Keith Cheveralls ’09, Daniel Beller ’10, and Netta Engelhardt ’11 awarded NSF Graduate Research Fellowships

Former physics majors Keith Cheveralls ’09 and Daniel Beller ’10 and current physics major Netta Engelhardt ’11 have been awarded the prestigious National Science Foundation Graduate Research Fellowship. The fellowship recognizes and supports outstanding graduate students in the US who have demonstrated exceptional promise in science research. Keith is currently a first year graduate student at UC Berkeley; while at Brandeis he did his senior thesis with Professor Jane Kondev and was a co-author on a paper that appeared last year in the Proceedings of the National Academy of Sciences. Dan, a first year graduate student at the University of Pennsylvania, completed his senior thesis at Brandeis with Professor Zvonimir Dogic and Professor Robert Meyer.  Currently, Dan is conducting research on liquid crystals in the group of Professor Randall Kamien at UPenn. Netta is currently doing her senior thesis with Professor Matthew Headrick, and is planning to attend graduate school in physics next year.

Molecular mechanisms of noisy transcription

In a recently published paper “Effect of promoter architecture on the cell-to-cell variability in gene expression” in PLoS Computational Biology, Alvaro Sanchez and co-workers investigated how the architecture of a model promoter region (characterized by number of transcription factor binding sites, the binding affinity and spacing on the DNA) affects the way in which individual cells respond to environmental stimuli. In particular, they examine, using stochastic chemical kinetics, how the intrinsic randomness in the binding and unbinding of transcription factors to their binding sites generates cell-to-cell differences in transcript and protein levels within a population. The analysis uses a combination of computational modeling and analytical mathematical methods. Sanchez, a recent Ph.D. graduate in Biophysics and Structural Biology performed this work with Jané Kondev (Physics), and in collaboration with Rob Phillips, Hernan Garcia and Daniel Jones (Caltech).

While previous population-average models explained well how promoter architecture affects the average response of a population of cells to changes in the concentration of transcription factors, the question of how the response of individual cells is determined by promoter region sequence remains generally unsolved and limited to simplified coarse-grain models. By way of an example, the authors of this study investigated the effect of cooperative binding between transcription factors in the level of variability in the transcriptional response to increasing concentrations of those factors. It is well known that cooperativity in gene regulation increases the sensitivity of the response of the promoter to changes in the intracellular concentration of transcription factors, leading to a switch-like response. By examining this architecture, Sanchez and co-workers found that cooperativity is also a source of large intrinsic cell-to-cell variability in gene expression: larger sensitivity comes accompanied with larger variability (even if all cells contain the exact same amount of repressor).

This investigation continues a collaboration between theorists at Brandeis and experimentalists at Caltech, which aims to connect the biochemical, molecular understanding of transcriptional regulation coming from in vitro biochemical experiments (which are also being done in the Gelles lab at Brandeis) with the phenotypic behavior of individual cells as determined by gene expression measurements in single live cells. Many of the predictions of this computational study are currently being tested in Rob Phillips’ lab.

 

Bouncy, sticky, slimy chemistry

Susannah Gordon-Messer, a graduate student in the Biophysics and Structural Biology Ph. D. program, talks about her experiences with science outreach in an article in NSF Discoveries. Her work with the Discovery Museums in Acton was supported as part of a training grant awarded to Brandeis by NSF’s IGERT program.

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