Competing endogenous RNA (CeRNA)

In molecular biology, competing endogenous RNAs (abbreviated ceRNAs) regulate other RNA transcripts by competing for shared microRNAs.[1]

Summary

MicroRNAs (miRNA) are an abundant class of small, non-coding RNAs (~22nt long), which negatively regulate gene expression at the levels of messenger RNAs (mRNAs) stability and translation inhibition. The human genome consists of over 500 miRNA, each one targeting hundreds of different genes. It is estimated that half of all genes of the genome are targets of miRNA, spanning a large layer of regulation on a post-transcriptional level.[2] The seed region, which comprises nucleotides 2-8 of the 5’ portion of the miRNA, is particularly crucial for mRNA recognition and silencing.[3]

Recent studies have shown that the interaction of the miRNA seed region with mRNA is not unidirectional, but that the pool of mRNAs, transcribed pseudogenes, long noncoding RNAs (lncRNA),[4] circular RNA (circRNA) [5][6] compete for the same pool of miRNA.[7] These competitive endogenous RNAs (ceRNAs) act as molecular sponges for a microRNA through their miRNA binding sites (also referred to as miRNA response elements, MRE), thereby de-repressing all target genes of the respective miRNA family. Experimental evidence for such a ceRNA crosstalk has been initially shown for the tumor suppressor gene PTEN, which is regulated by the 3’ untranslated region (3'UTR) of the pseudogene PTENP1 in a DICER-dependent manner.[8]

RNA transcripts, both protein-coding and non-coding, thus have the ability to compete for microRNA binding and co-regulate each other in complex ceRNA networks (ceRNETs).[9] The ceRNA language represents an added trans-regulatory dimension to RNA biology and suggests that even protein-coding genes can function as RNA, independently of their protein-coding function. The prediction and identification of ceRNAs for a given RNA enables the functionalization of the transcriptome irrespective of whether transcripts encode for proteins. The characterization of a breast-cancer ceRNET has been used to improve miRNA-target prediction.[10]

The biological relevance of the ceRNA hypothesis is being actively debated. It has recently been challenged by the quantitative assessment of miR-122 and its binding sites in liver.[11] The authors reported that very high numbers of competing target sites had to be added to observe ceRNA mediated effects, suggesting that ceRNA are unlikely to regulate the availability of miR-122 in liver cells. Bosson et al.[12] addressed these findings, suggesting that ceRNA is unlikely to alter the activity of highly abundant miRNAs such as miR-122 in liver cells. Supported by biochemical measurements in single cells, they found that ceRNA regulation is less likely to affect miRNAs with very high or very low abundance, but can substantially alter the activity of medium-abundance miRNAs. A more recent report found changes in miR-122 binding in liver cells due to ceRNA regulation.[13]

The PTEN ceRNA network (ceRNET)

PTEN is a critical tumor suppressor gene which is frequently altered in multiple human cancers and is a negative regulator of the oncogenic Phosphoinositide 3-kinase/Akt signaling pathway. Three recent studies have identified and successfully validated protein-coding transcripts as PTEN ceRNAs in prostate cancer,[7] glioblastoma[9] and melanoma.[14] PTEN ceRNAs CNOT6L, VAPA and ZEB2 have been shown to regulate PTEN expression, PI3K signaling, and cell proliferation in a 3’UTR- and microRNA-dependent manner.[7][14] Similarly, in glioblastoma, siRNA-mediated silencing of 13 predicted PTEN ceRNAs including Retinoblastoma protein (RB1), RUNX1 and VEGFA downregulated PTEN expression in a 3’UTR-dependent manner and increased tumor cell growth.[9]

Additionally, PTEN’s non protein-coding pseudogene, PTENP1, is able to affect PTEN expression, downstream PI3K signaling and cell proliferation by directly competing for PTEN-targeting microRNAs.[8]

Pan-Cancer and CLIP-Seq-supported ceRNA regulatory networks[15] has been constructed and is available at http://starbase.sysu.edu.cn/, computational predicted ceRDB has been generated and is available at http://www.oncomir.umn.edu/cefinder/

Other validated ceRNA regulators

KRAS1P

Another pseudogene shown to have ceRNA activity is that of the proto-oncogene KRAS, KRAS1P, which increases KRAS transcript abundance and accelerates cell growth.[8]

CD44

The CD44 3’UTR has been shown to regulate expression of the CD44 protein and cell cycle regulation protein, CDC42, by antagonizing the function of three microRNAs - miR-216, miR-330 and miR-608.[16]

Versican

The versican 3’UTR has been shown to regulate expression of the matrix protein fibronectin via antagonizing miR-199a function.[17][18]

Linc-MD1

Linc-MD1, a muscle-specific long non-coding RNA, activates muscle-specific gene expression by regulating expression of MAML1 and MEF2C via antagonizing miR-133 and miR-135.[19]

