Minor class splicing shapes the zebrafish transcriptome during development

Sebastian Markmiller; Nicole Cloonan; Rea M Lardelli; Karen Doggett; Maria-Cristina Keightley; Yeliz Boglev; Andrew J Trotter; Annie Y Ng; Simon J Wilkins; Heather Verkade; Elke Ober; Holly A Field; Sean M Grimmond; Graham J Lieschke; Didier Y R Stainier; Joan K Heath

doi:10.1073/pnas.1305536111

Minor class splicing shapes the zebrafish transcriptome during development

Sebastian Markmiller, Nicole Cloonan, Rea M Lardelli, Karen Doggett, Maria-Cristina Keightley, Yeliz Boglev, Andrew J Trotter, Annie Y Ng, Simon J Wilkins, Heather Verkade, Elke Ober, Holly A Field, Sean M Grimmond, Graham J Lieschke, Didier Y R Stainier, Joan K Heath

Laboratory

38 Citationer (Scopus)

Abstract

Minor class or U12-type splicing is a highly conserved process required to remove a minute fraction of introns from human pre-mRNAs. Defects in this splicing pathway have recently been linked to human disease, including a severe developmental disorder encompassing brain and skeletal abnormalities known as Taybi-Linder syndrome or microcephalic osteodysplastic primordial dwarfism 1, and a hereditary intestinal polyposis condition, Peutz-Jeghers syndrome. Although a key mechanism for regulating gene expression, the impact of impaired U12-type splicing on the transcriptome is unknown. Here, we describe a unique zebrafish mutant, caliban (clbn), with arrested development of the digestive organs caused by an ethylnitrosourea-induced recessive lethal point mutation in the rnpc3 [RNA-binding region (RNP1, RRM) containing 3] gene. rnpc3 encodes the zebrafish ortholog of human RNPC3, also known as the U11/U12 di-snRNP 65-kDa protein, a unique component of the U12-type spliceosome. The biochemical impact of the mutation in clbn is the formation of aberrant U11- and U12-containing small nuclear ribonucleoproteins that impair the efficiency of U12-type splicing. Using RNA sequencing and microarrays, we show that multiple genes involved in various steps of mRNA processing, including transcription, splicing, and nuclear export are disrupted in clbn, either through intron retention or differential gene expression. Thus, clbn provides a useful and specific model of aberrant U12-type splicing in vivo. Analysis of its transcriptome reveals efficient mRNA processing as a critical process for the growth and proliferation of cells during vertebrate development.

Originalsprog	Engelsk
Tidsskrift	Proceedings of the National Academy of Sciences of the United States of America
Vol/bind	111
Udgave nummer	8
Sider (fra-til)	3062-7
Antal sider	6
ISSN	0027-8424
DOI	https://doi.org/10.1073/pnas.1305536111
Status	Udgivet - 25 feb. 2014

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10.1073/pnas.1305536111

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Markmiller, S., Cloonan, N., Lardelli, R. M., Doggett, K., Keightley, M-C., Boglev, Y., Trotter, A. J., Ng, A. Y., Wilkins, S. J., Verkade, H., Ober, E., Field, H. A., Grimmond, S. M., Lieschke, G. J., Stainier, D. Y. R., & Heath, J. K. (2014). Minor class splicing shapes the zebrafish transcriptome during development. Proceedings of the National Academy of Sciences of the United States of America, 111(8), 3062-7. https://doi.org/10.1073/pnas.1305536111

Markmiller, S, Cloonan, N, Lardelli, RM, Doggett, K, Keightley, M-C, Boglev, Y, Trotter, AJ, Ng, AY, Wilkins, SJ, Verkade, H, Ober, E, Field, HA, Grimmond, SM, Lieschke, GJ, Stainier, DYR & Heath, JK 2014, 'Minor class splicing shapes the zebrafish transcriptome during development', Proceedings of the National Academy of Sciences of the United States of America, bind 111, nr. 8, s. 3062-7. https://doi.org/10.1073/pnas.1305536111

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title = "Minor class splicing shapes the zebrafish transcriptome during development",

abstract = "Minor class or U12-type splicing is a highly conserved process required to remove a minute fraction of introns from human pre-mRNAs. Defects in this splicing pathway have recently been linked to human disease, including a severe developmental disorder encompassing brain and skeletal abnormalities known as Taybi-Linder syndrome or microcephalic osteodysplastic primordial dwarfism 1, and a hereditary intestinal polyposis condition, Peutz-Jeghers syndrome. Although a key mechanism for regulating gene expression, the impact of impaired U12-type splicing on the transcriptome is unknown. Here, we describe a unique zebrafish mutant, caliban (clbn), with arrested development of the digestive organs caused by an ethylnitrosourea-induced recessive lethal point mutation in the rnpc3 [RNA-binding region (RNP1, RRM) containing 3] gene. rnpc3 encodes the zebrafish ortholog of human RNPC3, also known as the U11/U12 di-snRNP 65-kDa protein, a unique component of the U12-type spliceosome. The biochemical impact of the mutation in clbn is the formation of aberrant U11- and U12-containing small nuclear ribonucleoproteins that impair the efficiency of U12-type splicing. Using RNA sequencing and microarrays, we show that multiple genes involved in various steps of mRNA processing, including transcription, splicing, and nuclear export are disrupted in clbn, either through intron retention or differential gene expression. Thus, clbn provides a useful and specific model of aberrant U12-type splicing in vivo. Analysis of its transcriptome reveals efficient mRNA processing as a critical process for the growth and proliferation of cells during vertebrate development.",

