A predictive model for drug bioaccumulation and bioactivity in Caenorhabditis elegans

Burns, Andrew R.; Wallace, Iain; Wildenhain, Jan; Tyers, Mike; Giaever, Guri; Bader, Gary D.; Nislow, Corey; Cutler, Sean R.; Roy, Peter J.

doi:10.1038/nchembio.380

Cited by 174 publications

(180 citation statements)

References 43 publications

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“…Paired two-tailed Student's t tests were used for statistical comparisons (ns, not significant; *P ≤ 0.05; **P ≤ 0.001; ***P ≤ 0.0001). C. elegans are resistant to tissue accumulation of exogenously applied ethanol and accumulate only ∼12% of the exogenous dose (35) because their cuticle is extremely resistant to passage by chemicals (36). One possible explanation for the failure of SWI/SNF mutants to develop AFT is that they have altered ethanol entry or metabolism, resulting in tissue ethanol concentrations different from those of wild-type animals.…”

Section: Resultsmentioning

confidence: 99%

SWI/SNF chromatin remodeling regulates alcohol response behaviors in Caenorhabditis elegans and is associated with alcohol dependence in humans

Mathies¹,

Blackwell²,

Austin³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Alcohol abuse is a widespread and serious problem. Understanding the factors that influence the likelihood of abuse is important for the development of effective therapies. There are both genetic and environmental influences on the development of abuse, but it has been difficult to identify specific liability factors, in part because of both the complex genetic architecture of liability and the influences of environmental stimuli on the expression of that genetic liability. Epigenetic modification of gene expression can underlie both genetic and environmentally sensitive variation in expression, and epigenetic regulation has been implicated in the progression to addiction. Here, we identify a role for the switching defective/sucrose nonfermenting (SWI/SNF) chromatin-remodeling complex in regulating the behavioral response to alcohol in the nematode Caenorhabditis elegans. We found that SWI/SNF components are required in adults for the normal behavioral response to ethanol and that different SWI/SNF complexes regulate different aspects of the acute response to ethanol. We showed that the SWI/SNF subunits SWSN-9 and SWSN-7 are required in neurons and muscle for the development of acute functional tolerance to ethanol. Examination of the members of the SWI/SNF complex for association with a diagnosis of alcohol dependence in a human population identified allelic variation in a member of the SWI/SNF complex, suggesting that variation in the regulation of SWI/SNF targets may influence the propensity to develop abuse disorders. Together, these data strongly implicate the chromatin remodeling associated with SWI/SNF complex members in the behavioral responses to alcohol across phyla.SWI/SNF | alcohol | C. elegans | chromatin remodeling | GWAS

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Section: Resultsmentioning

confidence: 99%

SWI/SNF chromatin remodeling regulates alcohol response behaviors in Caenorhabditis elegans and is associated with alcohol dependence in humans

Mathies¹,

Blackwell²,

Austin³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The nematode cuticle is an effective barrier for many toxins and limits the effectiveness of some pharmacological compounds (15), but it does not appear to be an effective barrier to water diffusion. Worms rapidly swell or shrink when exposed to hypotonicity or hypertonicity, respectively (18 -19, 42, 59, 107).…”

Section: Volume Recovery and Wnk/gck VI Signalingmentioning

confidence: 99%

Physiological and molecular mechanisms of salt and water homeostasis in the nematodeCaenorhabditis elegans

