March 21, 2012 § Leave a comment
Signals and transcription: a view from the binding site, with thoughts on the informatics of patterning
23 Mar 2012
Department of Cell and Developmental Biology
University of Michigan Medical School
A handful of ancient cell-cell signaling pathways, whose function is purely informational, are major determinants of developmental pattern, organogenesis, stem cell fates, and cancer (which can be considered a disease of misinformation). These signal transduction pathways, including Hedgehog, Wnt, Notch, and RTK/Ras/MAPK, act primarily by regulating specific transcription factors (TFs), which bind to specific DNA sequences within enhancers of pathway target genes and control their expression.
Our lab tries to understand the cell’s response to signaling by dissecting and decoding the cis-regulatory DNA of signal-regulated enhancers. In this chalk talk, several questions will be addressed (but probably not answered):
• Where is the complexity in the animal genome? (Hint: it’s not in the number of genes.)
• What is the information content of a single TF binding site?
• Do different TFs in various organisms carry different amounts, or distinct types, of patterning information?
• Does the enhancer really “integrate” patterning information from multiple TFs, and if so, how does this computation physically occur?
TL schedule here.
March 15, 2012 § Leave a comment
Spatial patterning of proteins at the single cell level
16 Mar 2012, WAB563, 12-1.30pm
Department of Molecular Genetics
Ohio State University
Many cells must segregate proteins to distinct areas of the cell in order to function properly, for instance when polarizing for directed motility or asymmetric cell division. However, many of these protein domains are not separated by a physical barrier and since diffusion would easily defeat any asymmetry on a cellular scale, there must be some active process or interaction that is maintaining these domains. In honour of The Alan Turing Year, I will discuss the conceptual basis of several theoretical models that have been proposed to investigate protein segregation and pattern formation on the cellular scale, including Turing’s morphogenesis model. I will open the discussion further to include the potential role of mechanical elements such as microtubules or the actin cytoskeleton as well as intercellular communication in establishing and maintaining distinct protein domains.
TL schedule here
March 1, 2012 § Leave a comment
Network and state space models: science and science fiction approaches to cell fate predictions
2 Mar 2012, 12-1.30 pm, WAB563
Computational Biology and Functional Genomics Laboratory
Dana Farber Cancer Institute and Harvard School of Public Health
Two trends are driving innovation and discovery in biological sciences: technologies that allow holistic surveys of genes, proteins, and metabolites and a realization that biological processes are driven by complex networks of interacting biological molecules. However, there is a gap between the gene lists emerging from genome sequencing projects and the network diagrams that are essential if we are to understand the link between genotype and phenotype. ‘Omic technologies were once heralded as providing a window into those networks, but so far their success has been limited, in large part because the high-dimensional they produce cannot be fully constrained by the limited number of measurements and in part because the data themselves represent only a small part of the complete story. To circumvent these limitations, we have developed methods that combine ‘omic data with other sources of information in an effort to leverage, more completely, the compendium of information that we have been able to amass. Here we will present a number of approaches we have developed, with an emphasis on how those methods have provided insights into the role that particular cellular pathways play in driving differentiation, and the role that variation in gene expression patterns influences the development of disease states. Looking forward, we will examine more abstract state-space models that may have potential to lead us to a more general predictive, theoretical biology.
Current TL schedule here.
February 22, 2012 § Leave a comment
Perturbation Biology of Cancer Cells
Computational Biology Program
Sloan Kettering Institute
24 Feb 2012, 12-2pm, Warren Alpert 563 – HMS
In analogy to perturbation experiments in physics, one can systematically perturb cells, measure their molecular response and computationally infer predictive network models. When applied to cancer cells, such systems biology models can lead to the design of promising combinatorial therapies.
TL schedule here.
February 15, 2012 § Leave a comment
Optimality in the development of intestinal crypts
17 Feb 2012, 12-2pm, Warren Alpert 563 – HMS
Intestinal crypts in mammals are comprised of long-lived stem cells and shorter-lived progenies, maintained under tight proportions during adult life. Here we ask what are the design principles that govern the dynamics of these proportions during crypt morphogenesis. We use optimal control theory to show that a stem cell proliferation strategy known as a “bang-bang” control minimizes the time to obtain a mature crypt. This strategy consists of a surge of symmetric stem cell divisions, establishing the entire stem cell pool first, followed by a sharp transition to strictly asymmetric stem cell divisions, producing non-stem cells with a delay. We validate these predictions using lineage tracing and single molecule fluorescent in-situ hybridization of intestinal crypts in newborn mice and find that small crypts are entirely composed of Lgr5 stem cells, which become a minority as crypts further grow. Our approach can be used to uncover similar design principles in other developmental systems.
