Helmholtz University Junior Research Group Molecular RNA Biology and Cancer
Dr. Sven Diederichs
Recent insights into RNA biology induced a paradigm shift towards the recognition of RNAs as functionally important molecules - beyond serving as messengers for protein-encoding genes. A large fraction of the human genome is transcribed into RNA (up to 70%), while only 2% are protein-encoding. Non-protein-coding RNAs execute important functions in the cell. Very short non-coding RNAs, the microRNAs, play important roles in gene regulation. The tumor-suppressive or oncogenic role of many microRNAs and their frequent deregulation in tumors allow a first glimpse of the striking role that non-coding RNAs could play in cancer. Novel long non-coding RNAs (ncRNA, lncRNA, lincRNA) fulfill important functions in epigenetic regulation, chromatin remodeling or splicing. Taken together, the human cell contains many more RNAs than previously anticipated and many of them might just await their discovery as functionally important molecules in cancer.
Our research focuses on two classes of non-coding RNAs:
1) microRNAs are short RNAs which regulate the expression of specific target genes. We elucidate the microRNA biogenesis pathway as well as regulatory steps therein including the regulation of microRNA biogenesis factors.
2) As a new and innovative research area, we analyze long non-coding RNAs and their role in cancer. After profiling the expression of thousands of ncRNAs in three tumor entities, we elucidate the cellular and molecular functions of differentially regulated ncRNAs in cancer.
microRNAs are short, single-stranded RNA molecules which regulate the expression of specific target genes. In complex with Argonaute proteins (RISC = RNA Induced Silencing Complex), microRNAs bind to complementary mRNAs and lead to their degradation, destabilization or block of translation and hence inhibit the expression of the targeted gene. The microRNA expression profiles in tumors are frequently altered, thus inducing or reducing respectively expression of their target gene. If the target gene is an oncogene and the microRNA is lost in human tumors, the oncogene would be activated and the microRNA would function as a tumor suppressor gene. One prominent example for such a pair is the microRNA let-7 which is downregulated in lung cancer and targets the well-known oncogene Ras. Our research group elucidates the mechanisms underlying regulation and processing of microRNAs and analyses their dysregulation in human tumors. One focus is the regulation of microRNA stability, the selection of the microRNA guide strand as well as the function and regulation of the Argonaute proteins.
As a new thriving research area, we analyze long non-coding RNAs (ncRNA) and their role in cancer. After profiling the expression of thousands of ncRNAs in three tumor entities – lung, liver and breast cancer – we now elucidate the cellular and molecular function of differentially regulated ncRNAs in cancer using innovative techniques like Zinc Finger Nucleases and RNA Affinity Purification.
Winter, J.; Jung, S.; Keller, S.; Gregory, R.I.; Diederichs, S. (2009). Many roads to maturity: microRNA Biogenesis pathways and their regulation. Nat. Cell Biol., 11, 228-234
Diederichs, S.; Jung, S.; Rothenberg, S.M.; Smolen, G.A.; Mlody, B.G. & Haber, D.A. (2008). Coexpression of Argonaute-2 enhances RNA interference toward perfect match binding sites. Proc. Natl Acad. Sci. U.S.A., 105, 9284-9289
Diederichs, S. & Haber, D.A. (2007). Dual role for Argonautes in microRNA processing and posttranscriptional regulation of microRNA expression. Cell, 131, 1097-1108
Gutschner T, Baas M, Diederichs S: "Non-coding RNA gene silencing through genomic integration of RNA destabilizing elements using zinc finger nucleases" Genome Research (2011) 21: 1944-1954