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?Alternate Interactomes
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By xerro five, Section Biology
Posted on Fri Apr 30th, 2010 at 11:39:26 PM PST
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Based on the recent publication, The Genetic Landscape of a Cell, and other similar studies, a lot of information is currently known about the basic "wiring" of molecular pathways leading to cellular function. Interaction maps such as the one produced for yeast by this paper are great descriptions of how a cell lives in controlled laboratory environments, but relatively less is known about compensatory pathways that could arise as a result of environmental change. It will be possible to take advantage of the existing data on standardized condition pathways as a control so as to discover any new interactions that become active in a modified environment. In light of this publication creating the most detailed interaction map for any organism to date, and the relative ease of use, let's begin with manipulation of yeast cells for this experiment. This type of analysis is something that Costanzo et al hint at a few times in their paper.
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At the gene interaction level, new pathways could be opened up based on concentration effects (where a DNA binding protein will occupy weaker sites when the concentration becomes high enough as is seen in phage T4 promoters) expression of new transcription factors that can establish a new set of genes that an activator will bind (or environmental cofactors that fulfill a similar role), or perhaps newly interacting pathways (as described below) could show up as being co-ordinately regulated under the new conditions rather than separately (i.e. they would show up in a cluster together) just to name a few possibilities.
If studying this at the protein network level, then examples of what may be seen in these new networks could be proteins participating in another pathway based on either expression of new genes that draws the protein away from an original pathway based on either higher quantity or affinity, expression (or degradation) of the individual protein changing such that there is enough to "leak" into the new pathway whereas there was not enough previously in a concentration-dependant manner, or allosteric modification of multi-functional proteins. At the broader level, pathways could be re-organized to interact with new pathways based on products, intermediates, etc.
Approach:
The following applies to analysis at the gene level. Although this would be ultimately most informative at the genome-wide scale, the feasibility of looking at numerous environmental conditions in such a manner seems quite low given how much work it was to produce the current model under standardized conditions. Therefore, perhaps focusing on a subset of basal pathways or ones that may seem likely to undergo interaction changes in response to environment (based on what we know from Costanzo et al's network) may be the best approach. A similar strategy could be used to select the environmental conditions to establish good combinations of both. Then, a synthetic genetic array (SGA) methodology (very similar to Costanzo et al's work) could be used to test the pairwise interactions of the determined subset of genes under each of the determined subset of environmental conditions. The number of genes and conditions will obviously depend on each other; if looking at more genes, then fewer conditions will be possible, and the conditions will be the limiting factors as they basically multiply the comparisons needed across all genes used.
The genetic landscape of a cell.
Costanzo M, Baryshnikova A, Bellay J, Kim Y, Spear ED, Sevier CS, Ding H, Koh JL, Toufighi K, Mostafavi S, Prinz J, St Onge RP, VanderSluis B, Makhnevych T, Vizeacoumar FJ, Alizadeh S, Bahr S, Brost RL, Chen Y, Cokol M, Deshpande R, Li Z, Lin ZY, Liang W, Marback M, Paw J, San Luis BJ, Shuteriqi E, Tong AH, van Dyk N, Wallace IM, Whitney JA, Weirauch MT, Zhong G, Zhu H, Houry WA, Brudno M, Ragibizadeh S, Papp B, Pál C, Roth FP, Giaever G, Nislow C, Troyanskaya OG, Bussey H, Bader GD, Gingras AC, Morris QD, Kim PM, Kaiser CA, Myers CL, Andrews BJ, Boone C.
Science. 2010 Jan 22;327(5964):425-31. |
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