| Summary: | <p>Abstract</p> <p>Background</p> <p>The yeast <it>Saccharomyces cerevisiae </it>is able to adapt and <it>in situ </it>detoxify lignocellulose derived inhibitors such as furfural and HMF. The length of lag phase for cell growth in response to the inhibitor challenge has been used to measure tolerance of strain performance. Mechanisms of yeast tolerance at the genome level remain unknown. Using systems biology approach, this study investigated comparative transcriptome profiling, metabolic profiling, cell growth response, and gene regulatory interactions of yeast strains and selective gene deletion mutations in response to HMF challenges during the lag phase of growth.</p> <p>Results</p> <p>We identified 365 candidate genes and found at least 3 significant components involving some of these genes that enable yeast adaptation and tolerance to HMF in yeast. First, functional enzyme coding genes such as <it>ARI1, ADH6, ADH7</it>, and <it>OYE3</it>, as well as gene interactions involved in the biotransformation and inhibitor detoxification were the direct driving force to reduce HMF damages in cells. Expressions of these genes were regulated by <it>YAP1 </it>and its closely related regulons. Second, a large number of PDR genes, mainly regulated by <it>PDR1 </it>and <it>PDR3</it>, were induced during the lag phase and the PDR gene family-centered functions, including specific and multiple functions involving cellular transport such as <it>TPO1, TPO4, RSB1, PDR5, PDR15, YOR1</it>, and <it>SNQ2</it>, promoted cellular adaptation and survival in order to cope with the inhibitor stress. Third, expressed genes involving degradation of damaged proteins and protein modifications such as <it>SHP1 </it>and <it>SSA4</it>, regulated by <it>RPN4</it>, <it>HSF1</it>, and other co-regulators, were necessary for yeast cells to survive and adapt the HMF stress. A deletion mutation strain <it>Δrpn4 </it>was unable to recover the growth in the presence of HMF.</p> <p>Conclusions</p> <p>Complex gene interactions and regulatory networks as well as co-regulations exist in yeast adaptation and tolerance to the lignocellulose derived inhibitor HMF. Both induced and repressed genes involving diversified functional categories are accountable for adaptation and energy rebalancing in yeast to survive and adapt the HMF stress during the lag phase of growth. Transcription factor genes <it>YAP1</it>, <it>PDR1, PDR3, RPN4</it>, and <it>HSF1 </it>appeared to play key regulatory rules for global adaptation in the yeast <it>S. cerevisiae</it>.</p>
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