HSUR 1, 2

T cells transformed by the primate virus Herpesvirus saimiri (HVS) have been shown to express viral U-rich noncoding RNAs called HSURs. Several of these HSURs are able to bind to and compete for three host-cell microRNAs and thus regulate host-cell gene expression.[20]

ESR1

ESR1 has been shown to be regulated by multiple miRNAs that are highly expressed in ER-negative breast cancer, and its 3' UTR was shown to regulate and be regulated by 3' UTRs of CCND1, HIF1A and NCOA3.[10]

Highly Up-regulated in liver cancer (HULC)

HULC is one of the most upregulated of all genes in hepatocellular carcinoma. CREB (cAMP response element binding protein) has been implicated in the upregulation of HULC.[21] HULC RNA inhibits miR-372 activity through a ceRNA function, leading to derepression of one of its target genes, PRKACB, which can then induce the phosphorylation and activation of CREB. Overall, HULC lncRNA is part of a self-amplifying autoregulatory loop in which it sponges miR-372 to activate CREB, and in turn upregulates its own expression levels.

BRAFP1

BRAFP1, the BRAF (gene) pseudogene, has been implicated in the development of cancer, including B-cell lymphoma, by acting as a ceRNA for BRAF. Upregulation of BRAFP1 led to an overexpression of the BRAF oncogene.[22]

