Single-Cell Analyses of ESCs Reveal Alternative Pluripotent Cell States and Molecular Mechanisms that Control Self-Renewal.
Analyses of gene expression in single mouse embryonic stem cells (mESCs) cultured in serum and LIF revealed the presence of two distinct cell subpopulations with individual gene expression signatures. Comparisons with published data revealed that cells in the first subpopulation are phenotypically similar to cells isolated from the inner cell mass (ICM). In contrast, cells in the second subpopulation appear to be more mature. Pluripotency Gene Regulatory Network (PGRN) reconstruction based on single-cell data and published data suggested antagonistic roles for Oct4 and Nanog in the maintenance of pluripotency states. Integrated analyses of published genomic binding (ChIP) data strongly supported this observation. Certain target genes alternatively regulated by OCT4 and NANOG, such as Sall4 and Zscan10, feed back into the top hierarchical regulator Oct4. Analyses of such incoherent feedforward loops with feedback (iFFL-FB) suggest a dynamic model for the maintenance of mESC pluripotency and self-renewal.
Department of Regenerative and Developmental Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA. Electronic address: dmitri.papatsenko@mssm.edu.
Dmitri
D
Papatsenko
Department of Regenerative and Developmental Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
Henia
H
Darr
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova Strasse 32, Moscow 119991, Russia; Department of Computational Systems Biology, Vavilov Institute of General Genetics, Russian Academy of Sciences, Gubkina Strasse 3, Moscow 119991, Russia.
Ivan V
IV
Kulakovskiy
Department of Regenerative and Developmental Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
Avinash
A
Waghray
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova Strasse 32, Moscow 119991, Russia; Department of Computational Systems Biology, Vavilov Institute of General Genetics, Russian Academy of Sciences, Gubkina Strasse 3, Moscow 119991, Russia.
Vsevolod J
VJ
Makeev
Centre for Human Development, Stem Cells, and Regeneration, Institute of Developmental Sciences, University of Southampton, Southampton SO17 1BJ, UK.
Ben D
BD
MacArthur
Department of Regenerative and Developmental Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Department of Pharmacology and System Therapeutics, Icahn School of Medicine at Mount Sinai, Systems Biology Center New York, One Gustave L. Levy Place, New York, NY 10029, USA. Electronic address: ihor.lemischka@mssm.edu.
Ihor R
IR
Lemischka
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D025461:Feedback, Physiological; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D059010:Single-Cell Analysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; D014157:Transcription Factors; C475540:Nanog protein, mouse; C494174:Pou5f1 protein, mouse; C509167:Sall4 protein, mouse; C514588:Zscan10 protein, mouse