Below are some short summaries of a few interesting papers I've read recently. A while ago I was planning on writing detailed yet generally accessible summaries of a range of papers, which turned out to be wildly time consuming; reading the paper and writing myself notes is easy - writing an accurate yet accessible summary is incredibly hard!
Šarić, A., Chebaro, Y. C., Knowles, T. P. J., & Frenkel, D. (2014)
Crucial role of nonspecific interactions in amyloid nucleation
Proceedings of the National Academy of Sciences, doi:10.1073/pnas.1410159111
In this work, the authors construct a coarse grained model for aggregation and run Monte Carlo simulations at limiting cases to define classes of aggregation mechanisms. Really well written and clear paper, and I reached out to Dr. Saric with a question, which she responded to fully and rapidly. Great paper.
Gu, X., Cantle, J. P., Greiner, E. R., Lee, C. Y. D., Barth, A. M., Gao, F., … Yang, X. W. (2015)
N17 Modifies Mutant Huntingtin Nuclear Pathogenesis and Severity of Disease in HD BAC Transgenic Mice
Neuron, 85(4), 726–741.
Nice work from the Yang lab looking at a BACHD mouse model which lacks the first 17 residues (N17) of the Huntingtin protein, and shows that loosing this region causes an increase in disease severity and better models the human disease. Specifically this has implications for the role of N17 in disease. I was lucky enough to have lunch with Dr. Yang in March 2015 and we discussed this paper, and some of his other work - he was an extremely engaging and interesting, and they have some awesome results coming up in the next few years.
Bah, A., Vernon, R. M., Siddiqui, Z., Krzeminski, M., Muhandiram, R., Zhao, C., … Forman-Kay, J. D. (2014)
Folding of an intrinsically disordered protein by phosphorylation as a regulatory switch
Using several biophysical techniques (NMR and ITC), the authors show that full phosphorylation of a region of the 4E-BP2 protein causes the region to fold into a four strand beta sheet structure. Without phosphorylation, this region is disordered. In the disordered state, a binding site made up of a YXXXXLΦ motif is exposed an can interact with eIF4E. However, upon folding this site becomes hidden and the affinity of 4E-BP2 for eIF4E drops ~4000 fold. I spent much of the day with Julie Forman-Kay in November of 2015 - her more recent work on the sequence determinants of phase separation overlaps very nicely with my PhD work, and they have some incredibly cool results on the horizon.
Sanders, D. W., Kaufman, S. K., DeVos, S. L., Sharma, A. M., Mirbaha, H., Li, A., Diamond, M. I. (2014)
Distinct tau prion strains propagate in cells and mice and define different tauopathies
Neuron, 82(6), 1271–1288.
In this work, Sanders and Kaufman explore the prion-like behavior of the tau protein, and, crucially, show that different types of tauopathies (diseases associated with tau aggregation) appear to explicitly have distinct tau structural strains associated with them. This strongly implicates a specific disease-to-structure mapping. This is going to be a pretty important paper (historically) in the prion/neurodegeneration field.
Weatheritt, R. J., Gibson, T. J., & Babu, M. M. (2014)
Asymmetric mRNA localization contributes to fidelity and sensitivity of spatially localized systems
Nature Structural & Molecular Biology 21(9), 833–839.
The authors demonstrate here how cellular localization can be archived by moving proteins around, or by moving mRNA and having it translated at distal locations. The authors find that proteins with disordered regions are preferentially transcribed at distal locations, and those distally translated proteins show distinct temporal regulation motifs.
Süel, G. M., Garcia-Ojalvo, J., Liberman, L. M., & Elowitz, M. B. (2006)
An excitable gene regulatory circuit induces transient cellular differentiation
Nature, 440(7083), 545–550.
One of two important papers examining how B. Subtilis carries out the switch into its competent state during the early part of stationary-phase growth. Specifically, this paper teases apart the regulatory network through a number of beautiful experiments showing correlation/anti-correlation in protein levels as predicted by feedback and feedforward networks in the regulatory system. An absolute classic in the dynamical systems world.
Maamar, H., Raj, A., & Dubnau, D. (2007)
Noise in gene expression determines cell fate in Bacillus subtilis
Science, 317(5837), 526–529.
This is an awesome paper. Basically, the authors show how stochastic noise at the transcription level defines a window in time whereby a fraction of cells in a B. subtilis population are competent. Specifically by having a low copy number of mRNA for key feed-forward components in the competence gene regulation network, stochastic behavior coupled to burst transcription facilitates bet-hedging behavior in a defined fraction of the population of cells in a well defined time window, effectively maximizing the populations ability to search the 'survival landscape' (as an analogy to the energy landscape).