See also

External links

References

  1. ↑ Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP (August 2011). "A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language?". Cell 146 (3): 353–8. doi:10.1016/j.cell.2011.07.014. PMC 3235919. PMID 21802130.
  2. ↑ Friedman, R. C. Farh, K. K. H. Burge, C. B. Bartel, D. P. (2009). "Most mammalian mRNAs are conserved targets of microRNAs". Genome Research 19 (1): 92–105. doi:10.1101/Gr.082701.108.
  3. ↑ Lewis, B. P. Burge, C. B. Bartel, D. P. (2005). "Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets". Cell 120 (1): 15–20. doi:10.1016/j.cell.2004.12.035. PMID 15652477.
  4. ↑ Cesana, M. Cacchiarelli, D. Legnini, I. Santini, T. Sthandier, O. Chinappi, M. Tramontano, A. Bozzoni, I. (2011). "A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA". Cell 147 (2): 358–69. doi:10.1016/j.cell.2011.09.028. PMC 3234495. PMID 22000014.
  5. ↑ Hansen, T. B. Jensen, T. I. Clausen, B. H. Bramsen, J. B. Finsen, B. Damgaard, C. K. Kjems, J. (2013). "Natural RNA circles function as efficient microRNA sponges". Nature 495 (7441): 384–388. Bibcode:2013Natur.495..384H. doi:10.1038/nature11993. PMID 23446346.
  6. ↑ Memczak, S. Jens, M. Elefsinioti, A. Torti, F. Krueger, J. Rybak, A. Maier, L. Mackowiak, S. D. Gregersen, L. H. Munschauer, M. Loewer, A. Ziebold, U. Landthaler, M. Kocks, C. le Noble, F. Rajewsky, N. (2013). "Circular RNAs are a large class of animal RNAs with regulatory potency". Nature 495 (7441): 333–338. Bibcode:2013Natur.495..333M. doi:10.1038/nature11928. PMID 23446348.
  7. 1 2 3 Tay Y., Kats L., Salmena L., Weiss D., Tan S.M., Ala U., Karreth F., Poliseno L., Provero P.; et al. (2011). "Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs". Cell 147 (2): 344–357. doi:10.1016/j.cell.2011.09.029. PMC 3235920. PMID 22000013.
  8. 1 2 3 Poliseno, L. Salmena, L. Zhang, J. Carver, B. Haveman, W. J. Pandolfi, P. P. (2012). "A coding-independent function of gene and pseudogene mRNAs regulates tumour biology". Nature 465 (7301): 1033–1038. Bibcode:2010Natur.465.1033P. doi:10.1038/nature09144. PMC 3206313. PMID 20577206.
  9. 1 2 3 Sumazin P., Yang X., Chiu H.-S., Chung W.-J., Iyer A., Llobet-Navas D., Rajbhandari P., Bansal M., Guarnieri P.; et al. (2011). "An extensive microRNA-mediated network of RNA-RNA interactions regulates established oncogenic pathways in glioblastoma". Cell 147 (2): 370–381. doi:10.1016/j.cell.2011.09.041. PMC 3214599. PMID 22000015.
  10. 1 2 Chiu, Hua-Sheng; Llobet-Navas, David; Yang, Xuerui; Chung, Wei-Jen; Ambesi-Impiombato, Alberto; Iyer, Archana; Kim, Hyunjae "Ryan"; Seviour, Elena G.; Luo, Zijun; Sehgal, Vasudha; Moss, Tyler; Lu, Yiling; Ram, Prahlad; Silva, José; Mills, Gordon B.; Califano, Andrea; Sumazin, Pavel (February 2015). "Cupid: simultaneous reconstruction of microRNA-target and ceRNA networks". Genome Research 25 (2): 257–67. doi:10.1101/gr.178194.114. PMID 25378249.
  11. ↑ Denzler, R. Agarwal, V. Stefano, J. Bartel, D. P. Stoffel, M. (2014). "Assessing the ceRNA hypothesis with quantitative measurements of miRNA and target abundance". Molecular Cell 54 (5): 766–776. doi:10.1016/j.molcel.2014.03.045.
  12. ↑ Bosson, AD Zamudio, JR Sharp, PA (2015). "Endogenous miRNA and target concentrations determine susceptibility to potential ceRNA competition". Mol Cell 56 (3): 347–359. doi:10.1016/j.molcel.2014.09.018.
  13. ↑ Luna, J.M. Scheel, T.KH. Danino, T. Shaw, K.S. Mele, A. Fak, J.J. Nishiuchi,E. Takacs, C.N. Catanese, M.T. de Jong, Y.P. Jacobson, I.M. Rice, C.M. Darnell, R.B. (2015). "Hepatitis C Virus RNA Functionally Sequesters miR-122". Cell 160 (6): 1099–1110. doi:10.1016/j.cell.2015.02.025.
  14. 1 2 Karreth F.A., Tay Y., Perna D., Ala U., Tan S.M., Rust A.G., DeNicola G., Webster K.A., Weiss D.; et al. (2011). "In vivo identification of tumor-suppressive PTEN ceRNAs in an oncogenic BRAF-induced mouse model of melanoma". Cell 147 (2): 382–395. doi:10.1016/j.cell.2011.09.032. PMC 3236086. PMID 22000016.
  15. ↑ Li, JH; Liu, S; Zhou, H; Qu, LH; Yang, JH (Dec 1, 2013). "starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data.". Nucleic Acids Research 42 (1): D92–7. doi:10.1093/nar/gkt1248. PMID 24297251.
  16. ↑ Jeyapalan Z., Deng Z., Shatseva T., Fang L., He C., Yang B.B. (2011). "Expression of CD44 3'-untranslated region regulates endogenous microRNA functions in tumorigenesis and angiogenesis". Nucleic Acids Research 39 (8): 3026–3041. doi:10.1093/nar/gkq1003. PMC 3082902. PMID 21149267.
  17. ↑ Lee D.Y., Jeyapalan Z., Fang L., Yang J., Zhang Y., Yee A.Y., Li M., Du W.W., Shatseva T.; et al. (2010). Najbauer, Joseph, ed. "Expression of versican 3'-untranslated region modulates endogenous microRNA functions". PLoS ONE 5 (10): e13599. Bibcode:2010PLoSO...513599L. doi:10.1371/journal.pone.0013599.
  18. ↑ Lee DY, Shatseva T, Jeyapalan Z, Du WW, Deng Z, Yang BB (2009). "A 3'-untranslated region (3'UTR) induces organ adhesion by regulating miR-199a* functions.". PLoS ONE 4 (2): e4527. doi:10.1371/journal.pone.0004527.
  19. ↑ Cesana M., Cacchiarelli D., Legnini I., Santini T., Sthandier O., Chinappi M., Tramontano A., Bozzoni I. (2011). "A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA". Cell 147 (2): 358–369. doi:10.1016/j.cell.2011.09.028. PMC 3234495. PMID 22000014.
  20. ↑ Cazalla D., Yario T., Steitz J.A. (2010). "Down-regulation of a host microRNA by a Herpesvirus saimiri noncoding RNA". Science 328 (5985): 1563–1566. Bibcode:2010Sci...328.1563C. doi:10.1126/science.1187197. PMC 3075239. PMID 20558719.
  21. ↑ Wang J., Liu X., Wu H., Ni P., Gu Z., Qiao Y., Chen N., Sun F., Fan Q.; et al. (2010). "CREB up-regulates long non-coding RNA, HULC expression through interaction with microRNA-372 in liver cancer". Nucleic Acids Res 38 (16): 5366–5383. doi:10.1093/nar/gkq285. PMC 2938198. PMID 20423907.
  22. ↑ Karreth, Florian A.; Reschke, Markus; Ruocco, Anna; Ng, Christopher; Chapuy, Bjoern; Léopold, Valentine; Sjoberg, Marcela; Keane, Thomas M.; Verma, Akanksha (2015-09-04). "The BRAF Pseudogene Functions as a Competitive Endogenous RNA and Induces Lymphoma In Vivo". Cell 161 (2): 319–332. doi:10.1016/j.cell.2015.02.043. ISSN 0092-8674. PMID 25843629.
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