Budding yeast escape commitment to the phosphate starvation program using gene expression noise

Cells must rapidly adapt to changes in nutrient availability. In budding yeast, limitation of phosphate rapidly induces the expression of the Pho regulon genes [1-4]. This starvation program depends on the transcription factor Pho4, which translocates to the nucleus within minutes when cells are transferred to a low-phosphate medium [5]. Contrasting its rapid induction, we report that the Pho regulon can remain induced for dozens of generations in cells transferred back to high phosphate levels. For example, about 40% of the cells that were starved for 2 hr maintained PHO4-dependent expression for over eleven generations of growing in high phosphate. This commitment to activation of the Pho regulon depends on two feedback loops that reduce internal phosphate, one through induction of the PHM1-4 genes that increase phosphate storage in the vacuoles and the second by induction of SPL2, which reduces incoming flux by inhibiting low-affinity transporters. Noise in SPL2 expression allows stochastic repression of the Pho regulon in committed cells growing at high phosphate, as we demonstrate using a novel method, DAmP multiple copy array (DaMCA), that reduces intrinsic noise in gene expression while maintaining mean abundance. Commitment is an integral part of the dual-transporter motif that helps cells prepare for nutrient depletion.