Overview of Research Interests
My laboratory focuses on the fundamental biology of cellular quiescence. In nature, most cells exit the cell cycle and enter a non-dividing state. This is seen not only in microbes, which do not have constant access to nutrients, but also within multicellular organisms, such as memory lymphocytes and most stem cells in the human body. The mis-regulation of this transition can have catastrophic consequences, and is one of the hallmarks of cancer cells. However, the molecular mechanisms underlying quiescence are still poorly understood. How does a cell maintain quiescence? To what extent are quiescence-maintaining pathways conserved throughout evolution?
To tackle these questions, we use the fission yeast Schizosaccharomyces pombe as a main model organism. This system is ideally suited to investigating quiescent pathways using genetics, genomics and bioinformatics approaches. We have found that even known pathways, such as RNA interference, are reprogrammed in quiescent cells1-4, illustrating the hidden complexity of this state. We are now investigating several RNA-centric pathways which are required for maintaining viability specifically during quiescence, and which involve components conserved throughout eukaryotic evolution—from yeasts to mammals.
Current projects in the lab include:
- We have identified a conserved transcriptional complex that is responsible for maintaining basal levels of transcription in quiescence. Preliminary data strongly suggests that it acts at the level of RNA polymerase II initiation, and we are using genomic and biochemistry approaches to decipher its molecular mechanism. In contrast, we have also identified several repressive factors keeping the rest of the transcriptome dormant.
- We are also developing genomic techniques to facilitate the identification of new genes required to maintain quiescence, using dense transposon mapping (Tn-seq), as well as the identification of important quiescent non-coding RNAs, such as by developing derivatives of CHAR-seq (genome-wide identification of trans-acting ncRNAs).
1. Roche B, Arcangioli B, Martienssen R. RNAi is essential for cellular quiescence. Science, 2016.
2. Roche B, Arcangioli B, Martienssen R. Transcriptional reprogramming in cellular quiescence. RNA Biology, 2017.
3. Roche B, Arcangioli B, Martienssen R. New roles for Dicer in the nucleolus and its relevance to cancer. Cell Cycle, 2017.
4. Gutbrod MJ, Roche B, Steinberg JI, Lakhani AA, Chang K, Schorn AJ, Martienssen RA. Dicer promotes genome stability via the bromodomain transcriptional co-activator BRD4. Nature Communications, 2022.