Culture-induced recurrent epigenetic aberrations in human pluripotent stem cells
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ABSTRACT:
PROVIDER: PRJNA389209 | ENA |
REPOSITORIES: ENA
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Project description:Human pluripotent stem cells (hPSCs) are an important player in disease modeling and regenerative medicine. Nonetheless, multiple studies uncovered their inherent genetic instability upon prolonged culturing, where specific chromosomal aberrations provide cells with a growth advantage. These positively selected modifications have dramatic effects on multiple cellular characteristics. Epigenetic aberrations also possess the potential of changing gene expression and altering cellular functions. In the current study, we assessed the landscape of DNA methylation aberrations during prolonged culturing of hPSCs, and defined a set of genes which are recurrently hypermethylated and silenced. We further focused on one of these genes, testis-specific Y-encoded like protein 5 (TSPYL5), and demonstrated that when silenced, differentiation-related genes and tumor-suppressor genes are downregulated, while pluripotency- and growth-promoting genes are upregulated. This process is similar to the hypermethylation-mediated inactivation of certain genes during tumor development. Our analysis highlights the existence and importance of recurrent epigenetic aberrations in hPSCs during prolonged culturing.
2017-08-17 | GSE99650 | GEO
Project description:Human pluripotent stem cells (hPSCs) are an important player in disease modeling and regenerative medicine. Nonetheless, multiple studies uncovered their inherent genetic instability upon prolonged culturing, where specific chromosomal aberrations provide cells with a growth advantage. These positively selected modifications have dramatic effects on multiple cellular characteristics. Epigenetic aberrations also possess the potential of changing gene expression and altering cellular functions. In the current study, we assessed the landscape of DNA methylation aberrations during prolonged culturing of hPSCs, and defined a set of genes which are recurrently hypermethylated and silenced. We further focused on one of these genes, testis-specific Y-encoded like protein 5 (TSPYL5), and demonstrated that when silenced, differentiation-related genes and tumor-suppressor genes are downregulated, while pluripotency- and growth-promoting genes are upregulated. This process is similar to the hypermethylation-mediated inactivation of certain genes during tumor development. Our analysis highlights the existence and importance of recurrent epigenetic aberrations in hPSCs during prolonged culturing.
2017-08-17 | GSE99651 | GEO
Project description:Human pluripotent stem cells (hPSCs) are an important player in disease modeling and regenerative medicine. Nonetheless, multiple studies uncovered their inherent genetic instability upon prolonged culturing, where specific chromosomal aberrations provide cells with a growth advantage. These positively selected modifications have dramatic effects on multiple cellular characteristics. Epigenetic aberrations also possess the potential of changing gene expression and altering cellular functions. In the current study we assessed the landscape of DNA methylation aberrations during prolonged culturing of hPSCs, and defined a set of genes which are recurrently hypermethylated and silenced. We further focused on one of these genes, testis-specific Y-encoded like protein 5 (TSPYL5), and demonstrated that when silenced, differentiation-related genes and tumor-suppressor genes are downregulated, while pluripotency- and growth promoting genes are upregulated. This process is similar to the hypermethylation-mediated inactivation of certain genes during tumor development. Our analysis highlights the existence and importance of recurrent epigenetic aberrations in hPSCs during prolonged culturing.
| S-EPMC5587343 | biostudies-literature
Project description:Human pluripotent stem cells hold great potential for regenerative medicine, but existing cell types have imitations. Human embryonic stem cells derived from fertilized embryos (IVF-ESCs) are considered the “gold standard”, but are allogeneic to potential recipients. Autologous induced pluripotent stem cells (iPSCs) can be produced from somatic cells by forced expression of pluripotency-associated factors, but are prone to genetic and epigenetic aberrations. To determine whether accumulation of such aberrations is intrinsic to somatic cell reprogramming, or secondary to the reprogramming method, we employed an alternative approach by somatic cell nuclear transfer (SCNT). SCNT-based reprogramming to NT-ESCs is mediated by factors present in oocyte’s cytoplasm, thus mimicking early embryogenesis. We generated genetically matched pluripotent stem cells and conducted genome-wide genetic, epigenetic and transcriptional analyses. We discovered that unlike iPSCs, NT-ESCs have a low burden of de novo copy number variations (CNVs), reflecting superior maintenance of genetic stability. Moreover, DNA methylation and transcriptome profiles of NT-ESCs corresponded closely to those of IVF-ESCs. In contrast, iPSCs harbored methylation abnormalities including residual CpG methylation typical of parental fibroblasts, suggesting incomplete reprogramming. We conclude that human somatic cells can be faithfully reprogrammed to pluripotency by SCNT with the potential to satisfy the clinical requirements for cell replacement therapies. Bisulphite converted DNAs of two IVF-ESCs, two sendai produced iPSC lines, two retro-virus produced iPSC lines, four NT-ESCs, and the parental fibroblast were hybridized to the Illumina Infinium HumanMethylation 450K Beadchip
2014-07-08 | E-GEOD-53060 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-08-17 | GSE99652 | GEO
