Ascorbic acid prevents loss of Dlk1-Dio3 imprinting and facilitates generation of all–iPS cell mice from terminally differentiated B cells

Stadtfeld, Matthias; Apostolou, Effie; Ferrari, Francesco; Choi, Jiho; Walsh, Ryan; Chen, Taiping; Ooi, Steen K.T.; Kim, Sang Yong; Bestor, Timothy H.; Shioda, Toshi; Park, Peter J.; Hochedlinger, Konrad

doi:10.1038/ng.1110

Cited by 253 publications

(270 citation statements)

References 34 publications

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“…New mouse study from the Hochedlinger group showed that VC attenuated hypermethylation of Dlk1-Dio3 by disenabling intergenic differentially methylated region (IG-DMR) to recruit Dnmt3a (a DNA methyltransferase) in the progress of reprogramming. Interestingly, mature B cell-derived iPSCs were enabled to generate entire adult mice (all-iPSCs mice) when VC was added to the culture medium (Stadtfeld et al, 2012). The results are in agreement with a previous report that iPSCs with aberrant silenced Dlk1-Dio3 cluster failed to yield viable all-iPSCs mice (Stadtfeld et al, 2010).…”

supporting

confidence: 90%

Non-viral iPSCs: a safe way for therapy?

Zhang

Guan

et al. 2012

Protein Cell

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supporting

confidence: 90%

Non-viral iPSCs: a safe way for therapy?

Zhang

Guan

et al. 2012

Protein Cell

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“…Dnmt3a and Dnmt3b have also been shown to be responsible for the methylation of most imprinted regions. Analyses of differentially methylated regions (DMR) indicated that aberrant DNA methylation is responsible for the transcriptional silencing of the Dlk1-Dio3 region in partially reprogrammed pluripotent iPSCs [20,42]. We found that, through targeting Dnmt3a and Dnmt3b, miR29b enhanced the expression of E-cadherin, Epcam, and Cldn3 while inhibiting the expression of mesenchymal genes including Snail, Zeb1, and Cdh2 during the reprogramming process.…”

Section: Discussionmentioning

confidence: 97%

microRNA-29b is a novel mediator of Sox2 function in the regulation of somatic cell reprogramming

Guo¹,

Liu

Wang

et al. 2012

Cell Res

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Fibroblasts can be reprogrammed into induced pluripotent stem cells (iPSCs) by the application of Yamanaka factors (OSKM), but the mechanisms underlying this reprogramming remain poorly understood. Here, we report that Sox2 directly regulates endogenous microRNA-29b (miR-29b) expression during iPSC generation and that miR-29b expression is required for OSKM-and OSK-mediated reprogramming. Mechanistic studies show that Dnmt3a and Dnmt3b are in vivo targets of miR-29b and that Dnmt3a and Dnmt3b expression is inversely correlated with miR-29b expression during reprogramming. Moreover, the effect of miR-29b on reprogramming can be blocked by Dnmt3a or Dnmt3b overexpression. Further experiments indicate that miR-29b-DNMT signaling is significantly involved in the regulation of DNA methylation-related reprogramming events, such as mesenchymal-to-epithelial transition (MET) and Dlk1-Dio3 region transcription. Thus, our studies not only reveal that miR-29b is a novel mediator of reprogramming factor Sox2 but also provide evidence for a multistep mechanism in which Sox2 drives a miR-29b-DNMT signaling axis that regulates DNA methylation-related events during reprogramming.

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“…This set comprises genes with well-known effects on the reprogramming process, such as Meg3 and Notch1. 33,34 Additionally, it contains 5 genes from the metallothionein family, all of them located within a 50 kb region on chromosome 16, therefore indicating an involvement of this loci in the reprogramming process. Taken together, our data suggest that in iPSCs, mostly stochastic expression of the genes that are rarely found in ESCs is observed, although some genes aberrantly expressed in iPSCs could be effectively used to qualify reprogrammed cells.…”

Section: Discussionmentioning

confidence: 99%

An integrative analysis of reprogramming in human isogenic system identified a clone selection criterion

et al. 2016

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Kiselev (2016) An integrative analysis of reprogramming in human isogenic system identified a clone selection criterion, Cell Cycle, 15:7, 986-997, DOI: 10.1080/15384101.2016 ABSTRACTThe pluripotency of newly developed human induced pluripotent stem cells (iPSCs) is usually characterized by physiological parameters; i.e., by their ability to maintain the undifferentiated state and to differentiate into derivatives of the 3 germ layers. Nevertheless, a molecular comparison of physiologically normal iPSCs to the "gold standard" of pluripotency, embryonic stem cells (ESCs), often reveals a set of genes with different expression and/or methylation patterns in iPSCs and ESCs. To evaluate the contribution of the reprogramming process, parental cell type, and fortuity in the signature of human iPSCs, we developed a complete isogenic reprogramming system. We performed a genome-wide comparison of the transcriptome and the methylome of human isogenic ESCs, 3 types of ESC-derived somatic cells (fibroblasts, retinal pigment epithelium and neural cells), and 3 pairs of iPSC lines derived from these somatic cells. Our analysis revealed a high input of stochasticity in the iPSC signature that does not retain specific traces of the parental cell type and reprogramming process. We showed that 5 iPSC clones are sufficient to find with 95% confidence at least one iPSC clone indistinguishable from their hypothetical isogenic ESC line. Additionally, on the basis of a small set of genes that are characteristic of all iPSC lines and isogenic ESCs, we formulated an approach of "the best iPSC line" selection and confirmed it on an independent dataset.

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Ascorbic acid prevents loss of Dlk1-Dio3 imprinting and facilitates generation of all–iPS cell mice from terminally differentiated B cells

Cited by 253 publications

References 34 publications

Non-viral iPSCs: a safe way for therapy?

Non-viral iPSCs: a safe way for therapy?

microRNA-29b is a novel mediator of Sox2 function in the regulation of somatic cell reprogramming

An integrative analysis of reprogramming in human isogenic system identified a clone selection criterion

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