Epigenetics and chromatin dynamics in cancer
My laboratory is interested to understand the mechanisms the regulate nucleolar functions at the level of chromatin and epigenetics.
The nucleolus is a distinct subnuclear compartment that was first observed more than 200 years ago in which takes place transcription of ribosomal RNA (rRNA) genes and the assembly of ribosomes. As an average mammalian cell can produce up to 10,000 ribosomes per minute, cells have to invest a very large portion of their own metabolic effort to meet demand from protein synthesis. To limit excessive energy consume to produce ribosomes, that could potentially deplete the cells from nutrients which are required for other essential processes, cells keep transcriptional activity of rRNA genes under tight surveillance. For example, conditions that harm cellular metabolism, downregulate rDNA transcription. Conversely, rDNA transcription is upregulated upon reversal of such conditions and by agents that stimulate growth. Transcription of rRNA genes is highly regulated through cell cycle and during cell differentiation and associated with accurate cell growth and proliferation. Disruption of this balance can lead to several pathologies, including cancer.
To produce elevated number of ribosomes, cells have to achieve synthesis of large amounts of rRNA. Indeed, synthesis of rRNA represents the major transcriptional activity of the cell, accounting for 60% of total transcription in rapidly growing yeast cells and 35% in proliferating mammalian cells. To do this, cells evolved a unique and efficient transcription system by using a specific and efficient RNA polymerase (RNA polymerase I, Pol I) and by amplifying the number of rRNA genes to hundreds or even thousands of copies per genome.
Epigenetics and chromatin structure of rRNA genes play a fundamental role in regulating transcription of rDNA locus. In each cell, a fraction of rRNA genes is transcriptional active while the rest is silent. Our results showed that these two classes of rRNA genes are distinct in terms of chromatin structure and epigenetics. We showed that a network of non coding RNA and histone and DNA modifier factors governed by the nucleolar remodeling complex NoRC leads to establishment of rDNA heterochromatic structure, thus leading to transcriptional silencing. We also showed that silencing of rRNA genes does not only affect rRNA synthesis and ribosome biogenesis but also genome stability.
The main focus of our research is to determine the role and the function of epigenetic and chromatin changes at the rRNA genes in terms of metabolism, nuclear and nucleolus architecture and genome stability. We are also investigating the mechanistic insights of how rDNA chromatin is modulated, when and in which cellular processes these changes occur and whether imbalance of correct rDNA chromatin can lead to pathologies.
Our research is currently sponsored by SNF and Mäxi-Stiftung.
Although there might be no immediate openings advertised here at this time, I am always interested in excellent applications from postdoctoral candidates who are keen to succeed in a competitive academic environment. Please send your documents (CV, publication list and research interests) directly to firstname.lastname@example.org
We recruit PhD students through the Life Science Zurich Graduate School, which offers various competitive graduate courses. Applications can be submitted twice a year using the official website.