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5-hydroxymethylcytosine-mediated epigenetic modifications between iPSCs and hESCs

ABSTRACT: Mammalian somatic cells can be directly reprogrammed into induced pluripotent stem cells (iPSCs) by introducing defined sets of transcription factors. Somatic cell reprogramming involves epigenomic reconfiguration, conferring iPSCs with characteristics similar to embryonic stem (ES) cells. Human ES cells contain 5-hydroxymethylcytosine (5hmC), which is generated though the oxidation of 5-methylcytosine (5mC) by the TET family of enzymes. Here we show that 5hmC level increases significantly during reprogramming due to the activation of TET1. During this process, dynamic genome-wide 5hmC modification occurs across the genome with more modifications at telomere-proximal regions. Compared with hES cells, we found iPS cells tend to form large-scale (100kb-1.3Mb) aberrant reprogramming hotspots in subtelomeric regions, most of which display incomplete hydroxymethylation. Strikingly, these 5hmC aberrant hotspots largely coincide (>80%) with previously reported aberrant non-CG methylation regions. Our results suggest that 5hmC modification could play important roles during reprogramming to pluripotency, and contribute to the differences between iPSCs and hESCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE37050 | GEO | 2013/03/21

SECONDARY ACCESSION(S): PRJNA157831

REPOSITORIES: GEO

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5-hydroxymethylcytosine-mediated epigenetic modifications between iPSCs and hESCs

Project description:Mammalian somatic cells can be directly reprogrammed into induced pluripotent stem cells (iPSCs) by introducing defined sets of transcription factors. Somatic cell reprogramming involves epigenomic reconfiguration, conferring iPSCs with characteristics similar to embryonic stem (ES) cells. Human ES cells contain 5-hydroxymethylcytosine (5hmC), which is generated though the oxidation of 5-methylcytosine (5mC) by the TET family of enzymes. Here we show that 5hmC level increases significantly during reprogramming due to the activation of TET1. During this process, dynamic genome-wide 5hmC modification occurs across the genome with more modifications at telomere-proximal regions. Compared with hES cells, we found iPS cells tend to form large-scale (100kb-1.3Mb) aberrant reprogramming hotspots in subtelomeric regions, most of which display incomplete hydroxymethylation. Strikingly, these 5hmC aberrant hotspots largely coincide (>80%) with previously reported aberrant non-CG methylation regions. Our results suggest that 5hmC modification could play important roles during reprogramming to pluripotency, and contribute to the differences between iPSCs and hESCs. we generated comprehensive genome-wide profiles of 5hmC in somatic cells, iPS cell lines derived from a variety of origins, and multiple hES cell lines.

2013-03-21 | E-GEOD-37050 | biostudies-arrayexpress

Gene expression in pluripotent and TSKM-iPS induction cells.

Project description:We found that Tet1 (T) can substitute Oct4 and initiates somatic cell reprogramming in combination with Sox2 (S), Klf4 (K) and c-Myc (M). Moreover, the TSKM secondary reprogramming can proceed rapidly with widespread accompanying increase of 5hmC and 5mC at TSS and ES-active regulation regions followed by 5mC-5hmC pattern switchand, and the activation of endogenous Oct4 and Nanog was Tet1 and 5hmC involved in this process. We used microarray to explore the global expression change during the reprogramming process Examination of gene expression change in 3 different cell lines covering the main stages during the reprogramming process

2013-03-18 | E-GEOD-39637 | biostudies-arrayexpress

Gene expression in pluripotent and TSKM-iPS induction cells.

2013-03-18 | GSE39637 | GEO

The developmental potential of iPSCs is greatly influenced by the selection of the reprogramming factors (SNEL iPSC and H2A.X deposition pattern)

