Systematic Identification of Defined Conditions for Induction and Maintenance of Naive Human Pluripotency
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Rudolf Jaenisch
PROVIDER: E-GEOD-59435 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Embryonic stem cells (ESCs) of mice and humans have distinct molecular and biological characteristics, raising the question whether an earlier ‘naive’ state of pluripotency may exist in humans. Here we took a systematic approach to identify small molecules that support autonomous self-renewal of naive human ESCs based on maintenance of endogenous OCT4 distal enhancer activity, a molecular signature of ground state pluripotency. Iterative chemical screening identified a combination of five kinase inhibitors that induces and maintains OCT4 distal enhancer activity when applied directly to conventional human ESCs. These inhibitors generate a homogeneous population of human pluripotent stem cells in which transcription factors associated with the ground state of pluripotency are highly upregulated. Comparison with previously reported naive human ESCs indicates that our kinase inhibitor cocktail captures a novel pluripotent state in humans that closely resembles mouse ESCs. Expression analysis was performed on two groups of human ESC samples: WIBR2 (P12 and P14), WIBR3 (P9) and WIN1 (P10) human ESCs derived in our optimized naive medium (5i/L/A or 6i/L/A, as indicated), and parental WIBR2 and WIBR3 human ESCs in primed human ESC medium.
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Project description:The control of cell identity is orchestrated by transcriptional and chromatin regulators in the context of specific chromosome structures. With the recent isolation of human naive embryonic stem cells (ESCs) representative of the ground state of pluripotency, it is possible to deduce this regulatory landscape in one of the earliest stages of human development. Here we generate cohesin ChIA-PET chromatin interaction data in naive and primed human ESCs and use it to reconstruct and compare the 3D regulatory landscapes of these two stages of early human development. The results reveal shared and stage-specific regulatory landscapes of topological domains and their subdomains, which consist of CTCF-CTCF/cohesin loops and enhancer-promoter/cohesin loops. The enhancer-promoter loop data reveal that genes with key roles in pluripotency are nearly always regulated by one or more super-enhancers, and show that these genes tend to occur in insulated neighborhoods. Our results reveal the key features of the 3D regulatory landscape of early human cells that form the foundation for embryonic development. ChIP-seq data from naive and primed human embroynic stem cells.
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Project description:Genome-wide analysis of miRNA expression was performed in Activin A and Wnt3a-treated mouse ESCs during the different stages of DE differentiation to identify candidate miRNAs likely to be involved in Wnt3a and Activin A induced DE formation. Our analysis exhibited a distinct miRNA expression finger print. Furthermore, we found that forced expression of a subset of synergistically regulated miRNAs could partially mimic the roles of Wnt3a and Activin A. Pathway analyses also revealed the involvement of histone acetylation in Activin A/Wnt3a-driven DE differentiation, which is further confirmed by treating the cells with small molecular weight HDAC inhibitors as well as ChIP experiments. Our study established a regulatory cascade from extracellular cytokine treatment to miRNA expression to histone modification in cell nucleus during DE differentiation. ESCs were treated with 100ng/ml Activin A, or 50ng/ml Wnt3a, or 100ng/ml Activin A plus 50ng/ml Wnt3a, and the samples were collected at 1 day, 3 days, and 5 days after treatment, respectively. Cells treated with the same medium without growth factors were used as the negative controls for each time point.
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