Transcriptomic analysis reveals global and temporal transcription changes during Candida glabrata adaptation to an oxidative environment

Sethiya, Pooja; Nandan, Maruti; Rai, Rikky; Parsania, Chirag; Tan, Kaeling; Wong, Koon Ho

doi:10.1016/j.funbio.2019.12.005

Cited by 11 publications

(10 citation statements)

References 42 publications

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“…Consistent with this idea, the ROS increase was not associated with detectable lipid peroxidation or DNA damage. Although these results run contrary to the traditional view that ROS are exclusively damaging and lack other physiological functions, they are consistent with observations that C. glabrata is exceptionally resistant to oxidative stress (45) and in fact, it has recently been described that petite mutants of C. glabrata show a lack of oxidative stress susceptibility when incubated with hydrogen peroxide which is combined with a constitutive upregulation of environmental stress-response and heat-shock-proteinencoding genes (46). Relative to other species, C. glabrata exhibit a very restrained transcriptional response to phagocyte-induced ROS with insignificant upregulation of catalase (47).…”

Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

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The geometry of domain-general performance monitoring in the human medial frontal cortex

Beam

Chung

et al. 2021

Preprint

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Flexibly adapting behavior to achieve a desired goal depends on the ability to monitor one’s own performance. A key open question is how performance monitoring can be both highly flexible to support multiple tasks and specialized to support specific tasks. We characterized performance monitoring representations by recording single neurons in the human medial frontal cortex (MFC). Subjects performed two tasks that involve three types of cognitive conflict. Neural population representations of conflict, error and control demand generalized across tasks and time while at the same time also encoding task specialization. This arose from a combination of single neurons whose responses were task-invariant and non-linearly mixed. Neurons encoding conflict ex-post served to iteratively update internal estimates of control demand as predicted by a Bayesian model. These findings reveal how the MFC representation of evaluative signals are both abstract and specific, suggesting a mechanism for computing and maintaining control demand estimates across trials and tasks.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

The geometry of domain-general performance monitoring in the human medial frontal cortex

Beam

Chung

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…Consistent with this idea, the ROS increase was not associated with detectable lipid peroxidation or DNA damage. Although these results run contrary to the traditional view that ROS are exclusively damaging and lack other physiological functions, they are consistent with observations that C. glabrata is exceptionally resistant to oxidative stress (45) and in fact, it has recently been described that petite mutants of C. glabrata show a lack of oxidative stress susceptibility when incubated with hydrogen peroxide which is combined with a constitutive upregulation of environmental stress-response and heat-shock-protein-encoding genes (46). Relative to other species, C. glabrata exhibit a very restrained transcriptional response to phagocyte-induced ROS with insignificant upregulation of catalase (47).…”

Section: Discussionsupporting

confidence: 82%

“…Interestingly, recent evidence suggests a critical role of ROS in the communication between the mitochondria and other cellular processes to maintain homeostasis and promote adaptation to stress (48). Furthermore, some studies have also proposed a role for oxidative stress adaptation in promoting virulence and drug resistance in C. glabrata , as several genes implicated in virulence, biofilm formation, and drug transport were also induced during the oxidative adaptation response (45). These studies, together with our results, suggest that in C. glabrata responding to echinocandins ROS function as a signaling intermediate with as yet unknown specific downstream targets and contribution to fitness.…”

Section: Discussionmentioning

confidence: 99%

Multifactorial role of mitochondria in echinocandin tolerance revealed by transcriptome analysis of drug-tolerant cells

