Epigenetic landscapes explain partially reprogrammed cells and identify key reprogramming genes

PLoS Comput Biol. 2014 Aug 14;10(8):e1003734. doi: 10.1371/journal.pcbi.1003734. eCollection 2014 Aug.

Abstract

A common metaphor for describing development is a rugged "epigenetic landscape" where cell fates are represented as attracting valleys resulting from a complex regulatory network. Here, we introduce a framework for explicitly constructing epigenetic landscapes that combines genomic data with techniques from spin-glass physics. Each cell fate is a dynamic attractor, yet cells can change fate in response to external signals. Our model suggests that partially reprogrammed cells are a natural consequence of high-dimensional landscapes, and predicts that partially reprogrammed cells should be hybrids that co-express genes from multiple cell fates. We verify this prediction by reanalyzing existing datasets. Our model reproduces known reprogramming protocols and identifies candidate transcription factors for reprogramming to novel cell fates, suggesting epigenetic landscapes are a powerful paradigm for understanding cellular identity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Cellular Reprogramming / genetics*
  • Epigenesis, Genetic / genetics*
  • Gene Expression Regulation, Developmental / genetics*
  • Genomics / methods*
  • Humans
  • Mice
  • Models, Genetic*
  • Stem Cells

Grants and funding

AHL was supported by a Boston University Dean's Fellowship and a National Science Foundation Graduate Research Fellowship (NSF GRFP) under Grant No. DGE-1247312. PM was supported by a Sloan Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.