, vol. 16, no. 4, pp. 435-448. https://doi.org/10.1016/j.cmet.2012.08.010

TY - JOUR

T1 - Human β cell transcriptome analysis uncovers lncRNAs that are tissue-specific, dynamically regulated, and abnormally expressed in type 2 diabetes

AU - Morán, Ignasi

AU - Akerman, Ildem

AU - Van De Bunt, Martijn

AU - Xie, Ruiyu

AU - Benazra, Marion

AU - Nammo, Takao

AU - Arnes, Luis

AU - Nakić, Nikolina

AU - García-Hurtado, Javier

AU - Rodríguez-Seguí, Santiago

AU - Pasquali, Lorenzo

AU - Sauty-Colace, Claire

AU - Beucher, Anthony

AU - Scharfmann, Raphael

AU - Van Arensbergen, Joris

AU - Johnson, Paul R.

AU - Berry, Andrew

AU - Lee, Clarence

AU - Harkins, Timothy

AU - Gmyr, Valery

AU - Pattou, François

AU - Kerr-Conte, Julie

AU - Piemonti, Lorenzo

AU - Berney, Thierry

AU - Hanley, Neil

AU - Gloyn, Anna L.

AU - Sussel, Lori

AU - Langman, Linda

AU - Brayman, Kenneth L.

AU - Sander, Maike

AU - McCarthy, Mark I.

AU - Ravassard, Philippe

AU - Ferrer, Jorge

N1 - Funding Information: This work was funded by grants from the NIH-BCBC (2U01 DK072473-06 to J.F., P.R., and L.S.; U01-DK089567 to M.S. and J.F.), the Juvenile Diabetes Research Foundation (26-2008-633 to J.F. and 31-2008-416 to T.B., F.P., and L.P. to support human islet isolation), Ministerio de Economía y Competitividad (SAF2008-03116 to J.F. and a Ph.D. fellowship to Ignasi Morán). A.L.G. is a Wellcome Trust Senior Fellow in Basic Biomedical Research (WT 09510/Z/10/Z). We thank Rudolph Leibel (University of Columbia) for providing B6.V-Lepob/J mice, Bing Ren (Ludwig Institute for Cancer Research) for generating the ENCODE mouse tissue RNA-seq data, Kelli Bramlett (Genome Sequencing Collaborations Group) for her help in generation of SOLiD data and Viacyte, Inc. for performing implantations of hES cell derivatives. We are also grateful to Ayellet Segrè (Broad Institute) for helpful discussion on MAGENTA, and to Chris Stoeckert and Elisabetta Manduchi (University of Pennsylvania) for help with the online submission.

PY - 2012/10/3

Y1 - 2012/10/3

N2 - A significant portion of the genome is transcribed as long noncoding RNAs (lncRNAs), several of which are known to control gene expression. The repertoire and regulation of lncRNAs in disease-relevant tissues, however, has not been systematically explored. We report a comprehensive strand-specific transcriptome map of human pancreatic islets and β cells, and uncover >1100 intergenic and antisense islet-cell lncRNA genes. We find islet lncRNAs that are dynamically regulated and show that they are an integral component of the β cell differentiation and maturation program. We sequenced the mouse islet transcriptome and identify lncRNA orthologs that are regulated like their human counterparts. Depletion of HI-LNC25, a β cell-specific lncRNA, downregulated GLIS3 mRNA, thus exemplifying a gene regulatory function of islet lncRNAs. Finally, selected islet lncRNAs were dysregulated in type 2 diabetes or mapped to genetic loci underlying diabetes susceptibility. These findings reveal a new class of islet-cell genes relevant to β cell programming and diabetes pathophysiology.

AB - A significant portion of the genome is transcribed as long noncoding RNAs (lncRNAs), several of which are known to control gene expression. The repertoire and regulation of lncRNAs in disease-relevant tissues, however, has not been systematically explored. We report a comprehensive strand-specific transcriptome map of human pancreatic islets and β cells, and uncover >1100 intergenic and antisense islet-cell lncRNA genes. We find islet lncRNAs that are dynamically regulated and show that they are an integral component of the β cell differentiation and maturation program. We sequenced the mouse islet transcriptome and identify lncRNA orthologs that are regulated like their human counterparts. Depletion of HI-LNC25, a β cell-specific lncRNA, downregulated GLIS3 mRNA, thus exemplifying a gene regulatory function of islet lncRNAs. Finally, selected islet lncRNAs were dysregulated in type 2 diabetes or mapped to genetic loci underlying diabetes susceptibility. These findings reveal a new class of islet-cell genes relevant to β cell programming and diabetes pathophysiology.

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U2 - 10.1016/j.cmet.2012.08.010

DO - 10.1016/j.cmet.2012.08.010

M3 - Article

C2 - 23040067

AN - SCOPUS:84867070330

SN - 1550-4131

VL - 16

SP - 435

EP - 448

JO - Cell Metabolism

JF - Cell Metabolism

IS - 4

ER -

Human β cell transcriptome analysis uncovers lncRNAs that are tissue-specific, dynamically regulated, and abnormally expressed in type 2 diabetes

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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