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Exposure of<jats:italic>Clostridium<\/jats:italic>organisms to chemical and in particular toxic metabolite stress is ubiquitous in both natural (such as in the human microbiome) and engineered environments, engaging both the general stress response as well as specialized programs. Yet, despite its fundamental and applied significance, it remains largely unexplored at the systems level.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We generated a total of 96 individual sets of microarray data examining the transcriptional changes in<jats:italic>C. acetobutylicum,<\/jats:italic>a model<jats:italic>Clostridium<\/jats:italic>organism<jats:italic>,<\/jats:italic>in response to three levels of chemical stress from the native metabolites, butanol and butyrate. We identified 164 significantly differentially expressed transcriptional regulators and detailed the cellular programs associated with general and stressor-specific responses, many previously unexplored. Pattern-based, comparative genomic analyses enabled us, for the first time, to construct a detailed picture of the genetic circuitry underlying the stress response. Notably, a list of the regulons and DNA binding motifs of the stress-related transcription factors were identified: two heat-shock response regulators, HrcA and CtsR; the SOS response regulator LexA; the redox sensor Rex; and the peroxide sensor PerR. Moreover, several transcriptional regulators controlling stress-responsive amino acid and purine metabolism and their regulons were also identified, including ArgR (arginine biosynthesis and catabolism regulator), HisR (histidine biosynthesis regulator), CymR (cysteine metabolism repressor) and PurR (purine metabolism repressor).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Using an exceptionally large set of temporal transcriptional data and regulon analyses, we successfully built a STRING-based stress response network model integrating important players for the general and specialized metabolite stress response in<jats:italic>C. acetobutylicum<\/jats:italic>. Since the majority of the transcription factors and their target genes are highly conserved in other organisms of the<jats:italic>Clostridium<\/jats:italic>genus, this network would be largely applicable to other<jats:italic>Clostridium<\/jats:italic>organisms. The network informs the molecular basis of<jats:italic>Clostridium<\/jats:italic>responses to toxic metabolites in natural ecosystems and the microbiome, and will facilitate the construction of genome-scale models with added regulatory-network dimensions to guide the development of tolerant strains.<\/jats:p><\/jats:sec>","DOI":"10.1186\/1752-0509-7-120","type":"journal-article","created":{"date-parts":[[2013,11,7]],"date-time":"2013-11-07T00:01:46Z","timestamp":1383782506000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":67,"title":["Transcription factors and genetic circuits orchestrating the complex, multilayered response of Clostridium acetobutylicum to butanol and butyrate stress"],"prefix":"10.1186","volume":"7","author":[{"given":"Qinghua","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keerthi Prasad","family":"Venkataramanan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongzhan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleftherios T","family":"Papoutsakis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cathy H","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2013,11,6]]},"reference":[{"issue":"5","key":"1202_CR1","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1038\/ismej.2012.158","volume":"7","author":"P Van den Abbeele","year":"2013","unstructured":"Van den Abbeele P, et al: Butyrate-producing Clostridium cluster XIVa species specifically colonize mucins in an in vitro gut model. 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