Genetic and epigenetic instability of human pluripotent stem cells

Chung, Tung-Liang, Thaker, Nilay Y. and Wolvetang, Ernst J. (2011) Genetic and epigenetic instability of human pluripotent stem cells. The Open Stem Cell Journal, 3 1: 52-61. doi:10.2174/1876893801103010052

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Author Chung, Tung-Liang
Thaker, Nilay Y.
Wolvetang, Ernst J.
Title Genetic and epigenetic instability of human pluripotent stem cells
Journal name The Open Stem Cell Journal   Check publisher's open access policy
ISSN 1876-8938
Publication date 2011-01-01
Sub-type Critical review of research, literature review, critical commentary
DOI 10.2174/1876893801103010052
Open Access Status DOI
Volume 3
Issue 1
Start page 52
End page 61
Total pages 10
Place of publication Bussum, Netherlands
Publisher Bentham Open
Language eng
Subject 06 Biological Sciences
Abstract We tested whether DNA-methylation profiles account for inter-individual variation in body mass index (BMI) and height and whether they predict these phenotypes over and above genetic factors. Genetic predictors were derived from published summary results from the largest genome-wide association studies on BMI (n ∼ 350,000) and height (n ∼ 250,000) to date. We derived methylation predictors by estimating probe-trait effects in discovery samples and tested them in external samples. Methylation profiles associated with BMI in older individuals from the Lothian Birth Cohorts (LBCs, n = 1,366) explained 4.9% of the variation in BMI in Dutch adults from the LifeLines DEEP study (n = 750) but did not account for any BMI variation in adolescents from the Brisbane Systems Genetic Study (BSGS, n = 403). Methylation profiles based on the Dutch sample explained 4.9% and 3.6% of the variation in BMI in the LBCs and BSGS, respectively. Methylation profiles predicted BMI independently of genetic profiles in an additive manner: 7%, 8%, and 14% of variance of BMI in the LBCs were explained by the methylation predictor, the genetic predictor, and a model containing both, respectively. The corresponding percentages for LifeLines DEEP were 5%, 9%, and 13%, respectively, suggesting that the methylation profiles represent environmental effects. The differential effects of the BMI methylation profiles by age support previous observations of age modulation of genetic contributions. In contrast, methylation profiles accounted for almost no variation in height, consistent with a mainly genetic contribution to inter-individual variation. The BMI results suggest that combining genetic and epigenetic information might have greater utility for complex-trait prediction.
Formatted abstract
The preservation of the genetic and epigenetic integrity of human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) during in vitro propagation is critical for their use in both research and future therapeutic applications. It has been reported that hESCs and iPSCs have the ability to adapt to various culture conditions. However, human pluripotent stem cells cultured in serum free media can frequently accumulate point mutations, aneuploidy, and progressive epigenetic changes over prolonged culture in vitro for reasons that are poorly understood. The phenotypic and epigenetic changes brought about by the culture conditions can have significant impacts on their use in research and in clinical applications. An increased understanding of the potential effects of in vitro culture environments on pluripotent stem cell growth can enhance the development of improved culture systems for hESCs or iPSCs, and facilitate any future therapeutic applications using these cells. In this review, we first focus on the occurrence, potential causes and consequences of genetic and epigenetic unstable human pluripotent stem cells in vitro. We further discuss the current methods for detection and characterization of abnormal pluripotent stem cells that involve simply traditional karyotype analysis. All these observations highlight the need for novel screening strategies to determine the safety of hESCs or iPSCs and optimization and standardization of procedures for the generation and culture of pluripotent stem cells that minimize culture-induced epigenetic and genetic instability.
2011 Bentham Open
Keyword Pluripotent stem cells
Induced pluripotent stem cells
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID BB/F019394/1
Institutional Status UQ
Additional Notes Special Issue: "Present Status and Future Trends in Adult and Embryonic Stem Cell Research".

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collections: Official 2012 Collection
School of Medicine Publications
Australian Institute for Bioengineering and Nanotechnology Publications
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Created: Wed, 09 Mar 2011, 18:45:39 EST by Associate Professor Ernst Wolvetang on behalf of Aust Institute for Bioengineering & Nanotechnology