It has been proposed that the differentiation of some cell-types has a stochastic aspect, but in many instances, extra-cellular cues play an essential role in controlling cell-fate, although the details of the pathway from extra-cellular cue to intrinsic differentiation determinants are not always clear. Interestingly, the synthesis and degradation rates of key transcription factors have been shown in different instances to be regulated (see zur Lage, 2004, Ebert, 2003, Lim, 2004, for examples of regulated synthesis rates, and Trott, 2001, Horwitz, 1996, Sriuranpong, 2002, Viñals, 2004, for examples of regulated degradation rates). The activity of transcription factors can be directly regulated by post-translational modifications such as phosphorylation (for example phosphorylation of myogenic factors can decrease their activity, Zhou, 1994, Suelves, 2004, Winter, 1993, and this can also be the case for class A proteins, Page, 2004), by physical interactions with other proteins (Perry, 2001, Bengal, 1992), or indirectly by affecting cofactors (Seo, 2005, Simone, 2004). Phosphorylation can also modulate the propensity of bHLH proteins to form heterodimers (this can be the case for class B proteins, Firulli, 2003, class A proteins, Lluis, 2005, Sloan, 1996, and also Id proteins, Deed, 1997, Hara, 1997). It seems to generally be the case that upon cell differentiation, the activity of transcription factors associated with the cell-fate is enhanced.
Within the framework proposed here, the biasing of complex cell-fate decisions to specific outcomes can be mediated by the up- or down-regulation of synthesis rates or affinity for common class A activators, or down- or up-regulation of degradation rates, for class B genes associated to favored and unfavored outcomes, respectively. Different signaling pathways can act on one or many factors and do not need to directly cross-talk, as all the inputs are integrated by the competition between the switch elements.
The result of the decision can be regulated by the synthesis, class A-affinities, and degradation rates of the switch elements, while its timing is dependent on the level of competition in the system: an increase in the competition level, which can for example be mediated by an increase in Id protein expression (shown in many experimental contexts, see references in Cinquin, 2005) sequestering the common activator away from all the elements of the switch, will force the weakest elements to be turned off. The efficiency with which Id proteins sequester the common activator can also be modulated by phosphorylation, which can also just be modeled by a change in the quantity of common activator available for switch elements. Some Id proteins, despite being paradoxically called "Inhibitors of differentiation", have indeed been shown recently to drive tumor-suppression and differentiation (Yu, 2005, Russell, 2004), as suggested by Cinquin (2005).