Temporal enhancer profiling of parallel lineages identifies AHR and GLIS1 as regulators of mesenchymal multipotency

Nucleic Acids Res. 2019 Feb 20;47(3):1141-1163. doi: 10.1093/nar/gky1240.


Temporal data on gene expression and context-specific open chromatin states can improve identification of key transcription factors (TFs) and the gene regulatory networks (GRNs) controlling cellular differentiation. However, their integration remains challenging. Here, we delineate a general approach for data-driven and unbiased identification of key TFs and dynamic GRNs, called EPIC-DREM. We generated time-series transcriptomic and epigenomic profiles during differentiation of mouse multipotent bone marrow stromal cell line (ST2) toward adipocytes and osteoblasts. Using our novel approach we constructed time-resolved GRNs for both lineages and identifed the shared TFs involved in both differentiation processes. To take an alternative approach to prioritize the identified shared regulators, we mapped dynamic super-enhancers in both lineages and associated them to target genes with correlated expression profiles. The combination of the two approaches identified aryl hydrocarbon receptor (AHR) and Glis family zinc finger 1 (GLIS1) as mesenchymal key TFs controlled by dynamic cell type-specific super-enhancers that become repressed in both lineages. AHR and GLIS1 control differentiation-induced genes and their overexpression can inhibit the lineage commitment of the multipotent bone marrow-derived ST2 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism
  • Animals
  • Cell Differentiation / genetics
  • Cell Line
  • Cell Lineage / genetics
  • DNA-Binding Proteins / metabolism*
  • Enhancer Elements, Genetic*
  • Gene Regulatory Networks
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism*
  • Mice
  • Osteoblasts / metabolism
  • Receptors, Aryl Hydrocarbon / metabolism*
  • Transcription Factors / metabolism*


  • DNA-Binding Proteins
  • Glis1 protein, mouse
  • Receptors, Aryl Hydrocarbon
  • Transcription Factors