Project description:Induced pluripotent stem cells (iPSCs) are commonly generated by transduction of Oct4, Sox2, Klf4 and Myc (OSKM) into somatic cells. Though iPSCs are pluripotent, they frequently exhibit high variation in their quality as measured by chimera contribution and tetraploid (4n) complementation. Thus, improving the quality of iPSCs is an indispensable prerequisite for future iPSC-based therapy. Here we show that one major determinant for iPSCs quality is the selection of the reprogramming factors combination. Ectopic expression of Sall4, Nanog, Esrrb and Lin28 (SNEL) in MEFs efficiently generated high quality iPSCs as compared to other combinations of factors. SNEL-iPSCs produced approximately 5 times more efficiently “all-iPSC” mice compared to OSKM-iPSCs. While differentially methylated regions, transcript number of master regulators, establishment of ESC-specific super enhancers, and global aneuploidy were comparable between the lines, aberrant expression of 1,765 genes, trisomy of chromosome 8 and abnormal H2A.X deposition were frequently observed in poor quality OSKM-iPSCs. For high-quality iPSCs, H2A.X pattern of SNEL is most similar to that of ESC, OSK and OSKM have more devoid regions than SNEL iPSCs. Compare H2A.X deposition pattern of the OSKM 4-factor iPS cell lines (4N-), SNEL 4-factor iPS cell lines (4N+) with ChIP-Seq. The same background ES cell line as the control line.

2014-09-07 | E-GEOD-55731 | biostudies-arrayexpress

Transcription factor occupancy is linked to DNA methylation turnover at active regulatory regions [MeDIP-Seq]

Project description:Genome wide analysis revealed that distal regulatory elements form Low Methylated Regions (LMRs). Even though transcription factor binding is required for LMR formation, we show for the test case CTCF that actual occupancy does not distinguish DNA methylation states. However, in line with a dynamic model of binding and DNA methylation turnover, we find that the product of active demethylation, 5-hydroxymethylcytosine (5hmC), is enriched at LMRs. 5hmC is present at active regulatory regions in stem and somatic cells and as a result a substantial fraction of changes in 5hmC occurs at LMRs. This suggests that transcription factor binding mediates active turnover of DNA methylation as an integral part of reprogramming of regulatory regions. hMeDIP sequencing in mouse embryonic stem cells (ES) and derived neuronal progenitors (NP).

2013-12-24 | E-GEOD-39738 | biostudies-arrayexpress

Genome-wide maps of 5hmC/5mC state in pluripotent and (T-)iPS induction cells.

Project description:We performed 5hmC/5mC DNA Immunoprecipitation followed high-throughput sequencing using the cell sample along the whole TSKM secondary reprogramming system. The TSKM 0D is the fibroblasts deried from TSKM-iPS mouse as the starting cells of the reprogramming.The intermediate cells is 3-days induced cells which are refered as TSKM 3D cells, and the final reprogrammed cells is the iPS cells with full pluripotency driven from this secondary system. We compared the profiling of 5-hydroxymethylcytosine and 5-methylcytosine modifications in these different cell lines. We found that: a widespread accompanying increase of 5hmC and 5mC at TSS and ES-active regulation regions followed by 5mC-5hmC pattern switch. Taking the advantage of the newly established TSKM secondary reprogramming system, the epigenetic remodeling and regulation mechanisms can be further investigated to advance our understanding of the epigenetic barriers and decipher the dynamic mechanism in somatic cell reprogramming. Examination of 5-hydroxymethylcytosine/5-methylcytosine modifications in a Tet1-mediated secondary reprogramming system

2013-03-18 | E-GEOD-39638 | biostudies-arrayexpress

Coordination of engineered factors with TET1/2 promotes early stage epigenetic modification during somatic cell reprogramming

Project description:Somatic cell reprogramming towards induced pluripotent stem cells (iPSCs) holds great promise in future regenerative medicine, however, the reprogramming process mediated by the traditional defined factors (OSNK) is slow and extremely inefficient. Here we show that a combination of modified reprogramming factors (OySyNyK), in which the transactivation domain of the Yes-associated protein is fused to OCT4, SOX2 and NANOG respectively, could be used to establish a highly efficient and rapid reprogramming system for iPSC generation. We show that the efficiency of OySyNyK-induced iPSCs was up to 100-fold higher than that of induction by traditional OSNK. Moreover we show that the reprogramming by OySyNyK is very rapid (initiated at 24 h versus 5 d by OSNK). Compared with OSNK, we found that OySyNyK factors significantly increased the expression of Tet1/2 at the early stage, which will interact with OSNK factors, and co-occupy pluripotency loci in the genome for somatic cell reprogramming. Our studies not only establish a rapid and highly efficient iPSC reprogramming system, but also uncover a novel mechanism by which OSNK factors coordinate with TET proteins to regulate 5hmC-mediated epigenetic control, thereby promoting somatic cell reprogramming. We examined DNA hydroxymethylation progression of reprogramming intermediates. To this end, we profiled the genome-wide 5hmC distribution in MEFs, the reprogramming intermediates at different stages induced by either the OSNK or OySyNyK methods, and iPSCs using the chemical capture approach

