Gene Regulatory Network Inference: In Silico Hypotheses and Experimental Validation
Description
The literature is replete with various approaches to extracting gene regulatory networks from
microarray profiling data. Although many of these methods have produced networks which appear
biologically plausible, based on circumstantial evidence from the literature, very little work has
been done on validating the model networks experimentally. In this paper we present new results
from a microarray time series study of adaptation to cold and successive re-adaptation to optimal
temperatures in E. coli. Model networks were inferred from the data using the variational Bayesian
state space modelling approach of Beal et al. (2005). Analysis of the biological implications of
these network models is still on-going, but preliminary analysis has already revealed some promising
novel biological hypotheses relating to the transcriptional response of bacterial cells adapting to
the temperature shift. Our model places a number of genes at the higher level of the hierarchy
(“hubs”) in the temperature shifted network, including hns and hybC. Encouragingly, the model
network reveal some of the known regulatory interactions in the literature. The model also indicates
that hns downregulates genes involved in aerobic metabolism and upregulates genes involved in
anaerobic metabolism. This immediately suggests the hypothesis that hns plays a key role in
regulating a switch between aerobic and anaerobic metabolism during the temperature adaptation.
The experimental verification of this hypothesis is extremely simple. The hns- mutant exhibits
the phenotype of growing at 10oC but stops growing if switched from 10oC to 37oC. Time series
microarray data collected from this mutant strain should directly address the question of whether
the expression of genes involved in aerobic/anaerobic metabolism during re-adaptation to 37oC is
dependent on the expression of hns. Regulatory interactions which are either confirmed or not
confirmed by this experiment will be used to define Bayesian priors for iterative retraining of the
state space model by including the time series data collected from the perturbed system. We
present results from a full cycle of this iterative procedure.
| Slides | |
| 0:00 | Gene Regulatory Network Inference: In Silico Hypotheses and Experimental Validation |
| 0:18 | Outline |
| 0:43 | Motivation and Background |
| 2:03 | Temperature adaptation in E. coli |
| 2:54 | A Gaussian State-Space Model with Feedback - part 1 |
| 3:43 | A Gaussian State-Space Model with Feedback - part 3 |
| 3:50 | A Gaussian State-Space Model with Feedback - part 4 |
| 4:36 | Our Approach - part 1 |
| 4:50 | Our Approach - part 2 |
| 5:01 | Our Approach - part 3 |
| 5:24 | Our Approach - part 4 |
| 5:28 | Our Approach - part 5 |
| 5:41 | Variational Bayesian Approach |
| 6:09 | Lower Bounding the Marginal Likelihood |
| 8:34 | Prior Specification |
| 9:45 | Incorporating Prior Information - 8 replicates |
| 10:52 | Experimental Setup |
| 11:15 | Experimental Setup |
| 12:28 | Principal Components Analysis |
| 13:17 | Functional Classification of Genes - Temperature Shifted Data |
| 14:07 | Gene Selection - Method of Tai and Speed |
| 15:10 | Inferred Network - Temperature Shifted Data |
| 15:47 | Regulatory Interactions in RegulonDB |
| 16:10 | Subset of Interactions - Temperature Shifted Data |
| 17:54 | Profiles of glpC and glpQ |
| 18:52 | Ongoing Work - part 1 |
| 18:55 | Profiles of glpC and glpQ |
| 19:11 | Principal Components Analysis |
| 19:30 | Subset of Interactions - Temperature Shifted Data |
| 19:50 | Ongoing Work - part 1 |
| 20:13 | Ongoing Work - part 2 |
| 20:26 | Subset of Interactions - Temperature Shifted Data |
| 23:27 | Conclusions - part 1 |
| 24:08 | Conclusions - part 2 |
| 24:19 | Acknowledgements - part 1 |
| 24:21 | Acknowledgements - part 2 |
| 24:35 | Acknowledgements - part 3 |
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