Recurrent Variations in DNA Methylation in Human Pluripotent Stem Cells and Their Differentiated Derivatives

Nazor, Kristopher L.; Altun, Gülşah; Lynch, C.; Tran, Ha Thi Thanh; Harness, Julie V.; Slavin, Ileana; Garitaonandia, Ibon; Müller, Franz‐Josef; Wang, Yu-Chieh; Boscolo, Francesca S.; Fakunle, Eyitayo S.; Dumevska, Biljana; Lee, Sunray; Park, Hyun Sook; Olee, Tsaiwei; D’Lima, Darryl D.; Semechkin, Ruslan; Parast, Mana M.; Galat, Vasiliy; Laslett, Andrew L.; Schmidt, Uli; Keirstead, Hans S.; Loring, Jeanne F.; Laurent, Louise C.

doi:10.1016/j.stem.2012.02.013

Cited by 360 publications

(487 citation statements)

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“…For example, the analysis of whole-genome DNA methylation profiles at single-nucleotide resolution in hiPSCs, their somatic cells of origin, and hESCs revealed the presence of more than 1,000 differentially methylated regions (DMRs) between hiPSCs and hESCs (11). Moreover, this analysis, and many others, demonstrated both the persistence of specific epigenetic marks from the somatic cell of origin (residual methylation) and the acquisition of unique methylation patterns in mouse iPSCs (miPSCs) and hiPSCs (11,(13)(14)(15)(16)(17)(18)(19)(20)(21). Interestingly, hiPSC lines also show incomplete reprogramming of non-CG methylation in regions proximal to telomeres and centromeres (11).…”

mentioning

confidence: 77%

Identification of a specific reprogramming-associated epigenetic signature in human induced pluripotent stem cells

Ruíz

Diep

Gore

et al. 2012

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

148

145

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Generation of human induced pluripotent stem cells (hiPSCs) by the expression of specific transcription factors depends on successful epigenetic reprogramming to a pluripotent state. Although hiPSCs and human embryonic stem cells (hESCs) display a similar epigenome, recent reports demonstrated the persistence of specific epigenetic marks from the somatic cell type of origin and aberrant methylation patterns in hiPSCs. However, it remains unknown whether the use of different somatic cell sources, encompassing variable levels of selection pressure during reprogramming, influences the level of epigenetic aberrations in hiPSCs. In this work, we characterized the epigenomic integrity of 17 hiPSC lines derived from six different cell types with varied reprogramming efficiencies. We demonstrate that epigenetic aberrations are a general feature of the hiPSC state and are independent of the somatic cell source. Interestingly, we observe that the reprogramming efficiency of somatic cell lines inversely correlates with the amount of methylation change needed to acquire pluripotency. Additionally, we determine that both shared and linespecific epigenetic aberrations in hiPSCs can directly translate into changes in gene expression in both the pluripotent and differentiated states. Significantly, our analysis of different hiPSC lines from multiple cell types of origin allow us to identify a reprogrammingspecific epigenetic signature comprised of nine aberrantly methylated genes that is able to segregate hESC and hiPSC lines regardless of the somatic cell source or differentiation state.I nduction of pluripotency in human somatic cells is an inefficient process that can be achieved by the expression of defined transcription factors (1-5). This reprogramming process involves global epigenetic remodeling and overcoming similar roadblocks present during cell transformation, which might affect genomic and epigenomic integrity (6). In fact, several recent reports have shown that human induced pluripotent stem cells (hiPSCs) contain genetic and epigenetic aberrations throughout their genome compared with their parental somatic cell populations or to human embryonic stem cells (hESCs) (7-12). For example, the analysis of whole-genome DNA methylation profiles at single-nucleotide resolution in hiPSCs, their somatic cells of origin, and hESCs revealed the presence of more than 1,000 differentially methylated regions (DMRs) between hiPSCs and hESCs (11). Moreover, this analysis, and many others, demonstrated both the persistence of specific epigenetic marks from the somatic cell of origin (residual methylation) and the acquisition of unique methylation patterns in mouse iPSCs (miPSCs) and hiPSCs (11,(13)(14)(15)(16)(17)(18)(19)(20)(21). Interestingly, hiPSC lines also show incomplete reprogramming of non-CG methylation in regions proximal to telomeres and centromeres (11). Altogether, these epigenetic aberrations might explain some of the observed transcriptional variation between hESC and hiPSC lines (22)(23)(24). In one of the most co...

