Skip to main content
SpringerLink
Log in

Automated Formal Reasoning to Uncover Molecular Programs of Self-Renewal

  • Protocol
  • First Online:
Computational Stem Cell Biology

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1975))

Abstract

The Reasoning Engine for Interaction Networks (RE:IN) is a tool that was developed initially for the study of pluripotency in mouse embryonic stem cells. A set of critical factors that regulate the pluripotent state had been identified experimentally, but it was not known how these genes interacted to stabilize self-renewal or commit the cell to differentiation. The methodology encapsulated in RE:IN enabled the exploration of a space of possible network interaction models, allowing for uncertainty in whether individual interactions exist between the pluripotency factors. This concept of an “abstract” network was combined with automated reasoning that allows the user to eliminate models that are inconsistent with experimental observations. The tool generalizes beyond the study of stem cell decision-making, allowing for the study of interaction networks more broadly across biology.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Chen X, Xu H, Yuan P et al (2008) Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133:1106–1117. https://doi.org/10.1016/j.cell.2008.04.043

    Article  CAS  PubMed  Google Scholar 

  2. Lu R, Markowetz F, Unwin RD et al (2009) Systems-level dynamic analyses of fate change in murine embryonic stem cells. Nature 462:358–362. https://doi.org/10.1038/nature08575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. van den Berg DLC, Snoek T, Mullin NP et al (2010) An Oct4-centered protein interaction network in embryonic stem cells. Cell Stem Cell 6:369–381. https://doi.org/10.1016/j.stem.2010.02.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Som A, Harder C, Greber B et al (2010) The PluriNetWork: an electronic representation of the network underlying pluripotency in mouse, and its applications. PLoS One 5:e15165. https://doi.org/10.1371/journal.pone.0015165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yeo J-C, Ng H-H (2013) The transcriptional regulation of pluripotency. Cell Res 23:20–32. https://doi.org/10.1038/cr.2012.172

    Article  CAS  PubMed  Google Scholar 

  6. Tyson JJ, Chen KC, Novak B (2003) Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell. Curr Opin Cell Biol 15:221–231. https://doi.org/10.1016/S0955-0674(03)00017-6

    Article  CAS  PubMed  Google Scholar 

  7. Kühl M, Kracher B, Groß A, Kestler HA (2014) Mathematical models of Wnt signaling pathways. In: Wnt Signal. Dev. Dis. John Wiley & Sons, Inc, Hoboken, NJ, USA, pp 153–160

    Chapter  Google Scholar 

  8. Davidson EH (2010) Emerging properties of animal gene regulatory networks. Nature 468:911–920. https://doi.org/10.1038/nature09645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. S a K (1969) Metabolic stability and epigenesis in randomly constructed genetic nets. J Theor Biol 22:437–467

    Article  Google Scholar 

  10. Thomas R (1973) Boolean formalization of genetic control circuits. J Theor Biol 42:563–585

    Article  CAS  PubMed  Google Scholar 

  11. Le Novère N (2015) Quantitative and logic modelling of molecular and gene networks. Nat Rev Genet 16:146–158. https://doi.org/10.1038/nrg3885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yordanov B, Dunn S-J, Kugler H et al (2016) A method to identify and analyze biological programs through automated reasoning. npj Syst Biol Appl 2:–16010. https://doi.org/10.1038/npjsba.2016.10

  13. Li F, Long T, Lu Y et al (2004) The yeast cell-cycle network is robustly designed. PNAS 101:4781–4786. https://doi.org/10.1073/pnas.0305937101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Szklarczyk D, Morris JH, Cook H et al (2017) The STRING database in 2017: quality-controlled protein–protein association networks, made broadly accessible. Nucleic Acids Res 45:D362–D368. https://doi.org/10.1093/nar/gkw937

    Article  CAS  PubMed  Google Scholar 

  15. Martello G, Bertone P, Smith AG (2013) Identification of the missing pluripotency mediator downstream of leukaemia inhibitory factor. EMBO J:1–14. https://doi.org/10.1038/emboj.2013.177

  16. Martello G, Sugimoto T, Diamanti E et al (2012) Esrrb is a pivotal target of the Gsk3/Tcf3 axis regulating embryonic stem cell self-renewal. Cell Stem Cell 11:491–504. https://doi.org/10.1016/j.stem.2012.06.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hall J, Guo G, Wray J et al (2009) Oct4 and LIF/Stat3 additively induce Krüppel factors to sustain embryonic stem cell self-renewal. Cell Stem Cell 5:597–609. https://doi.org/10.1016/j.stem.2009.11.003

    Article  CAS  PubMed  Google Scholar 

  18. Silva J, Nichols J, Theunissen TW et al (2009) Nanog is the gateway to the pluripotent ground state. Cell 138:722–737. https://doi.org/10.1016/j.cell.2009.07.039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Tai C-I, Ying Q-L (2013) Gbx2, a LIF/Stat3 target, promotes reprogramming to and retention of the pluripotent ground state. J Cell Sci 126:1093–1098. https://doi.org/10.1242/jcs.118273

    Article  CAS  PubMed  Google Scholar 

  20. Lanner F, Lee KL, Sohl M et al (2010) Heparan sulfation-dependent fibroblast growth factor signaling maintains embryonic stem cells primed for differentiation in a heterogeneous state. Stem Cells 28:191–200. https://doi.org/10.1002/stem.265

    Article  CAS  PubMed  Google Scholar 

  21. Dunn S-J, Martello G, Yordanov B et al (2014) Defining an essential transcription factor program for naive pluripotency. Science (80- ) 344:1156–1160. https://doi.org/10.1126/science.1248882

    Article  CAS  Google Scholar 

  22. Jain AK (2010) Data clustering: 50 years beyond K-means. Pattern Recogn Lett 31:651–666. https://doi.org/10.1016/j.patrec.2009.09.011

    Article  Google Scholar 

  23. Ying Q-L, Wray J, Nichols J et al (2008) The ground state of embryonic stem cell self-renewal. Nature 453:519–523. https://doi.org/10.1038/nature06968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. De Moura L, Bjørner N (2008) Z3: An efficient SMT solver. In: Tools algorithms constr. anal. syst. Springer, Berlin Heidelberg, pp 337–340

    Chapter  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Microsoft Research, Cambridge, UK

    Sara-Jane Dunn

Authors
  1. Sara-Jane Dunn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sara-Jane Dunn .

Editor information

Editors and Affiliations

  1. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA

    Patrick Cahan

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Dunn, SJ. (2019). Automated Formal Reasoning to Uncover Molecular Programs of Self-Renewal. In: Cahan, P. (eds) Computational Stem Cell Biology. Methods in Molecular Biology, vol 1975. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9224-9_4

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-9224-9_4

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-4939-9223-2

  • Online ISBN: 978-1-4939-9224-9

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation