Unknown,Transcriptomics,Genomics,Proteomics

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Viable Mice Produced from 3-factor Induced Pluripoent Stem (iPS) Cells through Tetraploid Complementation

ABSTRACT: Ectopic expression of four transcription factors including Oct4, Sox2, Klf4 and c-Myc in differentiated fibroblast cells could reset the cell fate of fibroblast cells to pluripotent state. Subsequently, fully pluripotency of these so-called induced pluripotent stem cells (iPSCs) has been demonstrated as viable mice could be generated autonomously from iPS cells through tetraploid blastocyst complementation. Moreover, the generation of human and patient-specific iPS cells have raised the possibility of utilizing iPS cells clinically. However, the utilization of c-Myc in iPS cells induction greatly increased the incidence of tumorigenecity in the iPS-chimeric mice and also might hinder the clinical application of human iPS cells in the future. Fortunately, c-Myc has been recently found dispensable for iPS induction even though the iPS induction efficiency is greatly reduced in the absence of c-Myc. However, it remains unknown if these three factors-induced iPS cells are fully pluripotent. In the present study, we have successfully demonstrated that 3-factor iPS cells could also be fully pluripotent as viable mice could be generated from 3-factor iPS cells autonomously via tetraploid complementation and moreover, our data indicated that the pluripotency regulatory mechanism in 3-factor iPS cells might be distinct from 4-factor iPS cells. We compared the gene expression profile of iPS cells with and without the tetraploid embryo complementation competence. Three biological repeats were included for each line.

ORGANISM(S): Mus musculus

SUBMITTER: Yu Zhang

PROVIDER: E-GEOD-24046 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Ten-eleven translocation (TET) family enzymes can convert 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) in DNA and have been proposed as potential DNA demethylase candidates1. Evidences from recent studies indicated that Tet1 is predominantly expressed in ES cells and plays dual functions in promoting transcription of pluripotency genes and as well as participating in the repression of developmental genes by facilitating recruitment of PRC21-5. These studies further raised the possibility that Tet1 might play a role in somatic cell reprogramming. Here, we provide evidence showing that Tet1 can substitute for pluripotent transcription factors in reprogramming differentiated somatic cells to pluripotent stem cells. Tet1 can replace any one of the four traditional transcription factors including Oct4, Sox2, Klf4 and c-Myc during somatic cell reprogramming. Subsequently, the chimeric mice with germline transmission capacity could be efficiently produced from all induced pluripotent stem (iPS) cell lines reprogrammed by OT (Oct4, Tet1), TSKM (Tet1, Sox2, Klf4, c-Myc), OTK, OTKM and OSTM combinations. Furthermore, the TSKM-reprogrammed iPS cells without using Oct4 could produce viable full-term iPS mice with normal fertility through tetraploid complementation and secondary iPS cells could be induced subsequently from the somatic cells retrieved from the iPS mice. Moreover, we demonstrated that conversion of 5mC into 5hmC in Nanog promoter occurred during reprogramming, which might account in part for the mechanism of Tet1 mediated reprogramming. To our knowledge, our study provides the first evidence demonstrating that DNA modifying enzyme Tet1 can replace the pluripotent transcription factors to reprogram differentiated somatic cells to iPS cells. Gene expression profile of iPS cells and ES cells were generated by Affymetrix Mouse Gene 1.0 ST Array. The Gene expression profile of ES cell R1 was used as control. Three biological repeats were included for each line.

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Viable Mice Produced from 3-factor Induced Pluripoent Stem (iPS) Cells through Tetraploid Complementation

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