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mentioning

confidence: 77%

Identification of a specific reprogramming-associated epigenetic signature in human induced pluripotent stem cells

Ruíz

Diep

Gore

et al. 2012

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

148

145

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“…We obtained the methylation data for 482,481 CpGs for 10 different tissues from (50), which used the Infinium HumanMethylation450 Beadchip. Each tissue had at least two biological replicates, which were averaged.…”

Section: Methodsmentioning

confidence: 99%

DNA methylation and evolution of duplicate genes

Keller

2014

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

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The evolutionary mechanisms underlying duplicate gene maintenance and divergence remain highly debated. Epigenetic modifications, such as DNA methylation, may contribute to duplicate gene evolution by facilitating tissue-specific regulation. However, the role of epigenetic divergence on duplicate gene evolution remains little understood. Here we show, using comprehensive data across 10 diverse human tissues, that DNA methylation plays critical roles in several aspects of duplicate gene evolution. We first demonstrate that duplicate genes are initially heavily methylated, before gradually losing DNA methylation as they age. Within each pair, DNA methylation divergence between duplicate partners increases with evolutionary age. Importantly, tissuespecific DNA methylation of duplicates correlates with tissuespecific expression, implicating DNA methylation as a causative factor for functional divergence of duplicate genes. These patterns are apparent in promoters but not in gene bodies, in accord with the complex relationship between gene-body DNA methylation and transcription. Remarkably, many duplicate gene pairs exhibit consistent division of DNA methylation across multiple, divergent tissues: For the majority (73%) of duplicate gene pairs, one partner is always hypermethylated compared with the other. This is indicative of a common underlying determinant of DNA methylation. The division of DNA methylation is also consistent with their chromatin accessibility profiles. Moreover, at least two sequence motifs known to interact with the Sp1 transcription factor mark promoters of more hypomethylated duplicate partners. These results demonstrate critical roles of DNA methylation, as well as complex interaction between genome and epigenome, on duplicate gene evolution.gene duplication | tissue specificity | epigenomics | genomics G ene duplication is a main process generating genomic repertoires for subsequent functional innovation (1, 2). Elucidating the mechanisms by which newly duplicated genes are retained and evolve new functions is one of the most fundamental problems in molecular evolution. Even though significant progresses have been made (3-9), detailed molecular mechanisms of duplicate gene divergence are not satisfactorily resolved (10, 11).Here we examine a relatively new avenue of research on duplicate gene evolution: the epigenetic divergence of duplicate genes and how this divergence might relate to functional differentiation of duplicate genes. We focus on DNA methylation. It has been proposed that epigenetic mechanisms such as DNA methylation may facilitate evolution by gene duplication (12). Rodin and Riggs (12) have demonstrated by computational modeling that rates of functional diversification such as subfunctionalization and neofunctionalization increase when epigenetic silencing of duplicates is possible. This advantage of epigenetic silencing is particularly significant when effective population sizes are small, as in humans (12).Some earlier observations are consistent with epigenetic silencing...

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“…To verify whether this CpG signature is also characteristic for other human PSC lines, these CpGs and CpG loci were used to distinguish between ESCs and iPSCs in the GSE31848 data set. 16 There were no clear ESC and iPSC clusters or altered methylation of the CBLN4 gene in iPSCs among pluripotent cells (Fig. 5D).…”

Section: Establishment Of the Hesm01-oskmn-dox Isogenic Systemmentioning

confidence: 97%

“…Thus, individual genome characteristics impact cell line diversity. Later, a comprehensive characterization of dozens of human PSC lines was performed, 4,16 demonstrating that as more cell lines are taken into analysis, fewer differences are observed. 17 Recently, an effective tool to validate selfrenewal potential, as well as differentiated states of iPSC lines with diverse genetic backgrounds, has been developed.…”

Section: Introductionmentioning

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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Recurrent Variations in DNA Methylation in Human Pluripotent Stem Cells and Their Differentiated Derivatives

Cited by 360 publications

References 50 publications

Identification of a specific reprogramming-associated epigenetic signature in human induced pluripotent stem cells

Identification of a specific reprogramming-associated epigenetic signature in human induced pluripotent stem cells

DNA methylation and evolution of duplicate genes

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

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