I developed a biochemical model 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 Michaelis-Menten 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 have now augmented the theory to steroid-mediated gene repression and to explaining partial agonist and antagonist action. Thus far, we have validated our theory by making predictions on how cofactors should influence the amount of gene product produced. I am now collaborating with experimentalists to attempt to reconcile the theory with single cell imaging data. To do so, I have developed a stochastic single gene model that is consistent with the previous model. We are currently testing the applicability of the model to both single RNA molecule live cell and FISH data.
| Chow, Carson C; Simons Jr, S Stoney (2018) An Approach to Greater Specificity for Glucocorticoids. Front Endocrinol (Lausanne) 9:76 |
| Lee, James J; Vattikuti, Shashaank; Chow, Carson C (2016) Uncovering the Genetic Architectures of Quantitative Traits. Comput Struct Biotechnol J 14:28-34 |
| 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 |
| 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 |
| 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 |
| Chow, Carson C; Finn, Kelsey K; Storchan, Geoffery B et al. (2015) Kinetically-defined component actions in gene repression. PLoS Comput Biol 11:e1004122 |
| 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 |
| 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 |
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