CircRNA accumulation: A new hallmark of aging?

Circular RNAs (circRNAs) are a newly appreciated class of RNAs found across phyla that are generated most commonly from back-splicing of protein-coding exons. Recent profiling of circRNAs genome-wide has shown that hundreds of circRNAs dramatically increase in expression during aging in the brains of multiple organisms. No other class of transcripts has been found to show such a strong correlation with aging as circRNAs-could they be playing a role in the aging process? Here, we discuss the different methods used to profile circRNAs and discuss current limitations of these approaches. We argue that age-related increases in global circRNA levels likely result from their high stability. The functions of circRNAs are only beginning to emerge, and it is an open question whether circRNA accumulation impacts the aging brain. We discuss experimental approaches that could illuminate whether age-accumulation of circRNAs are detrimental or protective to the aging brain.

[1]  M. Hardt,et al.  Selective release of circRNAs in platelet-derived extracellular vesicles , 2018, Journal of extracellular vesicles.

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

[3]  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.

[4]  Rhonda Bacher,et al.  Design and computational analysis of single-cell RNA-sequencing experiments , 2016, Genome Biology.

[5]  Li Yang,et al.  Coordinated circRNA Biogenesis and Function with NF90/NF110 in Viral Infection. , 2017, Molecular cell.

[6]  Xun Hu,et al.  Mutations in FUS, an RNA Processing Protein, Cause Familial Amyotrophic Lateral Sclerosis Type 6 , 2009, Science.

[7]  G. Wenning,et al.  Multiple-system atrophy. , 2015, The New England journal of medicine.

[8]  Rong Li,et al.  Tracing the expression of circular RNAs in human pre-implantation embryos , 2016, Genome Biology.

[9]  N. Rajewsky,et al.  Translation of CircRNAs , 2017, Molecular cell.

[10]  Jing Zhou,et al.  Quantifying circular RNA expression from RNA‐seq data using model‐based framework , 2017, Bioinform..

[11]  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.

[12]  Li Yang,et al.  The Biogenesis of Nascent Circular RNAs. , 2016, Cell reports.

[13]  Howard Y. Chang,et al.  Sensing Self and Foreign Circular RNAs by Intron Identity. , 2017, Molecular cell.

[14]  F. Slack,et al.  Ageing and the small, non-coding RNA world , 2013, Ageing Research Reviews.

[15]  Petar Glažar,et al.  Circular RNAs in the Mammalian Brain Are Highly Abundant, Conserved, and Dynamically Expressed. , 2015, Molecular cell.

[16]  H. Kaessmann,et al.  Conserved microRNA editing in mammalian evolution, development and disease , 2014, Genome Biology.

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

[18]  P. Pandolfi,et al.  Oncogenic Role of Fusion-circRNAs Derived from Cancer-Associated Chromosomal Translocations , 2016, Cell.

[19]  Weining Yang,et al.  Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2 , 2016, Nucleic acids research.

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

[21]  Daphne A. Cooper,et al.  Transcriptome profiling of aging Drosophila photoreceptors reveals gene expression trends that correlate with visual senescence , 2017, BMC Genomics.

[22]  Nikolaus Rajewsky,et al.  Identification and Characterization of Circular RNAs As a New Class of Putative Biomarkers in Human Blood , 2015, PloS one.

[23]  S. Horvath DNA methylation age of human tissues and cell types , 2013, Genome Biology.

[24]  Kai Wang,et al.  Circular RNA profile in gliomas revealed by identification tool UROBORUS , 2016, Nucleic acids research.

[25]  J. D. Mills,et al.  Characterization of circular RNAs landscape in multiple system atrophy brain , 2016, Journal of neurochemistry.

[26]  Alessio Colantoni,et al.  FUS affects circular RNA expression in murine embryonic stem cell-derived motor neurons , 2017, Nature Communications.

[27]  Frederico A. C. Azevedo,et al.  Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled‐up primate brain , 2009, The Journal of comparative neurology.

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

[29]  Zheng Yan,et al.  Widespread splicing changes in human brain development and aging , 2013 .

[30]  Junying Yuan,et al.  Single-Cell RNA Sequencing: Unraveling the Brain One Cell at a Time. , 2017, Trends in molecular medicine.

[31]  W. Koh,et al.  Noninvasive in vivo monitoring of tissue-specific global gene expression in humans , 2014, Proceedings of the National Academy of Sciences.

[32]  F. S. Foster,et al.  Foxo3 circular RNA promotes cardiac senescence by modulating multiple factors associated with stress and senescence responses , 2016, European heart journal.

[33]  Andreas W. Schreiber,et al.  The RNA Binding Protein Quaking Regulates Formation of circRNAs , 2015, Cell.

[34]  J. Sulston,et al.  Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. , 1977, Developmental biology.

[35]  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.

[36]  P. Miura,et al.  Emerging Functions of Circular RNAs , 2016, The Yale journal of biology and medicine.

