Sebastian Marquardt

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Languages of the Non-coding Genome

Genomes are the blueprints of life: the genomic DNA sequences contain the instructions for the formation of a given species. DNA sequence polymorphisms between individuals of the same species offer a hypothesis to understand the molecular bases of fitness differences. However, many polymorphisms are located in parts of the genome that we poorly understand: the non-coding genome. While polymorphisms that change the protein sequence offer a sufficiently clear path forward, my seminar outlines approaches and solutions to understand the non-coding genome.

Results from my laboratory illustrate different molecular mechanisms of how the non-coding genome promotes organismal fitness. We developed methods that reveal where the non-coding genome is transcribed by RNA polymerase II (Pol II) into RNAs. Here, a particular focus is on thousands of RNAs that are missed by many transcriptomics approaches even when located in important regions. While we find some cases of trans-acting RNAs, a common theme resulting from our functional characterization of specific non-coding loci is that the act of Pol II transcription explains the function of non-coding region, rather than the resulting RNA product. Essentially, chromatin-based signaling during Pol II transcription in the non-coding genome represses mRNA initiation when the transcription units overlap. Efforts to characterize non-coding RNA isoforms overlapping with genes involved a new class of non-coding RNAs: short promoter-proximal RNAs (sppRNAs). sppRNAs result from transcriptional termination at sites of promoter-proximal Pol II stalling and are positively correlated with gene expression. In conclusion, our results highlight different ways of how the non-coding genome communicates functional information, with intriguing implications for current models explaining non-coding genome conservation and function.