title: A landscape of circular RNA expression in the human heart.
abstract: Circular RNA (circRNA) is a newly validated class of single-stranded RNA, ubiquitously expressed in mammalian tissues and possessing key functions including acting as microRNA sponges and as transcriptional regulators by binding to RNA-binding proteins. While independent studies confirm the expression of circRNA in various tissue types, genome-wide circRNA expression in the heart has yet to be described in detail.
  
  
  
  We performed deep RNA-sequencing on ribosomal-depleted RNA isolated from 12 human hearts, 25 mouse hearts and across a 28-day differentiation time-course of human embryonic stem cell-derived cardiomyocytes. Using purpose-designed bioinformatics tools, we uncovered a total of 15 318 and 3017 cardiac circRNA within human and mouse, respectively. Their abundance generally correlates with the abundance of their cognate linear RNA, but selected circRNAs exist at disproportionately higher abundance. Top highly expressed circRNA corresponded to key cardiac genes including Titin (TTN), RYR2, and DMD. The most abundant cardiac-expressed circRNA is a cytoplasmic localized single-exon circSLC8A1-1. The longest human transcript TTN alone generates up to 415 different exonic circRNA isoforms, the majority (83%) of which originates from the I-band domain. Finally, we confirmed the expression of selected cardiac circRNA by RT-PCR, Sanger sequencing and single molecule RNA-fluorescence in situ hybridization.
  
  
  
  Our data provide a detailed circRNA expression landscape in hearts. There is a high-abundance of specific cardiac-expressed circRNA. These findings open up a new avenue for future investigation into this emerging class of RNA.
authors.affiliation: Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.|Cardiovascular Research Institute, National University Health System, Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore.
authors.forename: Wilson L W
authors.initials: WL
authors.lastname: Tan
authors.affiliation: Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.|Cardiovascular Research Institute, National University Health System, Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore.
authors.forename: Benson T S
authors.initials: BT
authors.lastname: Lim
authors.affiliation: Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.|Cardiovascular Research Institute, National University Health System, Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore.
authors.forename: Chukwuemeka G O
authors.initials: CG
authors.lastname: Anene-Nzelu
authors.affiliation: Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.|Cardiovascular Research Institute, National University Health System, Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore.
authors.forename: Matthew
authors.initials: M
authors.lastname: Ackers-Johnson
authors.affiliation: Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.|Cardiovascular Research Institute, National University Health System, Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore.
authors.forename: Albert
authors.initials: A
authors.lastname: Dashi
authors.affiliation: Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.
authors.forename: Kelvin
authors.initials: K
authors.lastname: See
authors.affiliation: Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.|Cardiovascular Research Institute, National University Health System, Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore.
authors.forename: Zenia
authors.initials: Z
authors.lastname: Tiang
authors.affiliation: Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.
authors.forename: Dominic Paul
authors.initials: DP
authors.lastname: Lee
authors.affiliation: Cardiovascular Research Institute, National University Health System, Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore.
authors.forename: Wee Woon
authors.initials: WW
authors.lastname: Chua
authors.affiliation: Cardiovascular Research Institute, National University Health System, Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore.
authors.forename: Tuan D A
authors.initials: TD
authors.lastname: Luu
authors.affiliation: Cardiovascular Research Institute, National University Health System, Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore.
authors.forename: Peter Y Q
authors.initials: PY
authors.lastname: Li
authors.affiliation: Cardiovascular Research Institute, National University Health System, Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore.
authors.forename: Arthur Mark
authors.initials: AM
authors.lastname: Richards
authors.affiliation: Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.|Cardiovascular Research Institute, National University Health System, Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore.
authors.forename: Roger S Y
authors.initials: RS
authors.lastname: Foo
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D002454:Cell Differentiation; D002460:Cell Line; D019295:Computational Biology; D030541:Databases, Genetic; D053595:Embryonic Stem Cells / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D056726:Genetic Association Studies; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006331:Heart Diseases / Q000175:diagnosis / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics* / Q000378:metabolism; D000079962:RNA, Circular; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D000072760:Single Molecule Imaging; D013997:Time Factors
chemical_list: D005819:Genetic Markers; D000079962:RNA, Circular; D012333:RNA, Messenger; D012313:RNA