Choi, P. J., Cai, L., Frieda, K., & Xie, X. S. (2008)
A stochastic single-molecule event triggers phenotype switching of a bacterial cell
Science, 322(5900), 442–446.
The lac operon is one of the first (if not the first) metabolic regulation system to be studied in E. coli. E coli are able to utilize lactose (a type of sugar) through a well tuned regulatory system. This paper involves using single molecule imaging to image individual lac-permease molecules and determines that in intermediate lac-inducer levels (TMG) the distribution of cells shows a strong biomodality (lac-operon on and lac-operon off). Further, the authors identify a threshold number of permease molecules needed to commit to the on state, and reconcile that surprisingly large threshold with previously made observations which suggest that this switching behavior depends on a small number of permease molecules. This reconciliation is based on the mode by which the lac repressor binds to the lac operon, and the authors propose a very neat model involving stochastic complete dissociation of the lac-repressor combined with a concentration dependent sequestration of the lac repressor, increasing the length of transcriptional bursts, but not their frequency.
Yoo, T. Y., Meisburger, S. P., Hinshaw, J., Pollack, L., Haran, G., Sosnick, T. R., & Plaxco, K. (2012)
Small-angle X-ray scattering and single-molecule FRET spectroscopy produce highly divergent views of the low-denaturant unfolded state
Journal of Molecular Biology, 418(3-4), 226–236.
There continues to be a debate in the field of protein folding biophysics with respect to how proteins undergo compaction from an expanded (denatured) state to a collapsed globular (folded) state. SAXS data suggests this is a first order transition (i.e. you're either expanded or collapsed) while FRET data indicates it's a continuos transition allowing intermediate states. In this paper a number of important players in this discussion come together to redo the SAXS experiments in methods/conditions much more similar to the smFRET experiments for the collapse of protein L. The authors still find a consistent difference, and have a nice, open discussion regarding origins and implications of this difference.
Acar, M., Becskei, A., & van Oudenaarden, A. (2005)
Enhancement of cellular memory by reducing stochastic transitions
Nature, 435(7039), 228–232.
After cell division there is often some sort of cellular memory, which can be thought of as some deviation from Markovian behavior into two or more distinct states. In this paper, the authors examine the GAL regulatory system and consider how various network motifs within that gene regulatory system (feed forward and feed backwards) contribute towards cellular memory. Although at times this paper is a little hard read it's a really neat analysis, and raises some ideas in cellular memory which I feel like could be leveraged in other systems (e.g. signal transduction, other regulatory networks, etc.)
Nevozhay, D., Adams, R. M., Murphy, K. F., Josić, K., & Balázsi, G. (2009)
Negative linearizes the dose–response and suppresses the heterogeneity of gene expression
Proceedings of the National Academy of Sciences, 106(13), 5123–5128.
Genetically identical cells can behave differently. This different behavior may be due to intrinsic noise (noise which is fundamental to the process occurring) or extrinsic noise (noise coming from environmental factors). Noise in gene expression can be both good and bad. Negative feedback can reduce noise. Using a TetR system in yeast, the authors observe that noise peaks during intermediate levels of components in the negative feedback loop, but is low at very low or very high levels of repression. The authors propose a stochastic model which recapitulates experimental data with almost uncanny accuracy.
Elowitz, M. B., & Leibler, S. (2000)
A synthetic oscillatory network of transcriptional regulators
Nature, 403(6767), 335–338.
Kind of a paper that everyone in computational/theoretical biology should have read - the original three component synthetic circuit. Pretty cool stuff!
Taniguchi, Y., Choi, P. J., Li, G.-W., Chen, H., Babu, M., Hearn, J., … Xie, X. S. (2010)
Quantifying E. coli Proteome and Transcriptome with Single-Molecule Sensitivity in Single Cells
Science, 329(5991), 533–538.
This paper is basically single molecule imaging of the entire E. coli proteome to determine proteomic copy number across all proteins. This is an unbelievably huge volume of work. Beyond just this, the authors go on to correlate noise with copy number, fit protein copy number to a specific distribution, and a range of other cool analysis.
Golding, I., Paulsson, J., Zawilski, S. M., & Cox, E. C. (2005)
Real-time kinetics of gene activity in individual bacteria
Cell, 123(6), 1025–1036.
This is a beautiful paper - the authors carry out single molecule imaging of real-time transcription and translation facilitating a pretty impressive and comprehensive analysis of stochastic cellular behavior, transcriptional bursting, variation between cells, and randomness of RNA partitioning during cell division, all of which are tackled using a combination of experiment and theory. Really neat work.