2013-08-08 | E-GEOD-46202 | biostudies-arrayexpress

Transcription factor occupancy is linked to DNA methylation turnover at active regulatory regions [Bisulfite-Seq]

Project description:Genome wide analysis revealed that distal regulatory elements form Low Methylated Regions (LMRs). Even though transcription factor binding is required for LMR formation, we show for the test case CTCF that actual occupancy does not distinguish DNA methylation states. However, in line with a dynamic model of binding and DNA methylation turnover, we find that the product of active demethylation, 5-hydroxymethylcytosine (5hmC), is enriched at LMRs. 5hmC is present at active regulatory regions in stem and somatic cells and as a result a substantial fraction of changes in 5hmC occurs at LMRs. This suggests that transcription factor binding mediates active turnover of DNA methylation as an integral part of reprogramming of regulatory regions. CTCF ChIP bisulfite sequencing in mouse embryonic stem cells and whole genome shotgun bisulfite sequencing of RESTko mouse embryonic stem (ES) cells

2013-12-24 | E-GEOD-39736 | biostudies-arrayexpress

AKT signaling promotes epigenetic reprogramming via upregulation of TET and its cofactor, alpha-ketoglutarate during iPSC generation

Project description:Phosphoinositide-3 kinase (PI3K)/AKT signaling participates in cellular proliferation, survival, and tumorigenesis as well as cellular reprogramming including generation of induced pluripotent stem cells (iPSCs). In this study, we revealed that activation of AKT in somatic cells undergoing reprogramming enhances epigenetic reprogramming. Activated AKT in reprogramming cells triggers elevated anabolic glucose metabolism, and, accordingly, increases the level of α-ketoglutarate (αKG) which is an essential cofactor for the enzymatic activity of the 5-methylcytosine (5mC) dioxygenase TET. Additionally, the level of TET was upregulated. Consistent with upregulated KG production and TET, we observed a genome-wide increase in 5-hydorxymethylcytosine (5hmC) which is an intermediate in the DNA demethylation process. Moreover, DNA methylation level at ES-cell super-enhancers of pluripotency-related genes was significantly decreased, leading upregulation of associated genes. Taken together, our results indicate that AKT signaling is associated with epigenetic regulation by hyperactivating TET at catalytical and transcriptional levels during the somatic cell reprogramming.

2021-09-29 | GSE161399 | GEO

AKT signaling promotes epigenetic reprogramming via upregulation of TET and its cofactor, alpha-ketoglutarate during iPSC generation.

Project description:Phosphoinositide-3 kinase (PI3K)/AKT signaling participates in cellular proliferation, survival, and tumorigenesis as well as cellular reprogramming including generation of induced pluripotent stem cells (iPSCs). In this study, we revealed that activation of AKT in somatic cells undergoing reprogramming enhances epigenetic reprogramming. Activated AKT in reprogramming cells triggers elevated anabolic glucose metabolism, and, accordingly, increases the level of α-ketoglutarate (αKG) which is an essential cofactor for the enzymatic activity of the 5-methylcytosine (5mC) dioxygenase TET. Additionally, the level of TET was upregulated. Consistent with upregulated KG production and TET, we observed a genome-wide increase in 5-hydorxymethylcytosine (5hmC) which is an intermediate in the DNA demethylation process. Moreover, DNA methylation level at ES-cell super-enhancers of pluripotency-related genes was significantly decreased, leading upregulation of associated genes. Taken together, our results indicate that AKT signaling is associated with epigenetic regulation by hyperactivating TET at catalytical and transcriptional levels during the somatic cell reprogramming.

2021-09-29 | GSE161344 | GEO

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