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Minor Class Splicing Shapes the Zebrafish Transcriptome During Development

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Minor Class Splicing Shapes the Zebrafish Transcriptome During Development Minor class splicing shapes the zebrafish transcriptome during development Sebastian Markmillera,b,1, Nicole Cloonanc,2,3, Rea M. Lardellia,2,4, Karen Doggettd,e, Maria-Cristina Keightleyf, Yeliz Bogleva, Andrew J. Trottera, Annie Y. Nga,5, Simon J. Wilkinsc, Heather Verkadea,g, Elke A. Oberg,6, Holly A. Fieldg, Sean M. Grimmondc, Graham J. Lieschkef, Didier Y. R. Stainierg,7, and Joan K. Heatha,b,d,e,8 aLudwig Institute for Cancer Research, Melbourne-Parkville Branch, Parkville, VIC 3050, Australia; bDepartment of Surgery, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC 3050, Australia; cQueensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072, Australia; dWalter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; eDepartment of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia; fAustralian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia; and gDepartment of Biochemistry and Biophysics, University of California, San Francisco, CA 94158 Edited* by Joan A. Steitz, Howard Hughes Medical Institute, New Haven, CT, and approved January 16, 2014 (received for review March 31, 2013) Minor class or U12-type splicing is a highly conserved process splicing pathway has been an intriguing aspect of gene ex- required to remove a minute fraction of introns from human pre- pression. Interestingly, U12-type introns are nonrandomly dis- mRNAs. Defects in this splicing pathway have recently been linked to tributed across the genome (11) and their removal is thought to human disease, including a severe developmental disorder encom- be rate-limiting in the generation of mature mRNAs (12–14). passing brain and skeletal abnormalities known as Taybi-Linder Aberrant splicing is the basis of many human diseases and up syndrome or microcephalic osteodysplastic primordial dwarfism 1, to one-third of disease-causing mutations may lead to splicing and a hereditary intestinal polyposis condition, Peutz-Jeghers syn- defects (15). Although the majority of these defects occur in drome. Although a key mechanism for regulating gene expression, U2-type introns and splicing factors, perturbations in U12-type the impact of impaired U12-type splicing on the transcriptome is splicing have also been described. Most recently, mutations in the unknown. Here, we describe a unique zebrafish mutant, caliban U12-type U4atac snRNA were found to underlie the human devel- (clbn), with arrested development of the digestive organs caused opmental disorder Taybi-Linder syndrome (TALS)/microcephalic by an ethylnitrosourea-induced recessive lethal point mutation GENETICS in the rnpc3 [RNA-binding region (RNP1, RRM) containing 3] gene. Significance rnpc3 encodes the zebrafish ortholog of human RNPC3, also known as the U11/U12 di-snRNP 65-kDa protein, a unique compo- The accurate removal of introns by pre-mRNA splicing is a crit- nent of the U12-type spliceosome. The biochemical impact of the ical step in proper gene expression. Most eukaryotic genomes, mutation in clbn is the formation of aberrant U11- and U12-con- from plant to human, contain a tiny subset of “minor class” taining small nuclear ribonucleoproteins that impair the efficiency introns with unique sequence elements that require their own of U12-type splicing. Using RNA sequencing and microarrays, we splicing machinery. The significance of this second splicing show that multiple genes involved in various steps of mRNA pro- pathway has intrigued RNA biologists for two decades, but its cessing, including transcription, splicing, and nuclear export are biological relevance was recently underscored when defects in disrupted in clbn, either through intron retention or differential the process were firmly linked to human disease. Here, we use gene expression. Thus, clbn provides a useful and specific model of a novel zebrafish mutant with defective minor class splicing to aberrant U12-type splicing in vivo. Analysis of its transcriptome investigate how this pathway shapes the transcriptome during reveals efficient mRNA processing as a critical process for the vertebrate development. We link its pleiotropic phenotype to growth and proliferation of cells during vertebrate development. widespread changes in gene expression that disrupt essential cellular pathways, including mRNA processing. plicing, the excision of introns from pre-mRNA, is an es- Ssential step in gene expression and a major source of complexity Author contributions: S.M., R.M.L., and J.K.H. designed research; S.M., R.M.L., K.D., M.-C.K., in the transcriptome (1). The process is catalyzed by highly dynamic Y.B., A.J.T., A.Y.N., S.J.W., and H.V. performed research; N.C., H.V., E.A.O., H.A.F., S.M.G., and D.Y.R.S. contributed new reagents/analytic tools; S.M., N.C., R.M.L., K.D., M.