Epigenetic modulations rendering cell-to-cell variability and phenotypic metastability

Spencer, Shawal; Gugliotta, Agustina; Gödecke, Natascha; Hauser, Hansjörg; Wirth, Dagmar

doi:10.1016/j.jgg.2016.05.008

Cited by 4 publications

(2 citation statements)

References 57 publications

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“…Cancer or non-cancer cell lines may be useful as a "carrier" to investigate direct or indirect interactions of a chemical with a reporter system [447], but "normal" cells that have not already been transformed are preferred with respect to initiation of non-genotoxic carcinogenic processes. Historically, the responses of reporter assays can be biased by technical issues (selection of vector, transfecting reagents, antibiotic response, variable transgene expression [448]), by crosstalk with endogenous cell receptors, epigenetic silencing of the construct [449], and cellular heterogeneity [450], so their use requires adequate cell characterization and key mechanisms identification, in order to minimise the problems. The interpretation of the data from epigenetic reporter systems also need to be accompanied by considerations of the spatial context and locus (euchromatin, heterochromatin) proximal to the integration sites that can influence the spreading of epigenetic marks.…”

Section: Reporter Systems In the Cellular Environmentmentioning

confidence: 99%

Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications

Desaulniers

Vasseur

Jacobs

et al. 2021

IJMS

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Epigenetics involves a series of mechanisms that entail histone and DNA covalent modifications and non-coding RNAs, and that collectively contribute to programing cell functions and differentiation. Epigenetic anomalies and DNA mutations are co-drivers of cellular dysfunctions, including carcinogenesis. Alterations of the epigenetic system occur in cancers whether the initial carcinogenic events are from genotoxic (GTxC) or non-genotoxic (NGTxC) carcinogens. NGTxC are not inherently DNA reactive, they do not have a unifying mode of action and as yet there are no regulatory test guidelines addressing mechanisms of NGTxC. To fil this gap, the Test Guideline Programme of the Organisation for Economic Cooperation and Development is developing a framework for an integrated approach for the testing and assessment (IATA) of NGTxC and is considering assays that address key events of cancer hallmarks. Here, with the intent of better understanding the applicability of epigenetic assays in chemical carcinogenicity assessment, we focus on DNA methylation and histone modifications and review: (1) epigenetic mechanisms contributing to carcinogenesis, (2) epigenetic mechanisms altered following exposure to arsenic, nickel, or phenobarbital in order to identify common carcinogen-specific mechanisms, (3) characteristics of a series of epigenetic assay types, and (4) epigenetic assay validation needs in the context of chemical hazard assessment. As a key component of numerous NGTxC mechanisms of action, epigenetic assays included in IATA assay combinations can contribute to improved chemical carcinogen identification for the better protection of public health.

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Section: Reporter Systems In the Cellular Environmentmentioning

confidence: 99%

Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications

Desaulniers

Vasseur

Jacobs

et al. 2021

IJMS

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“…, isogenic cells can express individual proteins in a highly heterogeneous manner . This concerns endogenous genes − as well as recombinant genes − including synthetic expression cassettes and is considered to arise from a plethora of different mechanisms. Among these, variations in the cellular states ( e.g.…”

Section: Discussionmentioning

confidence: 99%

Rational Design of Single Copy Expression Cassettes in Defined Chromosomal Sites Overcomes Intraclonal Cell-to-Cell Expression Heterogeneity and Ensures Robust Antibody Production

et al. 2020

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The expression of endogenous genes as well as transgenes depends on regulatory elements within and surrounding genes as well as their epigenetic modifications. Members of a cloned cell population often show pronounced cell-to-cell heterogeneity with respect to the expression of a certain gene. To investigate the heterogeneity of recombinant protein expression we targeted cassettes into two preselected chromosomal hot-spots in Chinese hamster ovary (CHO) cells. Depending on the gene of interest and the design of the expression cassette, we found strong expression variability that could be reduced by epigenetic modifiers, but not by site-specific recruitment of the modulator dCas9-VPR. In particular, the implementation of ubiquitous chromatin opening elements (UCOEs) reduced cell-to-cell heterogeneity and concomitantly increased expression. The application of this method to recombinant antibody expression confirmed that rational design of cell lines for production of transgenes with predictable and high titers is a promising approach.

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Genotypic and metabolic approaches towards the segregation of Klebsiella pneumoniae strains producing different antibiotic resistant enzymes

et al. 2017

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Epigenetic modulations rendering cell-to-cell variability and phenotypic metastability

Cited by 4 publications

References 57 publications

Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications

Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications

Rational Design of Single Copy Expression Cassettes in Defined Chromosomal Sites Overcomes Intraclonal Cell-to-Cell Expression Heterogeneity and Ensures Robust Antibody Production

Genotypic and metabolic approaches towards the segregation of Klebsiella pneumoniae strains producing different antibiotic resistant enzymes

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