Systems Biology of Gene Regulation
To understand differential cell-fate outcome in response to the same uniform stimulus, we are exploring the link between regulatory network architecture and the genome-scale dynamics of the underlying entities (genes, mRNAs, and proteins). Recently, we found that at the protein level, the top-layer TFs (which trigger/initiate regulatory cascades) are relatively abundant, long-lived, and showed more cell-to-cell variability (noise) compared to the downstream (core- and bottom-layer) TFs. This and other results led us to conclude that the variability in expression of top-layer TFs might confer a selective advantage, as this may permit at least some members in a clonal cell population to initiate an effective response to fluctuating environments, whereas the tight regulation of the core- and bottom-layer TFs may minimize noise propagation and ensure fidelity in regulation. The dynamic variability in expression level of key regulatory proteins could permit differential sampling (i.e.,the survival network or the apoptotic network) of the same underlying regulatory network (governing all cells) by different members in a clonal population, which might result in divergent cell-fate outcomes among different individuals in an otherwise identical cell population. This result is critical to understanding phenotypic variability in fluctuating environments, e.g., fractional survival or cell-death in clonal cell populations upon drug treatment in diseases such as cancer. Our current research in this area is focused on identifying additional evidence support this notion, and understanding how cells adapt to changing environments, how different phenotypic outcomes are mediated in clonal cell populations, and how mutations that disrupt the dynamics of key regulatory proteins may influence disease conditions.