Gene expression is controlled at many levels, including by mRNA regulation. Whether a particular mRNA is translated, repressed, or degraded, depends on its interactions with a variety of RNA-binding proteins (RBPs) and regulatory RNAs, which in turn recruit diverse co-factors. Our interest is in elucidating the molecular mechanisms by which conserved RBPs control mRNA fate. We are also interested in explaining how these mechanisms influence fundamental biological processes explained below.
Cellular reprograming is fundamental for development and tissue homeostasis. A profound developmental reprograming occurs during the transition from a differentiated germ cell to a pluripotent embryo. This reprograming is critical for the formation of a new individual and for the life cycle to continue. In the past, we demonstrated a critical role for both epigenetic and cytoplasm-based, posttranscriptional mechanisms, in controlling developmental reprograming. In addition to this line of research, we became interested in metabolic reprograming, which we study in the context of obesity and adaptation to extreme cold, with important biomedical implications.
The molecular mechanisms underlying cell fate commitment and reprograming are at the heart of all developmental decisions. Arguably, the most spectacular reprograming of all takes place during reproductive (germ) cell development, which is why germ cells and various pluripotent cell lines derived from them have been invaluable for dissecting the mechanisms controlling developmental plasticity, or pluripotency. The little worm C. elegans represents a convenient model system to dissect and understand the mechanisms of this phenomenon which is widespread in the animal world.
Rafal Ciosk’s lab demonstrated that pluripotency in germ cells is notably controlled by posttranscriptional regulation, mediated by GLD-1, a member of the STAR family of RBPs. They also observed that a premature acquisition of pluripotency in the germline is accompanied by the onset of embryonic genome activation (EGA). This finding prompted us to use the precocious onset of EGA in germ cells as the readout to identify novel regulators of pluripotency. In an unbiased genetic screen, they identified several mutants in which EGA occurs precociously in the germline. These mutants fall into two types.
Type A mutants that induce EGA and eventually form a teratoma. They found that mutations in LIN-41 are responsible for the EGA and teratoma formation in the type A mutants. This gene had been previsouly identified as a member of the so-called “heterochronic” pathway, which controls the timing of developmental transitions in the soma. The RNA binding protein LIN-41 is a member of the TRIM-NHL protein family and the tharget of the let-7 miRNA. Rafal Ciosk’s team’s results thus show that LIN-41 controls the timing of developmental transitions in both the soma and the germline. Their structure-function studies however suggest that it mediates these two processes via different mechanisms. Their future goal is to dissect the precise molecular mechanism and relevant mRNA targets of LIN-41.
Type B mutants induce EGA but do not form a teratoma. Thus, in these mutants, EGA is uncoupled from the subsequent teratomatous differentiation observed in the gld-1 and lin-41 mutants, giving them a molecular handle on dissecting the hierarchy of events underlying the reprograming of germ cells into pluripotency. So far, they have identified one gene that, when mutated, results in this phenotype and the future research will be directed toward understanding the molecular mechanisms involved.
Thus far, Rafal Ciosk’s research uncovered players of pluripotency regulation which are cytoplasmic repressors. Through dissecting their targets, he is working towards understanding how they control reprogramming. To complement this approach, he is conducting screens for EGA activators and expects to identify factors ‘downstream’ from GLD-1 and LIN-41, potentially directly involved in the transcriptional remodeling in the nucleus. If successful, this approach will provide us, for the first time in any animal, with a complete picture of the pathway controlling pluripotency during the oocyte-to-embryo transition.
This is of major interest for developmental biology and pluripotency research, with potential implications for regenerative medicine.
Dernière mise à jour : 31 juillet 2014
• 1995 M.Sc. in Molecular Biology and Biotechnology, University of Szeged, Hungary
• 1998 Ph.D. in Genetics, Institute of Molecular Pathology, Vienna, Austria, Kim Nasmyth's lab
• 1999 Post-doctoral Fellow, Institute of Molecular Pathology, Vienna, Austria, Kim Nasmyth's lab
• 2000-2005 Post-doctoral Fellow, Fred Hutchinson Cancer Research Center, Seattle, USA, James Priess' lab
• 2006-2012 Junior Group Leader, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
• 2012 Senior Group Leader
• The Leukemia and Lymphoma Society, Special Fellow Award, 2005-08
• Human Frontier Science Program Postdoctoral Fellowship, 2000-2003
• Amersham Pharmacia Biotech & Science Magazine Prize for Young Scientists, 2000
Nov 2016, Dev Cell