Regulation of DNA methylation landscape in human somatic cell reprogramming by miR-29 family
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PROVIDER: PRJNA322541 | ENA |
REPOSITORIES: ENA
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Project description:Reprogramming to pluripotency after overexpression of OCT4, SOX2, KLF4 and MYC is accompanied by global genomic and epigenomic changes. Histone modification and DNA methylation states in iPSCs have been shown to be highly similar with embryonic stem cells (ESCs). However, epigenetic differences still exist between iPSCs and ESCs. In particular, aberrant DNA methylation states found in iPSCs are a major concern for using iPSCs in a clinical setting. Thus, it is critical to find factors that regulate DNA methylation states in reprogramming. Here, we found that the miR-29 family is an important epigenetic regulator during human somatic cell reprogramming. Our global DNA methylation and hydroxymethylation analysis shows that DNA demethylation is a major event mediated by miR-29a depletion during early reprogramming, and that iPSCs derived from miR-29a depletion are epigenetically closer to ESCs. Our findings uncover an important miRNA-based approach to generate clinically robust iPSCs.
2016-05-24 | GSE81790 | GEO
Project description:Reprogramming to pluripotency after overexpression of OCT4, SOX2, KLF4 and MYC is accompanied by global genomic and epigenomic changes. Histone modification and DNA methylation states in iPSCs have been shown to be highly similar with embryonic stem cells (ESCs). However, epigenetic differences still exist between iPSCs and ESCs. In particular, aberrant DNA methylation states found in iPSCs are a major concern for using iPSCs in a clinical setting. Thus, it is critical to find factors that regulate DNA methylation states in reprogramming. Here, we found that the miR-29 family is an important epigenetic regulator during human somatic cell reprogramming. Our global DNA methylation and hydroxymethylation analysis shows that DNA demethylation is a major event mediated by miR-29a depletion during early reprogramming, and that iPSCs derived from miR-29a depletion are epigenetically closer to ESCs. Our findings uncover an important miRNA-based approach to generate clinically robust iPSCs.
2016-05-24 | GSE81793 | GEO
Project description:Reprogramming to pluripotency after overexpression of OCT4, SOX2, KLF4 and MYC is accompanied by global genomic and epigenomic changes. Histone modification and DNA methylation states in iPSCs have been shown to be highly similar with embryonic stem cells (ESCs). However, epigenetic differences still exist between iPSCs and ESCs. In particular, aberrant DNA methylation states found in iPSCs are a major concern for using iPSCs in a clinical setting. Thus, it is critical to find factors that regulate DNA methylation states in reprogramming. Here, we found that the miR-29 family is an important epigenetic regulator during human somatic cell reprogramming. Our global DNA methylation and hydroxymethylation analysis shows that DNA demethylation is a major event mediated by miR-29a depletion during early reprogramming, and that iPSCs derived from miR-29a depletion are epigenetically closer to ESCs. Our findings uncover an important miRNA-based approach to generate clinically robust iPSCs.
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Project description: Not available
| S-EPMC4945581 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2016-05-24 | GSE81794 | GEO
Project description:Somatic cell reprogramming by transcription factors and other modifiers such as small molecules or miRNAs has opened broad avenues for the study of developmental processes, cell fate determination, and interplay of molecular mechanisms in signaling pathways. However, many of the mechanisms that drive nuclear reprogramming itself remain yet to be elucidated. Here, we analyzed the role of miR-29 during reprogramming in more detail. Therefore, we evaluated miR-29 expression during reprogramming of fibroblasts transduced with lentiviral OKS and OKSM vectors and we show that addition of c-MYC to the reprogramming factor cocktail decreases miR-29 expression levels. Moreover, we found that transfection of pre-miR-29a strongly decreased OKS-induced formation of GFP+- colonies in MEF-cells from Oct4-eGFP reporter mouse, whereas anti-miR-29a showed the opposite effect. Furthermore, we studied two pathways which are important for reprogramming and which involve miR-29 targets: active DNA-demethylation and Wntsignaling. We show that inhibition of active DNA-demethylation as well as activation of Wnt-signaling leads to decreased reprogramming efficiency. Moreover, transfection of premiR-29 resulted in elevated expression of β-Catenin transcriptional target sFRP2 and increased TCF/LEF-reporter activity. Finally, we report that Gsk3-β is a direct target of miR-29 in MEF-cells. Together, our findings contribute to the understanding of the molecular mechanisms by which miR29 influences reprogramming.
2016-10-05 | GSE87609 | GEO
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2018-02-27 | GSE107003 | GEO
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2019-12-04 | PXD016575 | Pride
Project description:N6-methyladenosine (m6A), the most abundant reversible modification on eukaryote messenger RNA, is recognized by a series of readers, including the YT521-B homology domain family (YTHDF) proteins, which are coupled to perform physiological functions. Here, we report that YTHDF2 and YTHDF3, but not YTHDF1, are required for reprogramming of somatic cells into induced pluripotent stem cells (iPSCs). Mechanistically, we found that YTHDF3 recruits the PAN2-PAN3 deadenylase complex and conduces to reprogramming by promoting mRNA clearance of somatic genes, including Tead2 and Tgfb1, which parallels the activity of the YTHDF2-CCR4-NOT deadenylase complex. Ythdf2/3 deficiency further represses mesenchymal-to-epithelial transition (MET) and chromatin silencing at loci containing the TEAD motif, contributing to decreased reprogramming efficiency. Moreover, RNA interference of Tgfb1 or the Hippo signaling effectors Yap1, Taz, and Tead2 rescues Ythdf2/3-defective reprogramming. Overall, YTHDF2/3 couple RNA deadenylation and regulation with the clearance of somatic genes provides insights into iPSC reprogramming at the posttranscriptional level.
2020-08-19 | GSE156437 | GEO
Project description:Members of the GATA protein family play important roles in lineage specification and transdifferentiation. Previous reports show that some members of GATA protein family also can induce pluripotency in somatic cells by substituting for the key pluripotency-associated factor Oct4. However, the mechanism that links the lineage specifying cues and activation of pluripotency remains elusive. Here, we report that all GATA family members can substitute for Oct4 to induce pluripotency. We found that all members of the GATA family can inhibit elevated ectodermal-lineage genes, which is consistent with previous reports that a balance of different lineage-specifying forces is important for restoration of pluripotency. A conserved DNA-binding domain in the C-terminal zinc finger is critical for the GATA family to induce pluripotency. Using RNA-seq and ChIP-seq we identified that the pluripotency-related gene Sall4 is a direct target of GATA family members during reprogramming, serving as a bridge linking the lineage-specific GATA family to the pluripotency circuit. Thus, the GATA family is the first family of proteins wherein all members can function as inducers of the reprogramming process that can substitute for Oct4. Our results suggest that the roles of the GATA family in reprogramming have been greatly underestimated, and that the GATA family may serve as a general mediator for cell fate conversion.
2014-12-02 | GSE57849 | GEO