Novel insights into embryonic stem cell self-renewal revealed through comparative human and mouse systems biology networks

Karen G. Dowell, Allen K. Simons, Hao Bai, Braden Kell, Zack Z. Wang, Kyuson Yun, Matthew A. Hibbs

Research output: Contribution to journalArticle

Abstract

Embryonic stem cells (ESCs), characterized by their ability to both self-renew and differentiate into multiple cell lineages, are a powerful model for biomedical research and developmental biology. Human and mouse ESCs share many features, yet have distinctive aspects, including fundamental differences in the signaling pathways and cell cycle controls that support self-renewal. Here, we explore the molecular basis of human ESC self-renewal using Bayesian network machine learning to integrate cell-type-specific, high-throughput data for gene function discovery. We integrated high-throughput ESC data from 83 human studies (â̂1.8 million data points collected under 1,100 conditions) and 62 mouse studies (â̂2.4 million data points collected under 1,085 conditions) into separate human and mouse predictive networks focused on ESC self-renewal to analyze shared and distinct functional relationships among protein-coding gene orthologs. Computational evaluations show that these networks are highly accurate, literature validation confirms their biological relevance, and reverse transcriptase polymerase chain reaction (RT-PCR) validation supports our predictions. Our results reflect the importance of key regulatory genes known to be strongly associated with self-renewal and pluripotency in both species (e.g., POU5F1, SOX2, and NANOG), identify metabolic differences between species (e.g., threonine metabolism), clarify differences between human and mouse ESC developmental signaling pathways (e.g., leukemia inhibitory factor (LIF)-activated JAK/STAT in mouse; NODAL/ACTIVIN-A-activated fibroblast growth factor in human), and reveal many novel genes and pathways predicted to be functionally associated with self-renewal in each species. These interactive networks are available online at www.StemSight.org for stem cell researchers to develop new hypotheses, discover potential mechanisms involving sparsely annotated genes, and prioritize genes of interest for experimental validation.

Original languageEnglish (US)
Pages (from-to)1161-1172
Number of pages12
JournalStem Cells
Volume32
Issue number5
DOIs
StatePublished - 2014

Fingerprint

Systems Biology
Embryonic Stem Cells
Genes
Leukemia Inhibitory Factor
Developmental Biology
Fibroblast Growth Factors
Genetic Association Studies
Cell Lineage
Threonine
Regulator Genes
Cell Cycle Checkpoints
Reverse Transcriptase Polymerase Chain Reaction
Biomedical Research
Stem Cells
Research Personnel
Cell Self Renewal
Human Embryonic Stem Cells
Proteins
Mouse Embryonic Stem Cells

Keywords

  • Biomathematical modeling
  • Cell signaling, Genomics
  • Computational biology
  • Embryonic stem cells
  • Pluripotent stem cells

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine
  • Medicine(all)

Cite this

Novel insights into embryonic stem cell self-renewal revealed through comparative human and mouse systems biology networks. / Dowell, Karen G.; Simons, Allen K.; Bai, Hao; Kell, Braden; Wang, Zack Z.; Yun, Kyuson; Hibbs, Matthew A.

In: Stem Cells, Vol. 32, No. 5, 2014, p. 1161-1172.

Research output: Contribution to journalArticle

Dowell, Karen G. ; Simons, Allen K. ; Bai, Hao ; Kell, Braden ; Wang, Zack Z. ; Yun, Kyuson ; Hibbs, Matthew A. / Novel insights into embryonic stem cell self-renewal revealed through comparative human and mouse systems biology networks. In: Stem Cells. 2014 ; Vol. 32, No. 5. pp. 1161-1172.
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AU - Dowell, Karen G.

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AU - Hibbs, Matthew A.

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AB - Embryonic stem cells (ESCs), characterized by their ability to both self-renew and differentiate into multiple cell lineages, are a powerful model for biomedical research and developmental biology. Human and mouse ESCs share many features, yet have distinctive aspects, including fundamental differences in the signaling pathways and cell cycle controls that support self-renewal. Here, we explore the molecular basis of human ESC self-renewal using Bayesian network machine learning to integrate cell-type-specific, high-throughput data for gene function discovery. We integrated high-throughput ESC data from 83 human studies (â̂1.8 million data points collected under 1,100 conditions) and 62 mouse studies (â̂2.4 million data points collected under 1,085 conditions) into separate human and mouse predictive networks focused on ESC self-renewal to analyze shared and distinct functional relationships among protein-coding gene orthologs. Computational evaluations show that these networks are highly accurate, literature validation confirms their biological relevance, and reverse transcriptase polymerase chain reaction (RT-PCR) validation supports our predictions. Our results reflect the importance of key regulatory genes known to be strongly associated with self-renewal and pluripotency in both species (e.g., POU5F1, SOX2, and NANOG), identify metabolic differences between species (e.g., threonine metabolism), clarify differences between human and mouse ESC developmental signaling pathways (e.g., leukemia inhibitory factor (LIF)-activated JAK/STAT in mouse; NODAL/ACTIVIN-A-activated fibroblast growth factor in human), and reveal many novel genes and pathways predicted to be functionally associated with self-renewal in each species. These interactive networks are available online at www.StemSight.org for stem cell researchers to develop new hypotheses, discover potential mechanisms involving sparsely annotated genes, and prioritize genes of interest for experimental validation.

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