-C.K., Y.B., complexes of small nuclear ribonucleoproteins (snRNPs) called A.J.T., A.Y.N., S.J.W., G.J.L., and J.K.H. analyzed data; and S.M. and J.K.H. wrote the paper. spliceosomes (2). Not widely appreciated is the coexistence of two The authors declare no conflict of interest. types of introns in most eukaryotic genomes. The vast majority, the major class or U2-type introns, are marked by GT and AG at their *This Direct Submission article had a prearranged editor. 5′ and 3′ ends, respectively. Minor class or U12-type introns, of Freely available online through the PNAS open access option. which there are ∼700 in the human genome, were initially recog- Data deposition: The data reported in this paper have been deposited in the Gene Ex- nized by the presence of AT and AC in these positions, prompting pression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE53935). 1 their original name of AT-AC introns (3). However, we now know Present address: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla CA 92093. that most of these introns contain the same GT-AG termini found 2 in U2-type introns (4, 5) and are instead distinguished from them N.C. and R.M.L. contributed equally to this work. 3 by two highly conserved motifs: one adjacent to the 5′ splice site (ss) Present address: QIMR Berghofer Medical Research Institute, Genomic Biology Labora- tory, Herston, QLD 4006, Australia. and one corresponding to the branch point sequence (BPS), close ′ ′ 4Present address: Division of Biology, University of California, San Diego, La Jolla, to the 3 ss (6, 7). These introns also lack the 3 polypyrimidine CA 92093. tract characteristic of U2-type introns. Minor class introns are 5Present address: Institute of Medical Biology, Agency for Science, Technology and Re- excised by U12-type spliceosomes, which are analogous in search (A-STAR), Singapore 138648. function and similar in composition to U2-type spliceosomes; 6Present address: The Danish Stem Cell Centre, University of Copenhagen, 2200 Copenhagen, each comprise five small nuclear RNAs (snRNAs) and hun- Denmark. dreds of associated proteins (6). Although the U5 snRNA is 7Present address: Department of Developmental Genetics, Max Planck Institute for Heart shared between the two complexes, the U12-type spliceosome and Lung Research, D-61231 Bad Nauheim, Germany. contains four unique snRNAs (U11, U12, U4atac, and U6atac) 8To whom correspondance should be addressed. E-mail: [email protected]. – (7 9) and at least seven unique proteins (10). Since its discovery This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. two decades ago, the existence of this highly conserved, second 1073/pnas.1305536111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1305536111 PNAS Early Edition | 1of6 Downloaded by guest on October 5, 2021 osteodysplastic primordial dwarfism 1 (MOPD1) (16, 17). Other examples of diseases that can arise because of impaired splicing of U12-type introns include spinal muscular atrophy (18, 19) and Peutz-Jeghers syndrome (PJS), an intestinal polyposis syndrome that predisposes to cancer because of mutations in the tumor suppressor gene (TSG) LKB1 (liver kinase B1) (20). The observation that impaired U12-type splicing can affect TSG expression has in- teresting implications for other TSGs containing U12-type introns, such as PTEN (phosphatase and tensin homolog deleted on chromosome 10), where even a modest loss in PTEN function predisposes mice to cancer (21). To specifically study the role of U12-type introns in gene ex- pression and development, we exploited a zebrafish mutant, caliban (clbn), which carries a point mutation in rnpc3 [RNA-binding region (RNP1, RRM) containing 3], encoding the zebrafish ortholog of human RNPC3, one of seven proteins unique to the U12-type spliceosome (22). We found aberrant minor class spliceosomal snRNPs in clbn extracts and used microarray and RNA sequencing (RNAseq) to show that impairment of U12-type splicing impacts broadly on gene expression, disrupting multiple genes involved in mRNA processing, transcription, splicing, and nuclear export. As a result, clbn mutants develop a pleiotropic phenotype with early lethality. Results The Intestine, Liver, and Pancreas Are Abnormal in clbn. clbns846 was Fig. 1. The clbn phenotype is characterized by abnormalities in the digestive organs (A and B) Brightfield images of left lateral views and (C) histology of WT identified in a transgene-assisted ethylnitrosourea mutagenesis s846 screen for zebrafish mutants with defective endodermal organ and clbn larvae at 120 hpf show a thick, folded intestinal epithelium (black arrows in C) and inflated swim bladder in WT, whereas clbn displays a thin, development (23). Abnormalities in the gross morphology of unfolded intestinal epithelium, delayed yolk resorption, and smaller eyes. (D) clbn larvae are first detectable at 108 h postfertilization (hpf) and Two-photon microscopy of WT and clbns846 larvae on the Tg(gutGFP)s854 mutants die between 7 and 10 d postfertilization (dpf). The head, background and (E) epifluorescence microscopy on the Tg(fabp10:RFP,ela3l: eye, and lens are smaller, the swim bladder fails to inflate, and EGFP)gz12 background reveal smaller digestive organs in clbns846 compared with yolk absorption is delayed.
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