Unknown,Transcriptomics,Genomics,Proteomics

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Naive Pluripotent Stem Cells Display Transcriptional and Epigenetic Signatures of the Human Pre-Implantation Embryo

ABSTRACT: Significant interest has been devoted to the isolation of human pluripotent stem cells displaying the naive state of mouse embryonic stem cells. However, to what extent naive human cells isolated in culture resemble pluripotent cells in vivo remains unclear. Here we present three lines of evidence indicating that naive pluripotent stem cells generated in the absence of transgenes share defining molecular signatures with the human pre-implantation embryo. First, a comprehensive analysis of the transposcriptome reveals that naive human cells have a retroelement expression profile of human cleavage stage embryos. Second, base-resolution mapping of the DNA methylome in naive human cells reveals a genome-wide reduction in CpG and non-CpG methylation levels. Third, female naive cells exhibit an X chromosome status that is similar to that of the human blastocyst. Our work demonstrates that pluripotent stem cells with epigenomic hallmarks of the early human embryo can be directly captured in vitro. Examine the methylomes of 6 naÃ¯ve, 2 primed and 2 re-primed human embryonic stem cells

ORGANISM(S): Homo sapiens

SUBMITTER: Yupeng He

PROVIDER: E-GEOD-75868 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:In Arabidopsis, CHG DNA methylation is controlled by the H3K9 methylation mark through a self-reinforcing loop between DNA methyltransferase CHROMOMETHYLASE3 (CMT3) and H3K9 histone methyltransferase KRYPTONITE/SUVH4 (KYP). We report on the structure of KYP in complex with methylated DNA, substrate H3 peptide and cofactor SAH, thereby defining the spatial positioning of the SRA domain relative to the SET domain. The methylated DNA is bound by the SRA domain with the 5mC flipped out of the DNA, while the H3(1-15) peptide substrate binds between the SET and post-SET domains, with the epsilon-ammonium of K9 positioned adjacent to bound SAH. These structural insights complemented by in vivo functional data on key mutants of residues lining the 5mC and H3K9-binding pockets within KYP, establish how methylated DNA recruits KYP to the histone substrate. Together, the structures of KYP and previously reported CMT3 complexes provide insights into molecular mechanisms linking DNA and histone methylation. Plants homozygous for null mutations in the KRYPTONITE H3K9 methyltransferase were stably transformed with transgenes encoding the wildtype KYP protein or transgenes carrying induced point mutations in the KYP active site. The resulting lines were assayed for DNA methylation by whole-genome bisulfite sequencing to learn the efficiency with which wildtype and mutant versions of the KYP protein could restore DNA methylation lost in a kyp mutant. Samples 7 and 8 were run as single Illumina lanes and as such were compared to a previous Col sample (GSM881756), this Col sample was realigned to the TAIR10 genome for this study and as such updated processed files are available with this submission. These samples were used to define kyp mutant CHG context DMRs that were complemented upon introduction of the wildtype KYP protein. Samples 1-6 were run as multiplexed samples and were used to assay the degree of complementation for various point mutants. All plants are in the Col ecotype background.

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Naive Pluripotent Stem Cells Display Transcriptional and Epigenetic Signatures of the Human Pre-Implantation Embryo

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