Jan M. Skotheim's Tenure talk @ Stanford February 2015
Lab research overview
Underlying the wonderful diversity of natural forms is the ability of an organism to grow into its appropriate shape. It is hard to imagine a mouse the size of a hippopotamus, and, indeed, the laws of physics and physiology will prevent it from attaining such a size without a severe change in form. The regulation of growth ensures that cells grow, divide and select a fate so that the organism and its constitutive parts are properly proportioned and of a size suitable for their function. Although the size-control mechanism active in an individual cell is of fundamental importance to this process, it is difficult to isolate and study in complex multi-cellular systems and remains mysterious.
Often free from the constraints imposed by communal living, unicellular organisms are governed by simpler psychology: proliferate rapidly whenever environmental conditions permit. Cell cycle control then insures that growth is coupled to division and that the genome is duplicated only once before being accurately partitioned into two nascent cells. We study size control in the model organism budding yeast, whose study has often revealed conserved mechanisms, shared by both yeasts and humans.
Size control in budding yeast has been attributed to the G1/S transition known as Start (network diagram shown below). In the last 30 years, advances in our understanding of the molecular details of the cell cycle have been remarkable and many of the genes involved in the G1/S transition have been identified. Yet, in spite of all this molecular detail a fundamental question remains unanswered: where in the sequence of molecular interactions does size control occur? How does a cell measure its own size?
Understanding the principles underlying genetic control circuits will be a central aim of biological research in the coming decade. These principles, when found, should provide a unifying framework for understanding disparate natural systems and aid in the design of robust synthetic circuits for medical and engineering purposes.
Previously, the bias of biological research has been toward the identification of novel genes and their interactions; i.e., the construction of networks consisting of nodes and arrows corresponding to genes and interactions respectively. Over the past decade, high-throughput genomic methods have greatly facilitated this line or research and quantitatively minded researchers have mined the newly expanded networks for their statistical properties. Yet, it is becoming increasingly clear that this is not enough. Not all arrows are equal and parameters determine system behavior. In other words, for the same network, varying the strengths of the interactions can radically affect dynamics and function. This is not surprising since even simple systems can be very sensitive to parameter values, in particular, if they are poised near a bifurcation. Therefore, the adequate characterization of a given circuit requires careful quantitative analysis.
We have chosen to make headway on this problem via the in-depth study of a natural circuit: the cell cycle. Our study revealed a novel function of positive feedback, which is likely to exist in other evolutionarily unrelated natural circuits. Hopefully, our result will also prove useful in synthetic circuit design.
An early success for the lab has been the identification of 'feedback first' regulation at the G1/S transition.
In budding yeast, commitment to cell division corresponds to activating the positive feedback loop of
G1 cyclins controlled by the transcription factors SBF and MBF. This pair of transcription factors has
over 200 targets, implying that cell-cycle commitment coincides with genome-wide changes in transcription.
Here, we find that genes within this regulon have a well-defined distribution of transcriptional
activation times. Combinatorial use of SBF and MBF results in a logical OR function for gene expression
and partially explains activation timing. Activation of G1 cyclin expression precedes the activation
of the bulk of the G1/S regulon, ensuring that commitment to cell division occurs before largescale
changes in transcription. Furthermore, we find similar positive feedback-first regulation in the
yeasts S. bayanus and S. cerevisiae, as well as human cells. The widespread use of the feedbackfirst
motif in eukaryotic cell-cycle control, implemented by nonorthologous proteins, suggests its
frequent deployment at cellular transitions.
This is discussed in detail in Umut's thesis defense 12/14/12 linked below