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To provide mechanistic insights into transcriptional regulation, a couple of groups have recently presented thermodynamic-based models relating transcription factors (TFs)' binding of promoter DNA to downstream gene's transcript level (amount). However, TFs are not the only factors binding to promoters; other DNA binding factors (DBFs) bind as well, especially nucleosomes. Moreover, the nucleosomes influence not only TF binding probabilities, but also the structure of DBF binding configurations on promoter, like Nucleosome Free Region (NFR).

Here, we propose a model to predict transcript production rates or levels from genes' promoter occupancy profiles, and apply it to two types of problems. The promoter occupancy profile is produced by COMPETE, a software package implementing a model of continuous DNA binding that considers competition by diverse DBFs at given concentrations, and capable of doing so at genome-wide scale and single-nucleotide resolution.

Our model takes promoter sequences and DBF concentrations as inputs, generating transcript production rates or levels as outputs. Thereby, there are two types of problems. One studies the response of transcript production as the TF concentrations change over time, fixing promoter sequence and nucleosome concentration as other inputs. The other is about transcript production rate/level being being up or down, after mutations are executed on promoters. For the first type, the model is applied in the S. cerevisiae yeast to predict the instantaneous transcript production rate during the yeast cell cycle for each gene, given its promoter occupancy profile. For the second type, we apply the model in S. cerevisiae yeast to predict the averaged transcript production rate of mutant promoters and new promoters which have not been seen before in training set.

Advisor(s): Alexander Hartemink

Sayan Mukherjee, Raluca-Mihaela Gordan, Ryan Baugh