Backround and significance

Recent large-scale transcriptome studies revealed that a major portion of the genome is transcribed into ncRNAs that act as key regulators of cellular processes. In the nucleus, ncRNAs control chromatin structure, imprinting, dosage compensation and epigenetic reprogramming and may influence tumorigenesis. They also promote genomic stability by triggering heterochromatin formation and transcriptional silencing of repetitive DNA. Dysregulation of centromeric ncRNAs can result in chromosome missegregation and aneuploidy, and aberrant expression of telomeric ncRNAs causes telomere loss and chromosomal instability. Deciphering the function and cellular regulation of ncRNAs will hence be of utmost importance for understanding genome instability associated with aging and disease. In the cytoplasm, mi(cro)RNAs regulate translation or stability of up to one third of all mRNAs and thus participate in the control of virtually all cellular processes. Moreover, small ncRNAs can base-pair with viral RNA and influence host-virus interactions, and miRNA dysregulation is a hallmark of cancer. Neither the mechanisms how miRNAs assemble an RNAinduced silencing complex (RISC) and cause mRNA degradation, nor how they alternatively induce translational silencing are well understood.

 Further open questions are if and how RISC itself is regulated and where it acts in the living cell. Finally, the functions of most long ncRNAs remain obscure. Accordingly, ncRNA research has rapidly become an international top priority in academia and industry. A major focus is on application of ncRNAs either as tools for high-throughput genome- scale loss-of-function screening or as novel therapeutics for future clinical use in humans. Well-known examples include "The RNAi consortium" at MIT/Harvard that creates and distributes short hairpin RNA libraries, and the "RNA Therapeutics Institute" at the University of Massachusetts. In contrast, scientific centers focusing on the fundamental biology of ncRNAs are rare, although novel ncRNA classes and functions emerge almost on a daily basis. Of particular importance will be interdisciplinary efforts to unravel ncRNA biology at multiple levels - from the single ncRNA molecule via the active ribonucleoprotein complex to its dynamic localization and function in cells and organisms across major biological kingdoms.

CellNetworks and the Heidelberg campus are in an ideal position to fill this critical gap: First, they comprise a number of labs with long-standing expertise in RNA research. This includes the internationally renowned groups of Grummt and Hentze who are experts in transcription and translation, respectively, and have recently put a major focus on ncRNA research. Second, CellNetworks has implemented a series of core facilities that provide essential tools and support for ncRNA research, most notably, the RNAi screening facility, NIC, and the Deep Sequencing unit. Third, CellNetworks has recruited 2 new junior group leaders (Grimm and Maizel) focusing on ncRNA biology in humans and plants, and 1 new junior group leader (Erhardt), whose work on Drosophila centromeres includes the analysis of centromere- derived ncRNA. Their work is complemented by the additional junior investigators Stoecklin, Luke and Diederichs and the new CellNetworks professorship of Russell . Together with the core facilities and infrastructure in Z2 and Z3, these recruitments now provide an outstanding framework to pursue internationally competitive ncRNA research.