Circular RNAs mediated by transposons are associated with transcriptomic and phenotypic variation in maize.

Circular RNAs (circRNAs) are covalently closed RNA molecules. Recent studies have shown that circRNAs can arise from the transcripts of transposons. Given the prevalence of transposons in the maize genome and dramatic genomic variation driven by transposons, we hypothesize that transposons in maize may be involved in the formation of circRNAs and further modulate phenotypic variation. We performed circRNA-Seq on B73 seedling leaves and uncovered 2804 high-confidence maize circRNAs, which show distinct genomic features. Comprehensive analyses demonstrated that sequences related to LINE1-like elements (LLEs) and their Reverse Complementary Pairs (LLERCPs) are significantly enriched in the flanking regions of circRNAs. Interestingly, as the number of LLERCPs increase, the accumulation of circRNAs varies, whereas that of linear transcripts decreases. Furthermore, genes with LLERCP-mediated circRNAs are enriched among loci that are associated with phenotypic variation. These results suggest that circRNAs are likely to be involved in the modulation of phenotypic variation by LLERCPs. Further, we showed that the presence/absence variation of LLERCPs was associated with expression variation of circRNA-circ1690 and was related to ear height, potentially through the interplay between circRNAs and functional linear transcripts. Our first study of maize circRNAs uncovers a potential new way for transposons to modulate transcriptomic and phenotypic variations.

[1]  Dawn H. Nagel,et al.  The B73 Maize Genome: Complexity, Diversity, and Dynamics , 2009, Science.

[2]  Zhou Du,et al.  agriGO: a GO analysis toolkit for the agricultural community , 2010, Nucleic Acids Res..

[3]  Peter Tiffin,et al.  Pervasive gene content variation and copy number variation in maize and its undomesticated progenitor. , 2010, Genome research.

[4]  Ling-Ling Chen.  The biogenesis and emerging roles of circular RNAs , 2016, Nature Reviews Molecular Cell Biology.

[5]  P. Brown,et al.  Circular RNA Is Expressed across the Eukaryotic Tree of Life , 2014, PloS one.

[6]  Franck Vazquez,et al.  The biosynthetic pathways and biological scopes of plant small RNAs. , 2010, Trends in plant science.

[7]  Gonçalo R. Abecasis,et al.  The Sequence Alignment/Map format and SAMtools , 2009, Bioinform..

[8]  Xiaohong Yang,et al.  Characterization of a global germplasm collection and its potential utilization for analysis of complex quantitative traits in maize , 2011, Molecular Breeding.

[9]  Peter J. Bradbury,et al.  The Genetic Architecture Of Maize Height , 2014, Genetics.

[10]  F. Zhao,et al.  CIRI: an efficient and unbiased algorithm for de novo circular RNA identification , 2015, Genome Biology.

[11]  Jeffrey Ross-Ibarra,et al.  Improved maize reference genome with single-molecule technologies , 2017, Nature.

[12]  Jian Wang,et al.  Genome-wide patterns of genetic variation among elite maize inbred lines , 2010, Nature Genetics.

[13]  Jing Zhao,et al.  A maize wall-associated kinase confers quantitative resistance to head smut , 2014, Nature Genetics.

[14]  Qian-Hao Zhu,et al.  PlantcircBase: A Database for Plant Circular RNAs. , 2017, Molecular plant.

[15]  D. Bartel,et al.  Expanded identification and characterization of mammalian circular RNAs , 2014, Genome Biology.

[16]  Neva C. Durand,et al.  A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping , 2014, Cell.

[17]  Michael K. Slevin,et al.  Circular RNAs are abundant, conserved, and associated with ALU repeats. , 2013, RNA.

[18]  Tim Schneider,et al.  Exon circularization requires canonical splice signals. , 2015, Cell reports.

[19]  Li Chen,et al.  PcircRNA_finder: a software for circRNA prediction in plants , 2016, Bioinform..

[20]  Xiaohong Yang,et al.  RNA sequencing reveals the complex regulatory network in the maize kernel , 2013, Nature Communications.

[21]  Robert J. Elshire,et al.  A First-Generation Haplotype Map of Maize , 2009, Science.

