One key characteristic of the white and opaque cell types is their stability over thousands of generations under normal laboratory conditions; that is, upon cell division, white cells almost always give rise to white cell progeny and opaque cells to opaque progeny. It has been proposed that this behavior results from the topology of the transcriptional circuit underlying the switch; this circuit consists largely of interlocking positive feedback loops  [18••
Figure 2 Model of the white-opaque regulatory circuit and its activity in different cell types. (a) White boxes represent factors that are enriched in white cells compared with opaque cells, and yellow boxes represent opaque-enriched factors. Lines with arrows (more ...)
At the core of this circuit is a protein called WOR1, the first major regulator of the opaque state to be identified [19
]. WOR1 expression is required to switch from the white to the opaque state and ectopic expression of WOR1 can drive an entire population of white cells to the opaque state. WOR1 expression produces a direct positive feedback loop by binding its own promoter and turning on its own expression [19
]. Activation of this feedback loop produces a forty-fold increase in WOR1 transcript levels in opaque cells compared to white cells. The WOR1 promoter is directly repressed by the a
1–α2 heterodimer, thus explaining the inability of a
/α cells to switch from white to opaque  [9
Three additional transcriptional regulators, EFG1, WOR2, and CZF1, complete the known regulatory circuit  [18••
], and it has been proposed that this circuit can account for the major characteristics of the white-opaque switch. According to this model, the circuit is largely inactive in the white state; this is the default state . Switching occurs when the circuit becomes excited; because of the series of positive feedback loops, the circuit can remain excited for many generations . It has been hypothesized that inheritance of the opaque state results from molecules of the regulators being passed on to daughter cells following cell division; the concentrations of these regulators in the daughter cells would then be sufficiently high to re-excite the circuit and retain the opaque state. What triggers white-to-opaque switching in the first place? It has been proposed that when components of the switching circuit reach a critical threshold concentration, the circuit becomes excited. In principle, this could occur through random fluctuations in the levels of a critical molecule such as WOR1. The reverse process, opaque-to-white switching, would then occur when insufficient quantities of the regulators are passed on to a daughter cell and the circuit would wind down.
Layered on this core transcriptional circuit are several chromatin modifying factors whose presence also affects switching. For example, deletion of the histone deacetylase HDA1 slightly increases switching rates from white to opaque while deletion of RPD3, another histone deacetylase, increases switching in both directions [26
]. Recently, the acetyltransferase NAT4 and histone deacetylases HST2, SET3, and HOS2 have also been implicated in regulation of switching. Deletion of each of these genes reduced rates of white-to-opaque switching and all but HST2 increased switching from opaque to white [25••
]. It is not yet clear precisely what role these chromatin remodeling factors play in the switch; one simple model is that they serve to reinforce the characteristics of the transcriptional circuit described above.