Choe

2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Choe KP. Physiological and molecular mechanisms of salt and water homeostasis in the nematode Caenorhabditis elegans. Am J Physiol Regul Integr Comp Physiol 305: R175-R186, 2013. First published June 5, 2013 doi:10.1152/ajpregu.00109.2013.-Intracellular salt and water homeostasis is essential for all cellular life. Extracellular salt and water homeostasis is also important for multicellular organisms. Many fundamental mechanisms of compensation for osmotic perturbations are well defined and conserved. Alternatively, molecular mechanisms of detecting salt and water imbalances and regulating compensatory responses are generally poorly defined for animals. Throughout the last century, researchers studying vertebrates and vertebrate cells made critical contributions to our understanding of osmoregulation, especially mechanisms of salt and water transport and organic osmolyte accumulation. Researchers have more recently started using invertebrate model organisms with defined genomes and well-established methods of genetic manipulation to begin defining the genes and integrated regulatory networks that respond to osmotic stress. The nematode Caenorhabditis elegans is well suited to these studies. Here, I introduce osmoregulatory mechanisms in this model, discuss experimental advantages and limitations, and review important findings. Key discoveries include defining genetic mechanisms of osmolarity sensing in neurons, identifying protein damage as a sensor and principle determinant of hypertonic stress resistance, and identification of a putative sensor for hypertonic stress associated with the extracellular matrix. Many of these processes and pathways are conserved and, therefore, provide new insights into salt and water homeostasis in other animals, including mammals. osmoregulation; cell volume; ion; organic osmolyte; protein homeostasis; model organism SALT AND WATER HOMEOSTASIS is a fundamental requirement for metazoan life. Ion and water transport mechanisms that compensate for changes in composition and volume of intracellular and extracellular compartments have been generally well defined using vertebrate cell and in vivo models (38). Alternatively, the upstream molecular mechanisms that animal cells use to sense deviations in salt and water balance and regulate compensatory responses are still poorly characterized (20). Studies in brewer's yeast demonstrate that osmotic signal detection and transduction within a single eukaryotic cell can be highly complex with numerous components, acting in parallel pathways, that often cross-talk with other processes (40,55). Osmotic signal detection and transduction are likely to be even more complex in metazoans, which require homeostasis of both the extracellular and intracellular compartments and integration of responses between cells. Genetics is an extremely powerful approach for identifying and characterizing genes and proteins that function in complex biological processes but has been underutilized in the field of osmosensing and signal transduction in metazoans. In...

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“…As previously described, the external/internal concentration of chemical exposure in worms is variable. A recent C. elegans study, in which thousands of chemicals were screened, derived a model for identifying chemical substructures with both increased and decreased likelihood for bioaccumulation and bioactivity in worms [53]. These guidelines are an important resource for designing chemical libraries specifically suited for screening in C. elegans.…”

Section: Chemical Modifiers Are Readily Analyzed In C Elegans α-Synumentioning

confidence: 99%

A Predictable Worm: Application of Caenorhabditis elegans for Mechanistic Investigation of Movement Disorders

Dexter

Caldwell

2012

Neurotherapeutics

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Summary Ongoing investigations into causes and cures for human movement disorders are important toward the elucidation of diseases such as Parkinson's disease (PD) and dystonia. The use of animal model systems can provide links to susceptibility factors, as well as therapeutic interventions. In this regard, the nematode roundworm, Caenorhabditis elegans, is ideal for examining age-dependent neurodegenerative disease studies. It is genetically tractable, has a short lifespan, and a well-defined nervous system. Green fluorescent protein is readily visualized in C. elegans because it is a transparent organism, thus the nervous system and factors that alter the viability of neurons can be directly examined in vivo. Through expression of the human PD-associated protein (α-synuclein in the worm dopamine neurons), neurodegeneration is observed in an age-dependent manner. Furthermore, expression of the early-onset dystonia-related protein torsinA increases vulnerability to endoplasmic reticulum (ER) stress in C. elegans, because torsinA is located in the ER. Here we provide an overview of collaborative studies we have conducted that collectively demonstrate the usefulness of the nematode model to discern functional effectors of dopaminergic neurodegeneration and ER stress that translate to mammalian data in the fields of PD and dystonia. Taken together, the application of C.elegans toward the evaluation of genetic modifiers for movement disorders research has predictive value and serves to accelerate the path forward for therapeutic interventions.

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A predictive model for drug bioaccumulation and bioactivity in Caenorhabditis elegans

Cited by 174 publications

References 43 publications

SWI/SNF chromatin remodeling regulates alcohol response behaviors in Caenorhabditis elegans and is associated with alcohol dependence in humans

SWI/SNF chromatin remodeling regulates alcohol response behaviors in Caenorhabditis elegans and is associated with alcohol dependence in humans

Physiological and molecular mechanisms of salt and water homeostasis in the nematodeCaenorhabditis elegans

A Predictable Worm: Application of Caenorhabditis elegans for Mechanistic Investigation of Movement Disorders

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