Bi-stability of the master gene regulatory network of the common dendritic precursor cell: Implications for cell differentiation.

ABSTRACT

In cell lineage commitment decisions, a gene regulatory network (GRN) consisting of a limited number of transcription factors forms the regulatory pivot. Myeloid lineage dendritic cells or DCs are specialized cells having the antigen-presenting ability and are of immense importance in immune surveillance. In this report, we analyze the GRN that governs the lineage commitment of Common DC Progenitor (CDP) cells to conventional dendritic cells (cDC) and plasmacytoid dendritic cells (pDC). We have analyzed the quantitative behavior of the master regulatory circuit of CDP that governs the lineage commitment. Simulations showed that the GRN displays a bi-stable behavior within a range of parameter values. Several transcription factors, PU.1, IRF8, Flt3, and Stat3, whose concentrations vary significantly in the two steady states, appear to be the key players. We hypothesize that the two stable steady states are precursors of cDC and pDC, and the variation of concentration of these key transcription factors in the two states may be responsible for early events in lineage commitment.