Project description:Culture-induced recurrent epigenetic aberrations in human pluripotent stem cells [methylation]
| PRJNA389213 | ENA
Project description:Human pluripotent stem cells hold great potential for regenerative medicine, but available cell types have important limitations. While embryonic stem cells derived from fertilized embryos (IVF-ESCs) are considered the "gold standard" of pluripotency, they are allogeneic to potential recipients. Autologous induced pluripotent stem cells (iPSCs) are prone to epigenetic and transcriptional aberrations. To determine whether accumulation of such aberrations is intrinsic to somatic cell reprogramming or secondary to the reprogramming method, we generated a genetically matched collection of human IVF-ESCs, iPSCs, and ESCs derived by somatic cell nuclear transfer (SCNT; NT-ESCs), and subjected them to genome-wide genetic, epigenetic and transcriptional analyses. SCNT-based reprogramming is mediated by the full complement of oocyte cytoplasmic factors, thus closely recapitulating early embryogenesis. NT-ESCs and iPSCs derived from the same somatic donor cells contained comparable numbers of de novo copy number variations (CNVs), suggesting that the two reprogramming methods may not differ significantly in mutagenic or selective pressure. On the other hand, the DNA methylation and transcriptome profiles of NT-ESCs corresponded very closely to those of IVF-ESCs, while iPSCs differed markedly from IVF-ESCs and harbored residual DNA methylation patterns typical of parental fibroblasts, suggesting incomplete reprogramming. We conclude that human somatic cells can be faithfully reprogrammed to pluripotency by SCNT and are therefore ideal candidates for cell replacement therapies. Duplicate cDNA libraries of two IVF-ESCs, three sendai produced iPSC lines, two retro-virus produced iPSC lines, four NT-ESCs, and the parental fibroblast line were sequenced using Illumina HiSeq 2000. The sequence reads were mapped to hg19 reference genome and hits that passed quality filters were analyzed for differential expression.
2014-07-08 | E-GEOD-53094 | biostudies-arrayexpress
Project description:Culture-induced recurrent epigenetic aberrations in human pluripotent stem cells [RNA-seq]
| PRJNA389212 | ENA
Project description:Human pluripotent stem cells hold great potential for regenerative medicine, but existing cell types have imitations. Human embryonic stem cells derived from fertilized embryos (IVF-ESCs) are considered the “gold standard”, but are allogeneic to potential recipients. Autologous induced pluripotent stem cells (iPSCs) can be produced from somatic cells by forced expression of pluripotency-associated factors, but are prone to genetic and epigenetic aberrations. To determine whether accumulation of such aberrations is intrinsic to somatic cell reprogramming, or secondary to the reprogramming method, we employed an alternative approach by somatic cell nuclear transfer (SCNT). SCNT-based reprogramming to NT-ESCs is mediated by factors present in oocyte’s cytoplasm, thus mimicking early embryogenesis. We generated genetically matched pluripotent stem cells and conducted genome-wide genetic, epigenetic and transcriptional analyses. We discovered that unlike iPSCs, NT-ESCs have a low burden of de novo copy number variations (CNVs), reflecting superior maintenance of genetic stability. Moreover, DNA methylation and transcriptome profiles of NT-ESCs corresponded closely to those of IVF-ESCs. In contrast, iPSCs harbored methylation abnormalities including residual CpG methylation typical of parental fibroblasts, suggesting incomplete reprogramming. We conclude that human somatic cells can be faithfully reprogrammed to pluripotency by SCNT with the potential to satisfy the clinical requirements for cell replacement therapies.
2014-07-08 | GSE53060 | GEO
Project description:Human pluripotent stem cells hold great potential for regenerative medicine, but available cell types have important limitations. While embryonic stem cells derived from fertilized embryos (IVF-ESCs) are considered the "gold standard" of pluripotency, they are allogeneic to potential recipients. Autologous induced pluripotent stem cells (iPSCs) are prone to epigenetic and transcriptional aberrations. To determine whether accumulation of such aberrations is intrinsic to somatic cell reprogramming or secondary to the reprogramming method, we generated a genetically matched collection of human IVF-ESCs, iPSCs, and ESCs derived by somatic cell nuclear transfer (SCNT; NT-ESCs), and subjected them to genome-wide genetic, epigenetic and transcriptional analyses. SCNT-based reprogramming is mediated by the full complement of oocyte cytoplasmic factors, thus closely recapitulating early embryogenesis. NT-ESCs and iPSCs derived from the same somatic donor cells contained comparable numbers of de novo copy number variations (CNVs), suggesting that the two reprogramming methods may not differ significantly in mutagenic or selective pressure. On the other hand, the DNA methylation and transcriptome profiles of NT-ESCs corresponded very closely to those of IVF-ESCs, while iPSCs differed markedly from IVF-ESCs and harbored residual DNA methylation patterns typical of parental fibroblasts, suggesting incomplete reprogramming. We conclude that human somatic cells can be faithfully reprogrammed to pluripotency by SCNT and are therefore ideal candidates for cell replacement therapies. 16 matched samples, two IVF-ESCs, five sendai produced iPSC lines, two retro-virus produced iPSC lines, four NT-ESCs, the parental fibroblast line, and the sperm and oocyte donor were genotyped using the Illumina Omni5, which interrogates 4.3 million SNPs across the human genome. Additionally, matched samples from a patient with Leigh syndrome, a NT-ESC line, three iPSC lines, and the parental fibroblast line were genotyped using the Illumina Omni5.
2014-07-08 | E-GEOD-53141 | biostudies-arrayexpress