STEM: a tool for the analysis of short time series gene expression data

Ernst, Jason; Bar‐Joseph, Ziv

doi:10.1186/1471-2105-7-191

Cited by 1,357 publications

(911 citation statements)

References 27 publications

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“…To identify gene expression patterns during the course of the experiment, the absolute expression levels of all of the genes (2,533 genes in L. lactis KF147) were subjected to expression cluster anal- ysis with the STEM module, which employs a process of statistical clustering of time series data sets into precomposed patterns of expression (22). STEM analysis divided the expression patterns into 50 time-resolved model expression profiles, which were sorted on the basis of the number of genes assigned to the profile.…”

Section: Resultsmentioning

confidence: 99%

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Molecular and Metabolic Adaptations of Lactococcus lactis at Near-Zero Growth Rates

Ercan

Wels

Smid

et al. 2015

Appl Environ Microbiol

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f This paper describes the molecular and metabolic adaptations of Lactococcus lactis during the transition from a growing to a near-zero growth state by using carbon-limited retentostat cultivation. Transcriptomic analyses revealed that metabolic patterns shifted between lactic-and mixed-acid fermentations during retentostat cultivation, which appeared to be controlled at the level of transcription of the corresponding pyruvate dissipation-encoding genes. During retentostat cultivation, cells continued to consume several amino acids but also produced specific amino acids, which may derive from the conversion of glycolytic intermediates. We identify a novel motif containing CTGTCAG in the upstream regions of several genes related to amino acid conversion, which we propose to be the target site for CodY in L. lactis KF147. Finally, under extremely low carbon availability, carbon catabolite repression was progressively relieved and alternative catabolic functions were found to be highly expressed, which was confirmed by enhanced initial acidification rates on various sugars in cells obtained from near-zero-growth cultures. The present integrated transcriptome and metabolite (amino acids and previously reported fermentation end products) study provides molecular understanding of the adaptation of L. lactis to conditions supporting low growth rates and expands our earlier analysis of the quantitative physiology of this bacterium at near-zero growth rates toward gene regulation patterns involved in zerogrowth adaptation. Fundamental knowledge of microbial physiology and cellular regulation is obtained mainly from studies of microorganisms in batch cultures. However, the pace of life and its associated physiological phases in batch cultivation differ strongly from what is found in natural environments (1). During the early phase of batch cultivations, all nutrients, including carbon and energy sources, are usually present in excess and the specific growth rate of the microorganism equals the maximum specific growth rate (2). Thereby, our understanding of microbial energy metabolism originates mostly from microbial population studies performed under laboratory conditions that include rapid growth, high metabolic activity, and high cell density. However, natural microbial communities generally live under relative famine conditions with low specific growth and metabolic rates due to a limited supply of nutrients and energy sources (3). Analogously, under specific industrial fermentation conditions, microorganisms may experience strongly restricted access to nutrients for longer periods of time. For example, lactic acid bacteria (LAB) experience long periods of extremely low nutrient availability during the maturing process of dry sausage (4) and cheese (5) production. Despite these harsh conditions, several LAB survive these processes during months of maturation and may continue to contribute to flavor and aroma formation in the product matrix (4, 6, 7).Lactococcus lactis is used in food fermentation processes for several...

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Section: Resultsmentioning

confidence: 99%

“…The gene expression intensities were compared and clustered by Short Time-series Expression Miner (STEM, version 1.3.6; http://www.cs.cmu .edu/ϳjernst/stem/) (22). The STEM clustering algorithm was used to identify enrichment of Gene Ontology (GO) terms, with Bonferroni correction to determine significance and a maximum of 50 model profiles.…”

mentioning

confidence: 99%

Molecular and Metabolic Adaptations of Lactococcus lactis at Near-Zero Growth Rates

Ercan

Wels

Smid

et al. 2015

Appl Environ Microbiol

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show abstract

“…To identify gene expression changes during the course of the experiment, absolute expression levels of all genes (2,533 annotated genes in the L. lactis KF147 genome) were subjected to expression cluster analysis using STEM, which uses a process of statistical clustering of short-time-series data sets into precomposed patterns of time-dependent expression (22). STEM distributed the expression patterns into 8 time course model expression profiles, which were ordered on the basis of the number of genes assigned to the model profile.…”

Section: Resultsmentioning

confidence: 99%

“…The gene expression intensities were compared and clustered using Short Time-series Expression Minor (STEM) (version 1.3.6; http://www .cs.cmu.edu/ϳjernst/stem/) (22). The STEM clustering algorithm enriched with gene ontology (GO) terms was applied with the Bonferroni correction method, a maximum number of predefined, arbitrary model profiles of 8, and a minimum unit change in model profile between time points of 2 (ratio change of 1 in log 2 scale).…”

Section: Methodsmentioning

confidence: 99%

Genome-Wide Transcriptional Responses to Carbon Starvation in Nongrowing Lactococcus lactis