[37]  Daphne A. Cooper,et al.  Genome-Wide circRNA Profiling from RNA-seq Data. , 2018, Methods in molecular biology.

[38]  M. Erdos,et al.  Global genome splicing analysis reveals an increased number of alternatively spliced genes with aging , 2015, Aging cell.

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

[40]  M. T. Pellecchia,et al.  Progression of multiple system atrophy (MSA): A prospective natural history study by the European MSA Study Group (EMSA SG) , 2006, Movement disorders : official journal of the Movement Disorder Society.

[41]  Dawood B. Dudekula,et al.  High-purity circular RNA isolation method (RPAD) reveals vast collection of intronic circRNAs , 2017, Nucleic acids research.

[42]  Feng Li,et al.  The landscape of microRNA, Piwi-interacting RNA, and circular RNA in human saliva. , 2015, Clinical chemistry.

[43]  E. Schuman,et al.  Neural circular RNAs are derived from synaptic genes and regulated by development and plasticity , 2015, Nature Neuroscience.

[44]  Daphne A. Cooper,et al.  Global accumulation of circRNAs during aging in Caenorhabditis elegans , 2017, BMC Genomics.

[45]  S. Bandinelli,et al.  Human aging is characterized by focused changes in gene expression and deregulation of alternative splicing , 2011, Aging cell.

[46]  Carmen Birchmeier,et al.  Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function , 2017, Science.

[47]  Yan Li,et al.  Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs , 2016, Nature Communications.

[48]  Jannetta S. Steyn,et al.  Circular RNA enrichment in platelets is a signature of transcriptome degradation. , 2016, Blood.

[49]  T. Hou,et al.  Changing expression profiles of lncRNAs, mRNAs, circRNAs and miRNAs during osteoclastogenesis , 2016, Scientific Reports.

[50]  C. Holt,et al.  Dynamic Axonal Translation in Developing and Mature Visual Circuits , 2016, Cell.

[51]  Vikki M. Weake,et al.  Transcriptional Signatures of Aging. , 2017, Journal of molecular biology.

[52]  Jennifer A. Doudna,et al.  Biology and Applications of CRISPR Systems: Harnessing Nature’s Toolbox for Genome Engineering , 2016, Cell.

[53]  S. Bonn,et al.  De-regulation of gene expression and alternative splicing affects distinct cellular pathways in the aging hippocampus , 2014, Front. Cell. Neurosci..

[54]  R. de Cabo,et al.  Circular RNAs in monkey muscle: age-dependent changes , 2015, Aging.

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

[56]  L. Partridge,et al.  Genetics of longevity in model organisms: debates and paradigm shifts. , 2013, Annual review of physiology.

[57]  N. Rajewsky,et al.  Circ-ZNF609 Is a Circular RNA that Can Be Translated and Functions in Myogenesis , 2017, Molecular cell.

[58]  Daphne A. Cooper,et al.  CircRNA accumulation in the aging mouse brain , 2016, Scientific Reports.

[59]  J. Jankovic,et al.  The role of FUS gene variants in neurodegenerative diseases , 2014, Nature Reviews Neurology.

[60]  Honghui Lin,et al.  Heat stress alters genome-wide profiles of circular RNAs in Arabidopsis , 2018, Plant Molecular Biology.

[61]  S. Cherry,et al.  Combinatorial control of Drosophila circular RNA expression by intronic repeats, hnRNPs, and SR proteins , 2015, Genes & development.

[62]  G. Shan,et al.  Exon-intron circular RNAs regulate transcription in the nucleus , 2015, Nature Structural &Molecular Biology.

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

[64]  Roy Parker,et al.  Circular RNAs Co-Precipitate with Extracellular Vesicles: A Possible Mechanism for circRNA Clearance , 2016, PloS one.

[65]  O. Rossbach,et al.  CircRNA-protein complexes: IMP3 protein component defines subfamily of circRNPs , 2016, Scientific Reports.

[66]  Christoph Dieterich,et al.  Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals. , 2015, Cell reports.

[67]  Igor Ulitsky,et al.  Circular RNAs are long-lived and display only minimal early alterations in response to a growth factor , 2015, Nucleic acids research.

[68]  Shenmin Zhang,et al.  circRNA_100290 plays a role in oral cancer by functioning as a sponge of the miR-29 family , 2017, Oncogene.

[69]  Yang Zhang,et al.  Extensive translation of circular RNAs driven by N6-methyladenosine , 2017, Cell Research.

[70]  Jun Cheng,et al.  Specific identification and quantification of circular RNAs from sequencing data , 2016, Bioinform..

[71]  Kevin R. Parker,et al.  ciRS-7 exonic sequence is embedded in a long non-coding RNA locus , 2017, bioRxiv.

[72]  João Pedro de Magalhães,et al.  Meta-analysis of age-related gene expression profiles identifies common signatures of aging , 2009, Bioinform..