Transcriptional response to aminoglycoside antibiotics in cochlear hair cells at 3 hour
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE66775 | GEO | 2015/04/30
SECONDARY ACCESSION(S): PRJNA277942
REPOSITORIES: GEO
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Project description:We purified Atoh1-GFP positive hair cells from organotypic cultures of P1 cochlea 3 hours after 0.5mM gentamicin treatment and performed RNA sequencing to profile the early transcriptional response of hair cells to aminoglycoside antibiotics. Levels of mRNA in gentamicin-treated hair cells (three replicates) were compared to untreated hair cells (three replicates). GFP negative, non-hair cells populations from treated organs were compared to those from untreated organs (three replicates for each condition).
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Project description:Strategies to overcome irreversible cochlear hair cell (HC) damage and loss are of vital importance to develop a treatment for hearing loss. HC regeneration in adult cochlea relies on a two-phase process: 1) Reprogramming mature cochlear (SCs) to regain the properties of their younger selves; 2) Activating Atoh1, a gene responsible for HC fate-determining, in the reprogrammed adult SCs for HC regeneration. We have shown that, by transient co-activation of Myc and NICD (Notch1 intracellular domain), the adult mouse cochlea can be successfully reprogrammed to a relatively younger stage and regain progenitor capacity, with the regeneration of HCs following Atoh1 overexpression in vitro and in vivo. To identify molecules to reprogram mature cochlear SCs and HC regeneration, we utilized single-cell RNA sequencing and uncovered the pathways and their target genes underlying MYC/NICD-mediated reprogramming. We used an in-house adult cochlea explant culture system and carried out single-cell RNA sequencing to examine the gene expression profiles of cochlear explants from a transgenic mouse model, rtTa/tet-Myc/-tet-NICD, in response to Dox-induced MYC/NICD co-activation. We compared gene expression profiles between Atoh1 activation vs. MYC/NICD/Atoh1 co-activation.
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Project description:Enterobacter cloacae is a Gram-negative nosocomial pathogen of the ESKAPE priority group with increasing multi-drug resistance via the acquisition of resistance plasmids. However, E. cloacae can also display phenotypic antimicrobial resistance, such as heteroresistance or persistence. Here we report that E. cloacae ATCC 13047 and six strains isolated from patients with blood infections display heteroresistance or persistence to aminoglycosides. E. cloacae heteroresistance is transient, accompanied with formation of "petite" colonies and increased MIC against gentamicin and other aminoglycosides used in the clinic, but not other antibiotic classes. To explore the underlying mechanisms, we performed RNA sequencing of heteroresistant bacteria, which revealed global gene-expression changes and a signature of the CpxRA cell envelope stress response. Deletion of the cpxRA two-component system abrogated aminoglycoside heteroresistance and petite colony formation, pointing to its indispensable role in phenotypic resistance. The introduction of a constitutively active allele of cpxA led to high aminoglycoside MICs, consistent with cell envelope stress driving these behaviours in E. cloacae. Cell envelope stress can be caused by environmental cues, including heavy metals. Indeed, bacterial exposure to copper increased gentamicin MIC in the wild type, but not the ΔcpxRA mutant. Moreover, copper exposure also elevated the gentamicin MICs of bloodstream isolates, suggesting that CpxRA- and copper-dependent aminoglycoside resistance is broadly conserved in E. cloacae strains. Altogether, we establish that E. cloacae relies on transcriptional reprogramming via the envelope stress response pathway for transient resistance to a major class of frontline antibiotic.
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Project description:This study examined transcripts that are enriched in neonatal mouse cochlear hair cells. Hair cells were purified by FACS sorting for GFP fluorescence from the cochleas of transgenic mice in which the endogenous Atoh1 gene was fused with GFP Two replicates of GFP+ hair cells were compared with all other cochlear cell types that were GFP-
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Project description:This study examined transcripts that are enriched in neonatal mouse cochlear hair cells. Hair cells were purified by FACS sorting for GFP fluorescence from the cochleas of transgenic mice in which the endogenous Atoh1 gene was fused with GFP
2015-03-01 | GSE65633 | GEO
Project description:Strategies to overcome irreversible cochlear hair cell (HC) damage and loss are of vital importance to develop a treatment for hearing loss. HC regeneration in adult cochlea relies on a two-phase process: 1) Reprogramming mature cochlear (SCs) to regain the properties of their younger selves; 2) Activating Atoh1, a gene responsible for HC fate-determining, in the reprogrammed adult SCs for HC regeneration. We have shown that, by transient co-activation of Myc and NICD (Notch1 intracellular domain), the adult mouse cochlea can be successfully reprogrammed to a relatively younger stage and regain progenitor capacity, with the regeneration of HCs following Atoh1 overexpression in vitro and in vivo. We identified a combination (the cocktail) of drug-like molecules composing of small molecules and siRNAs to activate the pathways of Myc, Notch1, Wnt and cAMP. To identify molecules to reprogram mature cochlear SCs and HC regeneration, we utilized single-cell RNA sequencing and uncovered the pathways and their target genes underlying chemical-mediated reprogramming. We used an in-house adult cochlea explant culture system and carried out single-cell RNA sequencing to examine the gene expression profiles of cochlear explants, in response to chemical-induced reprogramming. We compared gene expression profiles between Vehicle/ad.Atoh1 activation vs. Cocktail (chemical reprogramming)/ad.Atoh1 activation.
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