Enhanceosome Formation

A stochastic model to investigate the underlying mechanisms leading to greater cell-to-cell variation in the IFNB1 mRNA than in a housekeeping gene, another induced transcript and viral RNA. The model suggests that the surprisingly high levels of IFNB1 transcript noise originate from the complexity of IFNB1 enhanceosome formation, which leads to a range up to many minutes in the differences within each cell in the time of activation of each allele (Chromosome-specific and noisy IFNB1 transcription in individual virus-infected human primary dendritic cells, Hu, Jianzhong et al., Nucleic Acids Research (2007), Volume 35, Issue 15, p.5232 - 5241).

The complexity of IFNB1 enhanceosome formation prior to transcription initiation is assumed to provide the dominant contribution to the stochastic behavior. This assembly involves binding of NFKB, AP-1, IRF, and HMG-I(Y) to form the enhanceosome. We denote HMG-I(Y) by P1, NFKB by P2, AP1 by P3 and the IRFs by P4. The model comprises four proteins P1, P2, P3 and P4 that bind without interacting, and represent the corresponding cooperative behavior through protein binding in a well-defined order. The relevant reactions are given by:

where D1 represents promoter region of allele 1. One has a similar set of equations for promoter region D2 of allele 2 where we have used the same reaction rate constants since the alleles are assumed to be functionally identical.