keywords = "Animals, Base Sequence, Gene Expression Profiling, Gene Expression Regulation, Developmental, Intestines, Liver, Microarray Analysis, Molecular Sequence Data, Pancreas, Point Mutation, Protein Conformation, RNA Splicing, RNA, Small Nuclear, RNA-Binding Proteins, Real-Time Polymerase Chain Reaction, Sequence Analysis, RNA, Spliceosomes, Zebrafish, Zebrafish Proteins",

author = "Sebastian Markmiller and Nicole Cloonan and Lardelli, {Rea M} and Karen Doggett and Maria-Cristina Keightley and Yeliz Boglev and Trotter, {Andrew J} and Ng, {Annie Y} and Wilkins, {Simon J} and Heather Verkade and Elke Ober and Field, {Holly A} and Grimmond, {Sean M} and Lieschke, {Graham J} and Stainier, {Didier Y R} and Heath, {Joan K}",

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doi = "10.1073/pnas.1305536111",

language = "English",

volume = "111",

pages = "3062--7",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "The National Academy of Sciences of the United States of America",

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TY - JOUR

T1 - Minor class splicing shapes the zebrafish transcriptome during development

AU - Markmiller, Sebastian

AU - Cloonan, Nicole

AU - Lardelli, Rea M

AU - Doggett, Karen

AU - Keightley, Maria-Cristina

AU - Boglev, Yeliz

AU - Trotter, Andrew J

AU - Ng, Annie Y

AU - Wilkins, Simon J

AU - Verkade, Heather

AU - Ober, Elke

AU - Field, Holly A

AU - Grimmond, Sean M

AU - Lieschke, Graham J

AU - Stainier, Didier Y R

AU - Heath, Joan K

PY - 2014/2/25

Y1 - 2014/2/25

N2 - Minor class or U12-type splicing is a highly conserved process required to remove a minute fraction of introns from human pre-mRNAs. Defects in this splicing pathway have recently been linked to human disease, including a severe developmental disorder encompassing brain and skeletal abnormalities known as Taybi-Linder syndrome or microcephalic osteodysplastic primordial dwarfism 1, and a hereditary intestinal polyposis condition, Peutz-Jeghers syndrome. Although a key mechanism for regulating gene expression, the impact of impaired U12-type splicing on the transcriptome is unknown. Here, we describe a unique zebrafish mutant, caliban (clbn), with arrested development of the digestive organs caused by an ethylnitrosourea-induced recessive lethal point mutation in the rnpc3 [RNA-binding region (RNP1, RRM) containing 3] gene. rnpc3 encodes the zebrafish ortholog of human RNPC3, also known as the U11/U12 di-snRNP 65-kDa protein, a unique component of the U12-type spliceosome. The biochemical impact of the mutation in clbn is the formation of aberrant U11- and U12-containing small nuclear ribonucleoproteins that impair the efficiency of U12-type splicing. Using RNA sequencing and microarrays, we show that multiple genes involved in various steps of mRNA processing, including transcription, splicing, and nuclear export are disrupted in clbn, either through intron retention or differential gene expression. Thus, clbn provides a useful and specific model of aberrant U12-type splicing in vivo. Analysis of its transcriptome reveals efficient mRNA processing as a critical process for the growth and proliferation of cells during vertebrate development.

AB - Minor class or U12-type splicing is a highly conserved process required to remove a minute fraction of introns from human pre-mRNAs. Defects in this splicing pathway have recently been linked to human disease, including a severe developmental disorder encompassing brain and skeletal abnormalities known as Taybi-Linder syndrome or microcephalic osteodysplastic primordial dwarfism 1, and a hereditary intestinal polyposis condition, Peutz-Jeghers syndrome. Although a key mechanism for regulating gene expression, the impact of impaired U12-type splicing on the transcriptome is unknown. Here, we describe a unique zebrafish mutant, caliban (clbn), with arrested development of the digestive organs caused by an ethylnitrosourea-induced recessive lethal point mutation in the rnpc3 [RNA-binding region (RNP1, RRM) containing 3] gene. rnpc3 encodes the zebrafish ortholog of human RNPC3, also known as the U11/U12 di-snRNP 65-kDa protein, a unique component of the U12-type spliceosome. The biochemical impact of the mutation in clbn is the formation of aberrant U11- and U12-containing small nuclear ribonucleoproteins that impair the efficiency of U12-type splicing. Using RNA sequencing and microarrays, we show that multiple genes involved in various steps of mRNA processing, including transcription, splicing, and nuclear export are disrupted in clbn, either through intron retention or differential gene expression. Thus, clbn provides a useful and specific model of aberrant U12-type splicing in vivo. Analysis of its transcriptome reveals efficient mRNA processing as a critical process for the growth and proliferation of cells during vertebrate development.

KW - Animals

KW - Base Sequence

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Developmental

KW - Intestines

KW - Liver

KW - Microarray Analysis

KW - Molecular Sequence Data

KW - Pancreas

KW - Point Mutation

KW - Protein Conformation

KW - RNA Splicing

KW - RNA, Small Nuclear

KW - RNA-Binding Proteins

KW - Real-Time Polymerase Chain Reaction

KW - Sequence Analysis, RNA

KW - Spliceosomes

KW - Zebrafish

KW - Zebrafish Proteins

U2 - 10.1073/pnas.1305536111

DO - 10.1073/pnas.1305536111

M3 - Journal article

C2 - 24516132

SN - 0027-8424

VL - 111

SP - 3062

EP - 3067

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 8

ER -

Minor class splicing shapes the zebrafish transcriptome during development

Abstract

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