Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice

Nature. 2015 May 21;521(7552):366-70. doi: 10.1038/nature14289. Epub 2015 Mar 18.

Abstract

Adult stem cells occur in niches that balance self-renewal with lineage selection and progression during tissue homeostasis. Following injury, culture or transplantation, stem cells outside their niche often display fate flexibility. Here we show that super-enhancers underlie the identity, lineage commitment and plasticity of adult stem cells in vivo. Using hair follicle as a model, we map the global chromatin domains of hair follicle stem cells and their committed progenitors in their native microenvironments. We show that super-enhancers and their dense clusters ('epicentres') of transcription factor binding sites undergo remodelling upon lineage progression. New fate is acquired by decommissioning old and establishing new super-enhancers and/or epicentres, an auto-regulatory process that abates one master regulator subset while enhancing another. We further show that when outside their niche, either in vitro or in wound-repair, hair follicle stem cells dynamically remodel super-enhancers in response to changes in their microenvironment. Intriguingly, some key super-enhancers shift epicentres, enabling their genes to remain active and maintain a transitional state in an ever-changing transcriptional landscape. Finally, we identify SOX9 as a crucial chromatin rheostat of hair follicle stem cell super-enhancers, and provide functional evidence that super-enhancers are dynamic, dense transcription-factor-binding platforms which are acutely sensitive to pioneer master regulators whose levels define not only spatial and temporal features of lineage-status but also stemness, plasticity in transitional states and differentiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological*
  • Adult Stem Cells / cytology*
  • Adult Stem Cells / metabolism
  • Animals
  • Base Sequence
  • Cell Differentiation / genetics*
  • Cell Lineage / genetics*
  • Chromatin / genetics
  • Chromatin / metabolism
  • Enhancer Elements, Genetic / genetics*
  • Female
  • Hair Follicle / cytology*
  • Mice
  • Organ Specificity
  • SOX9 Transcription Factor / metabolism*
  • Stem Cell Niche
  • Time Factors

Substances

  • Chromatin
  • SOX9 Transcription Factor
  • Sox9 protein, mouse

Associated data

  • GEO/GSE61316