TL schedule here.
February 10, 2012 § Leave a comment
Yes, it’s that happy time of year. The cycle of the seasons has turned the corner and the days are getting longer again. To add to your feeling of light and happiness, TL is back. Join us this week for:
Center for Complex Network Research
TODAY, 10 Feb 2012, 12:00-2.00pm
Warren Alpert 563 – HMS
The ultimate proof of our understanding of biological or technological systems is reflected in our ability to control them. While control theory offers mathematical tools to steer engineered and natural systems towards a desired state, we lack a framework to control complex self-organized systems. Here we develop analytical tools to study the controllability of an arbitrary complex directed network, identifying the set of driver nodes whose time-dependent control can guide the system’s entire dynamics. We apply these tools to several real networks, finding that the number of driver nodes is determined mainly by the network’s degree distribution. We show that sparse inhomogeneous networks, which emerge in many real complex systems, are the most difficult to control, but dense and homogeneous networks can be controlled via a few driver nodes. Counterintuitively, we find that in both model and real systems the driver nodes tend to avoid the hubs.
In collaboration with Y Liu and JJ Slotine.
Y Y Liu, J J Slotine, L Barabási, “Controllability of complex networks”, Nature 473:167-73 2011. PubMed
TL schedule here.
February 7, 2012 § Leave a comment
Anna Anderson (Paulsson lab)
Is stochastic degradation a substantial source of cellular heterogeneity?
12:30pm TODAY, February 7th
January 10, 2012 § Leave a comment
This course offers an intensive and critical analysis of systems approaches to circuits and principles controlling pattern formation and morphogenesis in animals. Students develop their own ideas and present them through mentored “chalk talks” and other interactive activities.
Taught by Marc Kirschner, Sean Megason and Angela DePace
Tu/Th 2-3.30, Warren Alpert (HMS) 436.
January 5, 2012 § Leave a comment
Plan ahead for the pizza talk next Tuesday, 01/10/2012:
Ilan Wapinski (Springer/Kishony Labs)
“Better together: complex environments enhance the growth of diverse genotypes”
Goldenson 122, 12.30 pm.
December 15, 2011 § Leave a comment
Yeep, I am late with this. Here you go:
Actomyosin spatiotemporal organization and rigidity sensing in spreading cells
Friday, 16 Dec 2011, 12-1.30, Warren Alpert 563
Sheetz Group, Department of Biological Sciences
Cell sensing of substrate rigidity is a critical function in both unicellular and multicellular organisms, and its breakdown is associated with many diseases. Here, I suggest that two recent discoveries in mammalian fibroblasts: 1) protrusion-retraction cycles of roughly 20s, accompanied by large-scale lateral waves at the leading edge on continuum substrates, and 2) a local contraction unit on micron scale able to generate constant displacements of elastomer pillars independent on the their stiffness, are two aspects of the same mechanism the cell uses during early spreading to sense substrate rigidity. Force map movies on pillars show protrusion-retraction cycles corresponding to organization of local contractions in a characteristic pattern along the cell leading edge. I will describe live images, with seconds and submicron resolution, in which fluorescent myosin, alpha-actinin, and different focal adhesion proteins display spatiotemporal correlations between their concentrations and the forces applied on pillars, suggesting alpha-actinin as a major force bearing protein. Taken all together these results suggest that the full dynamics of a spreading cell is given by the combined effect of local contractions on micron scale along the cell edge, and coupling of focal adhesion complexes with the actin rearward flow, which takes place on a larger space scale.
G Giannone, B J Dubin-Thaler, O Rossier, Y Cai, O Chaga, G Jiang, W Beaver, H G Dobereiner, Y Freund, G Borisy, M P Sheetz, “Lamellipodial actin mechanically links myosin activity with adhesion-site formation”, Cell, 128:561-75 2007. PubMed
TL schedule here