Identification and characterization of circular RNAs in differentiation and human disease
Developmental Biology
Evolutionary Cell and Developmental Biology (Zoology)
Cell Biology
Final Report Abstract
Non-coding regulatory RNAs like microRNAs or long non-coding RNAs have been investigated in diverse biological contexts of basic molecular and cellular process as well as with respect to potential roles in human disease. Recently, the largely ignored class of circular RNA as moved into focus of this research, after it was discovered that circRNA expression is substantial, prevalent and oftentimes conserved across animals. Although many thousand circRNAs were detected, mainly in in vitro models, only very few circRNAs are functionally characterized and a comprehensive list of candidate molecules for follow-up studies was elusive. In this project, we identified and characterized the circular transcriptome of clinically relevant samples comprising blood, a variety of human cell lines and primary tissues of healthy and diseased individuals. We report on an extensive catalogue of novel circRNAs across tissues and cell types and characterize circRNA expression specificity and expression level relative to linear RNA isoforms. To complement these initial findings, we use extensive experimental validation by sequencing-independent assays. This project revealed that circRNAs are potential novel biomarker for human disease since (1) we observed differential circRNA expression in diseases-associated genes between patients and controls (2) circRNAs are abundantly expressed in standard clinical blood samples and a pilot study suggested blood circRNA expression pattern could be specific for Alzheimer’s Disease (3) circRNAs are oftentimes the main transcriptional output of a genomic locus. The later point comprises cases in which linear RNA expression is virtually not detectable, illustrating that the circular transcriptome represents a so far not mined layer of cellular activity with unknown biological function. Thus, we provide the first insights, the computational tools and optimized experimental strategies to investigate circRNAs and their roles in human disease. The results as well as tools for circRNA analysis are freely available at our online database circbase.org.
Publications
- (2014). circRNA Biogenesis Competes with Pre-mRNA Splicing. Molecular Cell 56: 1–12
Ashwal-Fluss, R., Meyer, M., Pamudurti, N.R., Ivanov, A., Bartok, O., Hanan, M., Evantal, N., Memczak, S., Rajewsky, N., and Kadener, S.
(See online at https://doi.org/10.1016/j.molcel.2014.08.019) - (2015). Analysis of Intron Sequences Reveals Hallmarks of Circular RNA Biogenesis in Animals. Cell Reports 10: 170–177
Ivanov, A., Memczak, S., Wyler, E., Torti, F., Porath, H.T., Orejuela, M.R., Piechotta, M., Levanon, E.Y., Landthaler, M., Dieterich, C., et al.
(See online at https://doi.org/10.1016/j.celrep.2014.12.019) - (2015). Identification and characterization of circular RNAs as a new class of putative biomarkers in human blood. PLoS ONE 10, e0141214
Memczak, S., Papavasileiou, P., Peters, O., and Rajewsky, N.
(See online at https://doi.org/10.1371/journal.pone.0141214) - (2017). A map of human circular RNAs in clinically relevant tissues. J Mol Med
Maass, P.G., Glažar, P., Memczak, S., Dittmar, G., Hollfinger, I., Schreyer, L., Sauer, A.V., Toka, O., Aiuti, A., Luft, F.C., Rajewsky, N.
(See online at https://doi.org/10.1007/s00109-017-1582-9) - (2017). Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function. Science 357. Epub 2017 Aug 10
Piwecka, M., Glažar, P., Hernandez-Miranda, L.R., Memczak, S., Wolf, S.A., Rybak- Wolf, A., Filipchyk, A., Klironomos, F., Cerda Jara, C.A., Fenske, P., et al.
(See online at https://doi.org/10.1126/science.aam8526)
