In collaboration with Stoney Simons, I have developed a biophysical theory for steroid-mediated gene expression in the presence of various factors. Experiments have found that the dose-response curve for gene expression closely follows a first order Hill function and that factors can alter both the maximum value and location of half maximum of the function. We showed theoretically that this highly stringent constraint can only occur in a sequence of reactions if factors downstream of receptor-steroid binding interact weakly. The theory can then make precise predictions on the mechanisms and site of action of these cofactors. We used the theory to design a novel competition assay to predict the mechanisms and relative positions of the two cofactors and have applied it to several different factors. We are currently developing a theory for steroid-mediated gene repression. Thus far, we have validated our theory my making predictions on how cofactors should influence the amount of gene product produced. With my fellow Antoine Coulon, I have started a collaboration with NCI investigator Dan Larson to attempt to reconcile the theory with single cell imaging data.

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Budget End
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1
Fiscal Year
2012
Total Cost
$176,489
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Pradhan, Madhumita A; Blackford Jr, John A; Devaiah, Ballachanda N et al. (2016) Kinetically Defined Mechanisms and Positions of Action of Two New Modulators of Glucocorticoid Receptor-regulated Gene Induction. J Biol Chem 291:342-54
Lee, James J; Vattikuti, Shashaank; Chow, Carson C (2016) Uncovering the Genetic Architectures of Quantitative Traits. Comput Struct Biotechnol J 14:28-34
Chow, Carson C; Ong, Karen M; Kagan, Benjamin et al. (2015) Theory of partial agonist activity of steroid hormones. AIMS Mol Sci 2:101-123
Lenstra, Tineke L; Coulon, Antoine; Chow, Carson C et al. (2015) Single-Molecule Imaging Reveals a Switch between Spurious and Functional ncRNA Transcription. Mol Cell 60:597-610
Chow, Carson C; Finn, Kelsey K; Storchan, Geoffery B et al. (2015) Kinetically-defined component actions in gene repression. PLoS Comput Biol 11:e1004122
Stavreva, Diana A; Coulon, Antoine; Baek, Songjoon et al. (2015) Dynamics of chromatin accessibility and long-range interactions in response to glucocorticoid pulsing. Genome Res 25:845-57
Coulon, Antoine; Ferguson, Matthew L; de Turris, Valeria et al. (2014) Kinetic competition during the transcription cycle results in stochastic RNA processing. Elife 3:
Zhu, Rong; Lu, Xinping; Pradhan, Madhumita et al. (2014) A kinase-independent activity of Cdk9 modulates glucocorticoid receptor-mediated gene induction. Biochemistry 53:1753-67
Blackford Jr, John A; Brimacombe, Kyle R; Dougherty, Edward J et al. (2014) Research resource: modulators of glucocorticoid receptor activity identified by a new high-throughput screening assay. Mol Endocrinol 28:1194-206
Coulon, Antoine; Chow, Carson C; Singer, Robert H et al. (2013) Eukaryotic transcriptional dynamics: from single molecules to cell populations. Nat Rev Genet 14:572-84

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