[22]  Shane J. Neph,et al.  A comparative encyclopedia of DNA elements in the mouse genome , 2014, Nature.

[23]  Linda Szabo,et al.  Statistically based splicing detection reveals neural enrichment and tissue-specific induction of circular RNA during human fetal development , 2015, Genome Biology.

[24]  D. Lisch.  Epigenetic regulation of transposable elements in plants. , 2009, Annual review of plant biology.

[25]  André Beló,et al.  Allelic genome structural variations in maize detected by array comparative genome hybridization , 2009, Theoretical and Applied Genetics.

[26]  Qi Feng,et al.  Transcriptome-wide investigation of circular RNAs in rice , 2015, RNA.

[27]  H. Dooner,et al.  Maize Genome Structure Variation: Interplay between Retrotransposon Polymorphisms and Genic Recombination[W] , 2008, The Plant Cell Online.

[28]  Jianbing Yan,et al.  Metabolome-based genome-wide association study of maize kernel leads to novel biochemical insights , 2014, Nature Communications.

[29]  M. A. Pedraza,et al.  Insights into the Maize Pan-Genome and Pan-Transcriptome[W][OPEN] , 2014, Plant Cell.

[30]  Patrick Xuechun Zhao,et al.  psRNATarget: a plant small RNA target analysis server , 2011, Nucleic Acids Res..

[31]  Dongming Liang,et al.  Short intronic repeat sequences facilitate circular RNA production , 2014, Genes & development.

[32]  Charles Gawad,et al.  Circular RNAs Are the Predominant Transcript Isoform from Hundreds of Human Genes in Diverse Cell Types , 2012, PloS one.

[33]  Patrick S. Schnable,et al.  Maize Inbreds Exhibit High Levels of Copy Number Variation (CNV) and Presence/Absence Variation (PAV) in Genome Content , 2009, PLoS genetics.

[34]  M. Garcia-Blanco,et al.  Exon circularization in mammalian nuclear extracts. , 1996, RNA.

[35]  Data production leads,et al.  An integrated encyclopedia of DNA elements in the human genome , 2012 .

[36]  H. Fu,et al.  Intraspecific violation of genetic colinearity and its implications in maize , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[37]  Sebastian D. Mackowiak,et al.  Circular RNAs are a large class of animal RNAs with regulatory potency , 2013, Nature.

[38]  J. Bennetzen,et al.  Transposable elements, gene creation and genome rearrangement in flowering plants. , 2005, Current opinion in genetics & development.

[39]  N. Rajewsky,et al.  circRNA biogenesis competes with pre-mRNA splicing. , 2014, Molecular cell.

[40]  Qian-Hao Zhu,et al.  Widespread noncoding circular RNAs in plants. , 2015, The New phytologist.

[41]  C. Robin Buell,et al.  Maize (Zea mays L.) Genome Diversity as Revealed by RNA-Sequencing , 2012, PloS one.

[42]  K. Morris,et al.  The rise of regulatory RNA , 2014, Nature Reviews Genetics.

[43]  Jun Zhang,et al.  Diverse alternative back-splicing and alternative splicing landscape of circular RNAs , 2016, Genome research.

[44]  J. Kjems,et al.  Natural RNA circles function as efficient microRNA sponges , 2013, Nature.

[45]  U. Schmidt,et al.  Group II Introns: Structure and Catalytic Versatility of Large Natural Ribozymes , 2003, Critical reviews in biochemistry and molecular biology.

[46]  D. Nettleton,et al.  Genes and Small RNA Transcripts Exhibit Dosage-Dependent Expression Pattern in Maize Copy-Number Alterations , 2016, Genetics.

[47]  Howard Y. Chang,et al.  Genome regulation by long noncoding RNAs. , 2012, Annual review of biochemistry.

[48]  F. Ali,et al.  Genome Wide Association Studies Using a New Nonparametric Model Reveal the Genetic Architecture of 17 Agronomic Traits in an Enlarged Maize Association Panel , 2014, PLoS genetics.

[49]  Jianbing Yan,et al.  Genetic variation in ZmVPP1 contributes to drought tolerance in maize seedlings , 2016, Nature Genetics.

[50]  H. Ostrer,et al.  Inverted repeats are necessary for circularization of the mouse testis Sry transcript. , 1995, Gene.

