Identification and genetic dissection of convergent persister cell states
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA954422 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24136100.fastq.gz | Fastqsanger.gz | |||
| SRR24136101.fastq.gz | Fastqsanger.gz | |||
| SRR24136102.fastq.gz | Fastqsanger.gz | |||
| SRR24136103.fastq.gz | Fastqsanger.gz | |||
| SRR24136104.fastq.gz | Fastqsanger.gz |
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Project description:We generated a high-resolution single-cell RNA atlas of E. coli growth transitions, which revealed that a distinct persister state. We then used ultra-dense CRISPR-interference to determine how every E. coli gene contributes to persister formation across genetic models. ***Download data version 2 whenever present***
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Project description:Persister cells, rare phenotypic variants that survive normally lethal levels of antibiotics, present a major barrier to clearing bacterial infections1. However, understanding the precise physiological state and genetic basis of persister formation has been a longstanding challenge. Here we generated a high-resolution single-cell2 RNA atlas of Escherichia coli growth transitions, which revealed that persisters from diverse genetic and physiological models converge to transcriptional states that are distinct from standard growth phases and instead exhibit a dominant signature of translational deficiency. We then used ultra-dense CRISPR interference3 to determine how every E. coli gene contributes to persister formation across genetic models. Among critical genes with large effects, we found lon, which encodes a highly conserved protease4, and yqgE, a poorly characterized gene whose product strongly modulates the duration of post-starvation dormancy and persistence. Our work reveals key physiologic and genetic factors that underlie starvation-triggered persistence, a critical step towards targeting persisters in recalcitrant bacterial infections.
| S-EPMC11634777 | biostudies-literature
Project description:Bacterial persister cells are phenotypic variants of regular cells that are tolerant to antibiotics. High-persister (hip) mutants of Mycobacterium tuberculosis produce 10- to 1,000-fold more persister cells than the wild type strain when challenged with various antibiotics. Comparison of gene expression pattern of the hip mutants may provide clues as to the genetic mechanisms underlying persister formation. Transcriptome analysis will provide information on what differentiates M. tuberculosis hip strains from regular strains, which will be useful in the development of anti-persister therapy for persister cell eradication. Twelve independent M. tuberculosis hip mutants and the wild type strain were grown to stationary phase in duplicate. To avoid analyzing the drug effect, total RNA was extracted from the cultures prior to the addition of antibiotic for hybridization to Affymetrix microarrays. Data analysis was performed by comparing the hip mutants to the wild type control.
2014-04-07 | E-GEOD-55647 | biostudies-arrayexpress
Project description:Genetic dissection of the Fgf5 enhancer cluster
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Project description:Persisters are cells which evade stresses like antibiotics and which are characterized by reduced metabolism and a lack of genetic alterations required to achieve this state. We showed previously that MqsR and MqsA of Escherichia coli are a toxin-antitoxin pair that influence cell physiology (e.g., biofilm formation and motility) via RNase activity as well as through regulation of toxin CspD. Here, we show that deletion of the mqsRA locus decreases persister cell formation and, consistent with this result, overexpression of MqsR increases persister cell formation. Furthermore, toxins Hha, CspD, and HokA increase persister cell formation. In addition, by overproducing MqsR in a series of isogenic mutants, we show that Hha and CspD are necessary for persister cell formation via MqsR overexpression. Surprisingly, Hfq, a small RNA chaperone, decreases persistence. A whole-transcriptome study shows that Hfq induces transport-related genes (oppA, oppB, oppC, oppD, oppF, and dppA), outer membrane protein-related genes (ybfM and ybfN), toxins (hha), and proteases (clpX, clpP, and lon). Taken together, these results indicate that toxins CspD and Hha influence persister cell formation via MqsR and that Hfq plays an important role in the regulation of persister cell formation via regulation of transport or outer membrane proteins. Strains: E. coli BW25113 K-12 hfq deleted mutant vs. wild-type Medium: LB Culture: Planktonic cell grown OD=0.5, adjusted OD=1.0, and then exposed to 100 ug/mL ampicillin for 2 h.
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Project description:Bacterial persister cells are phenotypic variants of regular cells that are tolerant to antibiotics. High-persister (hip) mutants of Mycobacterium tuberculosis produce 10- to 1,000-fold more persister cells than the wild type strain when challenged with various antibiotics. Comparison of gene expression pattern of the hip mutants may provide clues as to the genetic mechanisms underlying persister formation. Transcriptome analysis will provide information on what differentiates M. tuberculosis hip strains from regular strains, which will be useful in the development of anti-persister therapy for persister cell eradication.
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Project description:Genetic dissection of the α-globin super-enhancer
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Project description:Acquired drug resistance prevents targeted cancer therapy from achieving stable and complete responses. Emerging evidence implicates a key role for nonmutational mechanisms including changes in cell state during early stages of acquired drug resistance. Targeting nonmutational resistance may therefore present a therapeutic opportunity to eliminate residual surviving tumor cells and impede relapse. A variety of cancer cell lines harbor quiescent, reversibly drug-tolerant âpersisterâ cells which survive cytotoxic drugs including targeted therapies and chemotherapies. These persister cells survive drug through nonmutational mechanisms which are poorly understood. Specifically targeting persister cells is a promising strategy to prevent tumor relapse. We sought to identify therapeutically exploitable vulnerabilities in persister cells using the HER2-amplified breast cancer line BT474 as an experimental model. Similar to other persister cell models, upon treatment with the HER2 inhibitor lapatinib (2uM concentration) for nine or more days, the majority of BT474 cells die, revealing a small population of quiescent surviving persister cells. Removal of lapatinib allows the persister cells to regrow and to re-acquire sensitivity to lapatinib. Subsequent lapatinib treatment re-derives persister cells. The reversibility of persister cell drug resistance indicates a nonmutational resistance mechanism. Here we provide RNAseq gene expression profiling data generated from parental BT474 cells compared to BT474 persister cells generated from nine days of treatment with 2 uM lapatinib. These data can be used to identify genes and pathways which are upregulated in persister cells, revealing potential therapeutic targets. 3 biological replicates of BT474 persister cells, two biological replicates of BT474 parental cells
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Project description:Genetic dissection of gene silencing mediated by H3K27 methylation
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Project description:Cancer persister cells which survive oncogene targeted therapies are sensitized to ferroptosis but mechanistic understanding of this vulnerability remains limited. Here, we found that while levels of iron, glutathione and various ferroptosis suppressing enzymes vary among persister cell types, ferroptosis suppressor protein 1 (FSP1) is downregulated in multiple persister cell types and persister cells which survive glutathione peroxidase 4 (GPX4) inhibition rely upon residual FSP1 to survive. Furthermore, persister cells which survive GPX4 inhibition downregulate oxidative phosphorylation, a key source of mitochondrial reactive oxygen species which are required for persister cell ferroptosis. We also found that persister cell treatment with histone deacetylase inhibitors induce reactive oxygen species and sensitize multiple persister cell types to GPX4 inhibition. Together, these findings reveal that FSP1 and histone deacetylases suppress persister cell ferroptosis.
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