Integrative analysis of reprogramming human fibroblast cells to naïve pluripotency
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA350224 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR4444890_1.fastq.gz | Fastqsanger.gz | |||
| SRR4444890_2.fastq.gz | Fastqsanger.gz | |||
| SRR4446070_1.fastq.gz | Fastqsanger.gz | |||
| SRR4446070_2.fastq.gz | Fastqsanger.gz | |||
| SRR4446080_1.fastq.gz | Fastqsanger.gz |
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Project description:Derivation of human naïve cells in the ground state of pluripotency provides promising avenues for developmental studies and therapeutic manipulations. However, the molecular mechanisms involved in establishment and maintenance of human naïve pluripotency remain poorly understood. Using the human inducible reprogramming system together with 5iLAF naïve induction strategy, we performed integrative analysis across the timeline from human fibroblasts to naïve iPSCs, which reveals ordered expression waves of gene networks sharing signatures with embryonic development process from post-implantation to pre-implantation stages. We also observed a significant transient re-activation of transcripts with 8-cell-stage-like characteristics in late naïve reprogramming stages. Moreover, combined quantitative proteomics analysis with transcriptional dynamics during naïve pluripotency induction, we identified ALPPL2 as the specific surface marker for human naïve pluripotency. Altogether, our study deepens the understanding of molecular mechanisms of human naïve pluripotency.
2018-03-03 | GSE89060 | GEO
Project description:Derivation of human naïve cells in the ground state of pluripotency provides promising avenues for developmental studies and therapeutic manipulations. However, the molecular mechanisms involved in establishment and maintenance of human naïve pluripotency remain poorly understood. Using the human inducible reprogramming system together with 5iLAF naïve induction strategy, we performed integrative analysis across the timeline from human fibroblasts to naïve iPSCs, which reveals ordered expression waves of gene networks sharing signatures with embryonic development process from post-implantation to pre-implantation stages. We also observed a significant transient re-activation of transcripts with 8-cell-stage-like characteristics in late naïve reprogramming stages. Moreover, combined quantitative proteomics analysis with transcriptional dynamics during naïve pluripotency induction, we identified ALPPL2 as the specific surface marker for human naïve pluripotency. Altogether, our study deepens the understanding of molecular mechanisms of human naïve pluripotency.
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Project description:Derivation of human naïve cells in the ground state of pluripotency provides promising avenues for developmental studies and therapeutic manipulations. However, the molecular mechanisms involved in establishment and maintenance of human naïve pluripotency remain poorly understood. Using the human inducible reprogramming system together with 5iLAF naïve induction strategy, we performed integrative analysis across the timeline from human fibroblasts to naïve iPSCs, which reveals ordered expression waves of gene networks sharing signatures with embryonic development process from post-implantation to pre-implantation stages. We also observed a significant transient re-activation of transcripts with 8-cell-stage-like characteristics in late naïve reprogramming stages. Moreover, combined quantitative proteomics analysis with transcriptional dynamics during naïve pluripotency induction, we identified ALPPL2 as the specific surface marker for human naïve pluripotency. Altogether, our study deepens the understanding of molecular mechanisms of human naïve pluripotency.
2018-03-03 | GSE89056 | GEO
Project description:Defining how human pluripotent cell identity is controlled and in particular how naïve pluripotency is acquired during cell reprogramming is crucial for the future applications of pluripotent stem cells. However, the regulatory pathways of naïve cell reprogramming remain incompletely understood. Here, we used genome-wide CRISPR-Cas9 screening to identify novel regulators of primed to naïve pluripotent stem cell reprogramming, including genes that are essential for reprogramming and genes that normally impede reprogramming and whose targeted deletion led to enhanced reprogramming. Integrated analysis defined specific chromatin complexes and signalling pathways as critical regulators of naïve reprogramming, and were largely distinct from regulators of somatic cell reprogramming. Mechanistically, PRC1.3 and PRDM14 are jointly required to transcriptionally repress developmental and gene regulatory factors to ensure naïve cell reprogramming. Additionally, small molecule inhibitors of reprogramming impediments increased the efficiency of naïve cell reprogramming, and are of practical benefit that can improve on current reprogramming methods. Taken together, we have identified novel regulators controlling the establishment of naïve pluripotency in human cells, which will open up new ways to exploit the full potential of pluripotent stem cells. These results also provide new insights into mechanisms that destabilise and reconfigure cell identity during cell state transitions.
