First Generation Stochastic Gene Episilencing (Step1) Model and Applications to in Vitro Carcinogen Exposure

A novel first-generation stochastic gene episilencing (STEP1) model is introduced for quantitatively characterizing the probability of in vitro epigenetically silencing (episilencing) specific tumor-suppressor-microRNA (miRNA) genes by carcinogen exposure. Although the focus is mainly on in-vitro exposure of human cells to ionizing radiation, the mathematical formulations presented are general and can be applied to other carcinogens. With the STEP1 model, a fraction fj of the surviving target cells can have their tumor-suppressor-miRNA gene of type j silenced while the remaining fraction, 1 - fj , of the surviving cells do not undergo gene episilencing. Suppressor gene episilencing is assumed to arise as a Poisson process characterized with and exponential distribution of episilencing doses with mean dj . In addition to providing mathematical functions for evaluating the single-target-gene episilencing probability, functions are also provided for the multi-target-gene episilencing probability for simultaneously silencing of multiple tumor-suppressor-miRNA genes. Functional relationships are first developed for moderate doses where adaptive responses are unlikely and are then modified for low doses where adaptation can occur. Results apply to a specific follow-up time t after carcinogen exposure that exceeds the maximum time for the occurrence of an induced episilencing event.