Garcia-Rubio

Jiménez‐Ortigosa

DeGregorio

et al. 2021

Preprint

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Fungal infections cause significant mortality and morbidity worldwide, and the limited existing antifungal reservoir is further weakened by the emergence of strains resistant to echinocandins, a first line of antifungal therapy. Candida glabrata is an opportunistic fungal pathogen that rapidly develops mutations in the echinocandin drug target, β-1,3-glucan synthase (GS), which are associated with drug resistance and clinical failure. Although echinocandins are considered fungicidal in Candida, a subset of C. glabrata cells survive echinocandin exposure, forming a drug-tolerant cell reservoir, from which resistant mutations are thought to emerge. Despite their importance, the physiology of rare drug-tolerant cells is poorly understood. We used fluorescence-activated cell sorting to enrich for echinocandin-tolerant cells, followed by modified single cell RNA sequencing to examine their transcriptional landscape. This analysis identified a transcriptional signature distinct from the stereotypical yeast environmental stress response and characterized by upregulation of pathways involved in chromosome structure and DNA topology and downregulation of oxidative stress responses, the latter of which was observed despite increased levels of reactive oxygen species. Further analyses implicated mitochondria in echinocandin tolerance, wherein inhibitors of mitochondrial complexes I and IV reduced echinocandin-mediated cell killing, but mutants lacking various mitochondrial components all showed an echinocandin hypo-tolerant phenotype. Finally, GS enzyme complexes purified from mitochondrial mutants exhibited normal in vitro inhibition kinetics, indicating that mitochondrial defects influence cell survival downstream of the drug-target interaction. Together, these results provide new insights into the C. glabrata response to echinocandins and reveal a multifactorial role of mitochondria in echinocandin tolerance.ImportanceEchinocandin drugs are a first line therapy to treat invasive candidiasis, which is a major source of morbidity and mortality worldwide. The opportunistic fungal pathogen Candida glabrata is a prominent bloodstream fungal pathogen and it is notable for rapidly developing echinocandin-resistant strains associated with clinical failure. Echinocandin resistance is thought to emerge within a small echinocandin-tolerant subset of C. glabrata cells that are not killed by drug exposure, but mechanisms underlying echinocandin tolerance are still unknown. Here we describe the unique transcriptional signature of echinocandin-tolerant cells and the results of follow-up analyses, which reveal a multifactorial role of mitochondria in C. glabrata echinocandin tolerance. In particular, although chemical inhibition of respiratory chain enzymes increased echinocandin tolerance, deletion of multiple mitochondrial components made C. glabrata cells hypo-tolerant to echinocandins. Together, these results provide new insights into the C. glabrata response to echinocandins and reveal the involvement of mitochondria in echinocandin tolerance.

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“…Like in S. cerevisiae , the C. glabrata Yap1 ortholog is one of the primary transcriptional regulators of genes required for oxidative stress adaptation [113]. Oxidative stress induces the expression of CgYAP1 , CgMSN2, and CgMSN4 along with either upregulation or downregulation of a number of ABC transporters [114]. While the role of the individual TFs has not been investigated yet, a ChIP‐seq dataset on the C. glabrata Yap TFs identified Cg Yap1 binding to the CgSNQ2 promoter, and Cg Yap2 binding to the CgYCF1 promoter [115].…”

Section: Yeast Adaptation To Oxidative Stress and Metal Stress Are Inmentioning

confidence: 99%

Transcription factors and ABC transporters: from pleiotropic drug resistance to cellular signaling in yeast

Buechel

Pinkett

2020

FEBS Letters

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Budding yeast S. cerevisiae survives in microenvironments utilizing networks of regulators and ATPbinding cassette (ABC) transporters to circumvent toxins and a variety of drugs. Our understanding of transcriptional regulation of ABC transporters in yeast is mainly derived from the study of multidrug resistance protein networks. Over the past two decades, this research has not only expanded the role of transcriptional regulators in pleiotropic drug resistance (PDR) but evolved to include the role that regulators play in cellular signaling and environmental adaptation. Inspection of the gene networks of the transcriptional regulators and characterization of the ABC transporters has clarified that they also contribute to environmental adaptation by controlling plasma-membrane composition, toxic-metal sequestration, and oxidative-stress adaptation. Additionally, ABC transporters and their regulators appear to be involved in cellular signaling for adaptation of S. cerevisiae populations to nutrient availability. In this review we summarize the current understanding of the S. cerevisiae transcriptional regulatory networks and highlight recent work in other notable fungal organisms, underlining the expansion of the study of these gene networks across the kingdom fungi.

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Transcriptomic analysis reveals global and temporal transcription changes during Candida glabrata adaptation to an oxidative environment

Cited by 11 publications

References 42 publications

The geometry of domain-general performance monitoring in the human medial frontal cortex

The geometry of domain-general performance monitoring in the human medial frontal cortex

Multifactorial role of mitochondria in echinocandin tolerance revealed by transcriptome analysis of drug-tolerant cells

Transcription factors and ABC transporters: from pleiotropic drug resistance to cellular signaling in yeast

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