[51]  Steven R. Eichten,et al.  Genome-wide discovery and characterization of maize long non-coding RNAs , 2014, Genome Biology.

[52]  Peter J. Bradbury,et al.  Maize HapMap2 identifies extant variation from a genome in flux , 2012, Nature Genetics.

[53]  J. Kjems,et al.  Comparison of circular RNA prediction tools , 2015, Nucleic acids research.

[54]  T. Cech,et al.  The intervening sequence of the ribosomal RNA precursor is converted to a circular RNA in isolated nuclei of tetrahymena , 1981, Cell.

[55]  Nadav S. Bar,et al.  Landscape of transcription in human cells , 2012, Nature.

[56]  W. J. Kent,et al.  BLAT--the BLAST-like alignment tool. , 2002, Genome research.

[57]  Jody Hey,et al.  The limits of selection during maize domestication , 1999, Nature.

[58]  Ling-Ling Chen,et al.  Complementary Sequence-Mediated Exon Circularization , 2014, Cell.

[59]  Sol Shenker,et al.  Genome-wide analysis of drosophila circular RNAs reveals their structural and sequence properties and age-dependent neural accumulation. , 2014, Cell reports.

[60]  Xiaohong Yang,et al.  CACTA-like transposable element in ZmCCT attenuated photoperiod sensitivity and accelerated the postdomestication spread of maize , 2013, Proceedings of the National Academy of Sciences.

[61]  Tyson A. Clark,et al.  Unveiling the complexity of the maize transcriptome by single-molecule long-read sequencing , 2016, Nature Communications.

[62]  Peter Goodfellow,et al.  Circular transcripts of the testis-determining gene Sry in adult mouse testis , 1993, Cell.

[63]  Kevin L. Childs,et al.  Draft Assembly of Elite Inbred Line PH207 Provides Insights into Genomic and Transcriptome Diversity in Maize[OPEN] , 2016, Plant Cell.

[64]  Damon Lisch,et al.  How important are transposons for plant evolution? , 2012, Nature Reviews Genetics.

[65]  Xiaofeng Cao,et al.  The effect of transposable elements on phenotypic variation: insights from plants to humans , 2016, Science China Life Sciences.

[66]  P. Zaphiropoulos,et al.  Circular RNAs from transcripts of the rat cytochrome P450 2C24 gene: correlation with exon skipping. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[67]  Martin Renqiang Min,et al.  An integrated encyclopedia of DNA elements in the human genome , 2012 .

[68]  Trees-Juen Chuang,et al.  Biogenesis, identification, and function of exonic circular RNAs , 2015, Wiley interdisciplinary reviews. RNA.

[69]  M. Freeling,et al.  An extrachromosomal form of the Mu transposons of maize. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[70]  Kathleen R. Cho,et al.  Scrambled exons , 1991, Cell.

[71]  Xiaohan Chen,et al.  Single-molecule long-read sequencing facilitates shrimp transcriptome research , 2018, Scientific Reports.

[72]  Rogerio Margis,et al.  Circular RNAs are miRNA sponges and can be used as a new class of biomarker. , 2016, Journal of biotechnology.

[73]  Association Mapping across Numerous Traits Reveals Patterns of Functional Variation in Maize , 2014 .

[74]  M. Coca-Prados,et al.  Electron microscopic evidence for the circular form of RNA in the cytoplasm of eukaryotic cells , 1979, Nature.

[75]  Li Yang,et al.  Regulation of circRNA biogenesis , 2015, RNA biology.

[76]  Xiaohong Yang,et al.  Genome-wide association study dissects the genetic architecture of oil biosynthesis in maize kernels , 2012, Nature Genetics.

[77]  R. Slotkin,et al.  Silencing of active transposable elements in plants. , 2015, Current opinion in plant biology.

[78]  R. Zeillinger,et al.  Correlation of circular RNA abundance with proliferation – exemplified with colorectal and ovarian cancer, idiopathic lung fibrosis, and normal human tissues , 2015, Scientific Reports.

[79]  W. Briggs,et al.  Role of root UV-B sensing in Arabidopsis early seedling development , 2008, Proceedings of the National Academy of Sciences.