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Project description:In contrast to conventional human pluripotent stem cells (hPSC) that are related to post-implantation embryo stages, naïve hPSC exhibit features of pre-implantation epiblast. Naïve hPSC are established by resetting conventional hPSC, or are derived from dissociated embryo inner cell masses. Here we investigate conditions for transgene-free reprogramming of human somatic cells to naïve pluripotency. We find that RNA-mediated induction of naïve pluripotency is enhanced by Wnt inhibition. We demonstrate application to independent human fibroblast cultures and endothelial progenitor cells and show that induced naïve hPSC can be clonally expanded with a diploid karyotype. They exhibit distinctive surface marker, transcriptome, and methylome properties of naïve epiblast identity. Induced naïve hPSC lines undergo somatic lineage differentiation following formative transition. Efficient, facile, and reliable induction of transgene free naïve hPSC offers a robust platform for delineation of human reprogramming trajectories and for evaluating the attributes of isogenic naïve versus conventional hPSC.
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Project description:Epigenetic reprogramming is a cancer hallmark but how it unfolds during early neoplastic events and its role in carcinogenesis and cancer progression is not fully understood. Here we show that resetting from primed to naïve human pluripotency results in acquisition of a DNA methylation landscape mirroring the cancer DNA methylome, with gradual hypermethylation of bivalent developmental genes. We hypothesised that unknown proteins and transcription factors play a role in the DNA hypermethylation process and analysed therefore the proteomics of the very early stages of the resetting process which involves overexpression of Nanog and Klf2. The samples analysed were Primed hESCs (Conventional stem cells), 72hours after induction and 1 week after induction, in triplicate. For our purposes we identified candidate transcription factors and subsequently knocked them down to test their involvement in the DNA hypermethylation (as described in the manuscript related to this data, Patani et al. Nature Communications). More broadly, we believe, this dataset is a useful resource for the wider community interested in pluripotency, resetting, reprogramming, cell identity transitions etc. Our results indicate that transition to naïve pluripotency and oncogenic transformation share common epigenetic trajectories, which implicates reprogramming and the pluripotency network as a central hub in cancer formation.
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Project description:We report conditions for transgene-free reprogramming of human somatic cells to naïve pluripotency. We find that Wnt inhibition promotes RNA-mediated induction of naïve pluripotency.
2019-12-02 | GSE138304 | GEO
Project description:Naïve pluripotent and expanded potential stem cells (EPSCs) represent the pre-implantation epiblast which are molecularly, epigenetically and developmentally distinct from conventional primed pluripotent stem cells representing the epiblast of post-implantation embryo. These stem cell types offer expanded developmental potential towards extraembryonic tissues, clonality at the single cell level, high homogeneity and are more amenable for genome engineering. Here we use a polycistronic cassette to directly reprogram fibroblasts into induced EPSCs without a detour to primed pluripotency. When we replace SOX2 with engineered SOX17 factor (eSOX17), we obtain 7 to 10 -fold more iEPSC colonies within shorter time periods. We next tested our reprogramming regimen in four media supporting naïve pluripotency reprogramming and could reproducibly obtain large numbers of clonally expandable colonies with eSOX17 whilst SOX2 occasionally fails. The resultant naïve pluripotent and expanded potential stem cells molecularly and functionally resemble their counterparts derived from embryonic stem cells. In sum, the use of engineered SOX17 factor enables a direct, fast, efficient and reproducible reprogramming of somatic cells into cells representative of the pre-implantation epiblast from somatic cells.
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Project description:Enhancing the direct reprogramming towards human naïve and expanded pluripotency
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Project description:Translational control plays a central role in regulation of gene expression and can lead to significant divergence between mRNA- and protein-abundance. The translational landscape of early mammalian development and its impact on cellular proteome, however, remains largely un-explored. Here we used genome-wide approaches combined with time-course analysis to measure the mRNA-abundance, mRNA-translation rate and protein expression during the transition of naïve into primed embryonic stem cells (ESCs). We found that the ground state ESCs cultured with GSK3- and MEK-inhibitors and LIF (2iL) display higher ribosome density on a selective set of mRNAs. These mRNAs show reduced translation during the exit from ground state pluripotency and transition to serum/LIF (SL) culture or upon commitment to primed epiblast-like stem cells (EpiLSCs). Strikingly, integrative analysis with cellular proteome indicate a strong translational buffering of this set of mRNAs in 2iL-ESCs leading to stable protein expression levels. Our data reveal that the global alteration of cellular proteome is largely accompanied by transcriptional rewiring. Furthermore, we identified a set of genes (including UHRF1 and KRAS) that undergo selective post-translational regulation during the transition of naïve into primed pluripotency and linked the observed changes to upstream GSK- and MEK/MAPK-signaling pathways using single inhibitor treated ESCs. Thus, we provide a comprehensive and detailed overview of the global changes in gene expression during the transition of naïve to primed pluripotency and dissect the relative contributions of RNA-transcription, translation and regulation of protein stability in controlling protein abundance.
2020-04-03 | PXD014528 | Pride