Pluripotent stem cells escape from senescence-associated DNA methylation changes

Koch, Carmen M.; Reck, Kristina; Shao, Kaifeng; Lin, Qiong; Joussen, Sylvia; Ziegler, Patrick; Walenda, Gudrun; Drescher, Wolf; Opalka, Bertram; May, Tobias; Brümmendorf, Tim H.; Zenke, Martin; Šarić, Tomo; Wagner, Wolfgang

doi:10.1101/gr.141945.112

Cited by 115 publications

(163 citation statements)

References 78 publications

(87 reference statements)

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“…These regulatory proteins included transcriptional repressor CTCF, polycomb protein EZH2 and histone 2A member Z. A previous study by Koch et al, using pluripotent stem cells, linked regions of senescence-associated hypomethylation to binding sites for polycomb proteins (49). While we could not access data for all of the polycomb proteins they investigated, both our study and theirs observed focal hypomethylation at EZH2 binding sites.…”

Section: Results Summary and Comparison With Literaturecontrasting

confidence: 41%

A methylome-wide study of aging using massively parallel sequencing of the methyl-CpG-enriched genomic fraction from blood in over 700 subjects

McClay¹,

Åberg²,

Clark³

et al. 2013

Human Molecular Genetics

150

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The central importance of epigenetics to the aging process is increasingly being recognized. Here we perform a methylome-wide association study (MWAS) of aging in whole blood DNA from 718 individuals, aged 25 -92 years (mean 5 55). We sequenced the methyl-CpG-enriched genomic DNA fraction, averaging 67.3 million reads per subject, to obtain methylation measurements for the ∼27 million autosomal CpGs in the human genome. Following extensive quality control, we adaptively combined methylation measures for neighboring, highly-correlated CpGs into 4 344 016 CpG blocks with which we performed association testing. Eleven age-associated differentially methylated regions (DMRs) passed Bonferroni correction (P-value < 1.15 3 10 28 ). Top findings replicated in an independent sample set of 558 subjects using pyrosequencing of bisulfite-converted DNA (min P-value < 10 230 ). To examine biological themes, we selected 70 DMRs with false discovery rate of <0.1. Of these, 42 showed hypomethylation and 28 showed hypermethylation with age. Hypermethylated DMRs were more likely to overlap with CpG islands and shores. Hypomethylated DMRs were more likely to be in regions associated with polycomb/regulatory proteins (e.g. EZH2) or histone modifications H3K27ac, H3K4m1, H3K4m2, H3K4m3 and H3K9ac. Among genes implicated by the top DMRs were protocadherins, homeobox genes, MAPKs and ryanodine receptors. Several of our DMRs are at genes with potential relevance for age-related disease. This study successfully demonstrates the application of next-generation sequencing to MWAS, by interrogating a large proportion of the methylome and returning potentially novel age DMRs, in addition to replicating several loci implicated in previous studies using microarrays.

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Section: Results Summary and Comparison With Literaturecontrasting

confidence: 41%

A methylome-wide study of aging using massively parallel sequencing of the methyl-CpG-enriched genomic fraction from blood in over 700 subjects

McClay¹,

Åberg²,

Clark³

et al. 2013

Human Molecular Genetics

150

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show abstract

“…iPS cells show high Ezh2 expression (Fig. 1A-D) and also overcome senescence [36]. Therefore, iPS cell generation appears to be linked to high Ezh2 expression.…”

Section: Forced Ezh2 Expression Enhances Reprogramming Efficiencymentioning

confidence: 99%

The Polycomb Protein Ezh2 Impacts on Induced Pluripotent Stem Cell Generation

DingXiaolei

WangXiaoying

SontagStephanie

et al. 2014

Stem Cells and Development

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“…Some of these senescence-associated DNAm (SA-DNAm) changes are almost linearly acquired during culture expansion and can therefore be used as biomarker for the state of cellular aging (5–7). Notably, SA-DNAm changes are enriched in developmental genes, such as homeobox genes, and they can be reversed by reprogramming into induced pluripotent stem cells (iPSCs) (4,7,8). This indicates that SA-DNAm changes—and hence also the process of replicative senescence—are somehow regulated, but the underlying mechanism is still unclear.…”

Section: Introductionmentioning

confidence: 99%

The lncRNA HOTAIR impacts on mesenchymal stem cellsviatriple helix formation

et al. 2016

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There is a growing perception that long non-coding RNAs (lncRNAs) modulate cellular function. In this study, we analyzed the role of the lncRNA HOTAIR in mesenchymal stem cells (MSCs) with particular focus on senescence-associated changes in gene expression and DNA-methylation (DNAm). HOTAIR binding sites were enriched at genomic regions that become hypermethylated with increasing cell culture passage. Overexpression and knockdown of HOTAIR inhibited or stimulated adipogenic differentiation of MSCs, respectively. Modification of HOTAIR expression evoked only very moderate effects on gene expression, particularly of polycomb group target genes. Furthermore, overexpression and knockdown of HOTAIR resulted in DNAm changes at HOTAIR binding sites. Five potential triple helix forming domains were predicted within the HOTAIR sequence based on reverse Hoogsteen hydrogen bonds. Notably, the predicted triple helix target sites for these HOTAIR domains were also enriched in differentially expressed genes and close to DNAm changes upon modulation of HOTAIR. Electrophoretic mobility shift assays provided further evidence that HOTAIR domains form RNA–DNA–DNA triplexes with predicted target sites. Our results demonstrate that HOTAIR impacts on differentiation of MSCs and that it is associated with senescence-associated DNAm. Targeting of epigenetic modifiers to relevant loci in the genome may involve triple helix formation with HOTAIR.

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Pluripotent stem cells escape from senescence-associated DNA methylation changes

Cited by 115 publications

References 78 publications

A methylome-wide study of aging using massively parallel sequencing of the methyl-CpG-enriched genomic fraction from blood in over 700 subjects

A methylome-wide study of aging using massively parallel sequencing of the methyl-CpG-enriched genomic fraction from blood in over 700 subjects

The Polycomb Protein Ezh2 Impacts on Induced Pluripotent Stem Cell Generation

The lncRNA HOTAIR impacts on mesenchymal stem cellsviatriple helix formation

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