We propose to integrate the research potential, expertise, and infrastructure of three research groups working in the fields of biology, chemistry, physics and computer science, in order to develop new interdisciplinary approaches to study the function and regulation of the transcriptome. Technology development in the post-genomic era challenged many established dogmas of gene expression. Recent data from the second-generation sequencing surprisingly showed that almost the entire human genome is transcribed and biochemically active. This pervasive transcription yields non-coding transcripts that have regulatory roles as they control gene expression and their improper function leads to genetic disorders or human diseases. Understanding the role and function of these non-coding RNA regulators is naturally the next challenge of biology, medicine and many other fields. The biogenesis and cellular function of non-coding RNAs are very difficult to capture as it involves characterization of many transient and weak interactions. However, our pilot studies, which were recently published in Cell (IF=32.4) and Genes and Development (IF=11.7), showed possibilities how these interactions could be studied. There is currently no systematic approach that would be able to grasp these complex mechanisms. Therefore, we need to develop new approaches based on the single-molecule analysis and characterization of transient interactions. Our new approach will be based on a combination of NMR, atomic force microscopy (AFM) combined with Raman spectroscopy, small-angle X-ray scattering (SAXS), molecular modeling, bioinformatics, and massive computing power. Integration of these interdisciplinary approaches will create a new methodology, which will be used in the future by us and other laboratories to decipher the complex regulatory network of the transcriptome. As these regulatory mechanisms have clear implications for human health, we anticipate that our newly developed methodology will contribute to discoveries of new biochemical pathways that could be used to design new strategies for treatment of human diseases.

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