(175bk) Dynamic Model of Intrathymic T-Cell Vs Myeloid Commitment

Transcription factor PU.1 promotes myeloid differentiation by downregulating several genes critical to T cell commitment, including GATA-3, MYB, and E proteins, while upregulating myeloid specific genes, such as Csf1r and Itgam. There is evidence suggesting that in early T-cell stages, when levels of both PU.1 and Notch signaling are high, the two factors act to blunt the efficiency of the other’s target activation. The system, however, is intrinsically biased against PU.1, as a result of its eventual silencing by Notch-activated GATA-3 and other factors.

Intrathymic development of the T-cell lineage depends on the temporal and quantitative coordination of numerous regulatory molecules needed to promote T-cell development and exclude alternative developmental pathways. The T-cell vs myeloid decision can be mainly viewed as a competition between the T-cell-promoting effects of Notch signaling, and the pro-myeloid effects of PU.1 target gene activation. We are developing a cybernetic framework that optimizes the T-cell or myeloid cell potential as the cybernetic goal/cell fate decision as a function of PU.1 and Notch signaling. Our model can qualitatively reproduce the experimental results observed during both absolute and temporally-graded levels of regulation by Notch and PU.1.