Ercan

Wels

Smid

et al. 2015

Appl Environ Microbiol

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f This paper describes the transcriptional adaptations of nongrowing, retentostat cultures of Lactococcus lactis to starvation. Near-zero-growth cultures ( ‫؍‬ 0.0001 h ؊1 ) obtained by extended retentostat cultivation were exposed to starvation by termination of the medium supply for 24 h, followed by a recovery period of another 24 h by reinitiating the medium supply to the retentostat culture. During starvation, the viability of the culture was largely retained, and the expression of genes involved in transcription and translational machineries, cell division, and cell membrane energy metabolism was strongly repressed. Expression of these genes was largely recovered following the reinitiation of the medium supply. Starvation triggered the elevated expression of genes associated with synthesis of branched-chain amino acids, histidine, purine, and riboflavin. The expression of these biosynthesis genes was found to remain at an elevated level after reinitiation of the medium supply. In addition, starvation induced the complete gene set predicted to be involved in natural competence in L. lactis KF147, and the elevated expression of these genes was sustained during the subsequent recovery period, but our attempts to experimentally demonstrate natural transformation in these cells failed. Mining the starvation response gene set identified a conserved cis-acting element that resembles the lactococcal CodY motif in the upstream regions of genes associated with transcription and translational machineries, purine biosynthesis, and natural transformation in L. lactis, suggesting a role for CodY in the observed transcriptome adaptations to starvation in nongrowing cells.L actococcus lactis has a long history of use in the manufacturing of fermented foods. In particular, dairy starter cultures containing L. lactis are important for primary acidification of cheese milk. In addition, L. lactis contributes to the texture and formation of flavor in cheese, which are key determinants of the product's sensory quality (1, 2). Next to these industrial food fermentation applications, L. lactis is frequently found in other environments, such as (decaying) plant material, especially when nutrients become available as a consequence of primary degradation of plant polymers by other microorganisms, including yeasts and fungi (3).In nature, microbial populations mostly live in nutrient-limiting conditions due to low carbon and energy source availability (4). Under these environmental conditions, microbes either develop adaptive responses to high-affinity substrate acquisition or scavenge the ecosystem for alternative nutrients, resulting in a survival advantage (5). Similarly, in industrial fermentation applications, microbes may encounter restricted access to carbon sources for longer periods of time. For example, lactic acid bacteria (LAB) encounter long periods of low or no carbon availability during the ripening of dried sausages (6) and cheese (1), but they are able to survive under these conditions during months of ripening (6,7,...

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“…With a Short Time-series Expression Miner software [16], genes whose expression changed C2 fold and had significant change patterns during culture were identified (Fig. 2c).…”

Section: Changes In Gene Expression During Hskp Senescencementioning

confidence: 99%

Senescence of human skin-derived precursors regulated by Akt-FOXO3-p27KIP1/p15INK4b signaling

Liu

Wang

Zhao

et al. 2015

Cell. Mol. Life Sci.

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Multipotent skin-derived precursors (SKPs) are dermal stem cells with the capacity to reconstitute the dermis and other tissues, such as muscles and the nervous system. Thus, the easily available human SKPs (hSKPs) hold great promises in regenerative medicine. However, long-term expansion is difficult for hSKPs in vitro. We previously demonstrated that hSKPs senesced quickly under routine culture conditions. To identify the underlying mechanisms so as to find an effective way to expand hSKPs, time-dependent microarray analysis of gene expression in hSKPs during in vitro culture was performed. We found that the senescence of hSKPs had a unique gene expression pattern that differs from reported typical senescence. Subsequent investigation ruled out the role of DNA damage and classical p53 and p16 INK4a signaling in hSKP senescence. Examination of cyclin-dependent kinase inhibitors revealed the involvement of p15 INK4b and p27 KIP1 . Further exploration about upstream signals indicated the contribution of Akt hypo-activity and FOXO3 to hSKP senescence. Forced activation of Akt and knockdown of FOXO3, p15 INK4b and p27 KIP1 effectively inhibited hSKP senescence and promoted hSKP proliferation. The unique senescent phenotype of human dermal stem cells and the role of Akt-FOXO3-p27 KIP1 /p15 INK4b signaling in regulating hSKP senescence provide novel insights into the senescence and self-renewal regulation of adult stem cells. The present study also points out a way to propagate hSKPs in vitro so as to fulfill their promises in regenerative medicine.

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STEM: a tool for the analysis of short time series gene expression data

Cited by 1,357 publications

References 27 publications

Molecular and Metabolic Adaptations of Lactococcus lactis at Near-Zero Growth Rates

Molecular and Metabolic Adaptations of Lactococcus lactis at Near-Zero Growth Rates

Genome-Wide Transcriptional Responses to Carbon Starvation in Nongrowing Lactococcus lactis

Senescence of human skin-derived precursors regulated by Akt-FOXO3-p27KIP1/p15INK4b signaling

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