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 Citations (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.

Original language	English
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	111
Issue number	8
Pages (from-to)	3062-7
Number of pages	6
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.1305536111
Publication status	Published - 25 Feb 2014

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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, vol. 111, no. 8, pp. 3062-7. https://doi.org/10.1073/pnas.1305536111

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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.",

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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

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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

Keywords

UN SDGs

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