BMC Genomics 2008, 9:627 http://www.biomedcentral.com/1471-2164/9/627 growth rate [7-9], given their function and the fact they only transiently respond and are not differentially expressed among treatments where the grow rate differs nearly 2-fold (aerobiosis vs. anaerobiosis) suggests they may be part of a systems level response for balancing ener- getic supply and demand and coordinating entry into the cell cycle in response to the abrupt cessation of respira- tion. Discussion This study has revealed novel insight into the transcrip- tomic response referred to as the "common environmen- tal response" (CER) [4] or "environmental stress response" (ESR) [2] and differentiates between networks that respond to respiratory inhibition and those that respond to oxygen deprivation. First, we show that the acute inhibition of respiration by either oxygen depriva- tion (anoxia) or chemical means (antimycin A) in catabo- lite non-repressed conditions evokes a transient ESR/CER- like response. Gene network analyses suggest that changes in the activity of Fhl1 and PAC/RRPE-associated factors result in the transient down-regulation of genes involved in energetically costly programs of ribosomal biogenesis, protein synthesis, and rRNA transcription/processing. Simultaneously, transient changes in the activity of the SBF (Swi4-Swi6) and MBF complexes (Mbp1-Swi6) result in the down-regulation of genes involved in late G1 and the G1/S transition of the cell cycle and a predicted delay in its progression as mass and energy are assessed before committing to another round. At the same time Msn2/4- regulated networks involved in carbohydrate import/utili- zation and reserve energy metabolism are transiently acti- vated. When viewed together it seems clear that the transient changes in the activity of these gene networks may be required for balancing energy supply and demand and regulating entrance into the cell cycle. Functional gene network analyses suggest this program includes simulta- neously bolstering catabolic potential, regulating reserve energy supplies (trehalose and glycogen), and sparing energetic demand by down-regulating early steps in the biogenesis of the cytoplasmic ribosomes. Given that changes in the activity of these gene networks are not observed when respiration is inhibited well before (3 gen- erations) the aerobic-to-anaerobic transition, we hypoth- esize these networks may respond to the acute decrease in energy status that accompanies respiratory inhibition as it is clear they do not respond directly to the change in oxy- gen availability. This conclusion is further supported by previous genomic comparisons of the anaerobic shift in catabolite-repressed and non-repressed cells [5,6], which showed that these networks also fail to respond during the aerobic-to-anaerobic transition when respiration is inhib- ited by the presence of glucose and, thus, when the transi- tion precedes with no change in growth rate or energetic status. During the review of this manuscript, an additional genomic study examining the switch to fermentation also concluded that the mere depletion of oxygen does not evoke a stress response [11]. After a substantive delay (≥ 2 generations), more chronic changes in gene network activity were observed under anaerobiosis that were not observed under aerobiosis in the presence of antimycin A. Network analyses show these included the chronic down-regulation of Hap1- and Hap2/3/4/5-regulated ones involved in mitochondrial functions as well as Rox1-regulated ones involved in redox regulation and carbohydrate usage. The last net- works to respond (≥ 1 generation) were Upc2-regulated ones involved in cell wall functions and sterol homeosta- sis. These same networks responded with similar kinetics to anoxia in the presence of antimycin A. An extensive body of previous research (reviewed in [12-14]) has shown that changes in the activity of these trans-acting fac- tors result from decreased heme levels as a result of the loss of oxygen for its synthesis and, thus, it is not surpris- ing that these networks fail to respond to antimycin A treatment under normoxic conditions. Others include those involved in mitochondrial ribosomal biogenesis that have apparently lost their 5' ancestral cis-regulatory sites and appear to be regulated post-transcriptionally by Puf3 [15]. Although some genes were found to respond in a unique manner to each treatment, clustering analyses reveal the same or similar gene networks respond to oxy- gen deprivation both the presence and absence of inhibi- tor. Given that both oxygen deprivation and antimycin A poi- soning require metabolic retooling of mitochondrial functions, it is reasonable to postulate that many of the observed changes in gene expression result from retro- grade signaling [16]. The retrograde response signals mitochondrial dysfunction to the nucleus and causes changes in the expression of genes associated with perox- isomal activities and anaplerotic pathways that mitigate the loss of the tricarboxylic acid cycle activity [17]. This response also correlates metabolism with stress responses, chromatin-dependent gene activation, and genome stabil- ity in yeast aging [18]. Not surprisingly, many of the known RTG-dependent genes responded to antimycin A treatment in air [19]. However, there was surprisingly lit- tle overlap (21%) between the genes identified here to respond to antimycin A treatment and those from Epstein et. al's study [17], differences that most likely can be attributed to the time points that were sampled in each study, array platforms and differences in experimental conditions. Rather, it is clear that the gene networks that respond to anoxia as well as antimycin A treatment are those involved in the general cellular response to stress. Page 8 of 14 (page number not for citation purposes)