NFI transcription factors provide chromatin access to maintain stem cell identity while preventing unintended lineage fate choices

Nat Cell Biol. 2020 Jun;22(6):640-650. doi: 10.1038/s41556-020-0513-0. Epub 2020 May 11.

Abstract

Tissue homeostasis and regeneration rely on resident stem cells (SCs), whose behaviour is regulated through niche-dependent crosstalk. The mechanisms underlying SC identity are still unfolding. Here, using spatiotemporal gene ablation in murine hair follicles, we uncover a critical role for the transcription factors (TFs) nuclear factor IB (NFIB) and IX (NFIX) in maintaining SC identity. Without NFI TFs, SCs lose their hair-regenerating capability, and produce skin bearing striking resemblance to irreversible human alopecia, which also displays reduced NFIs. Through single-cell transcriptomics, ATAC-Seq and ChIP-Seq profiling, we expose a key role for NFIB and NFIX in governing super-enhancer maintenance of the key hair follicle SC-specific TF genes. When NFIB and NFIX are genetically removed, the stemness epigenetic landscape is lost. Super-enhancers driving SC identity are decommissioned, while unwanted lineages are de-repressed ectopically. Together, our findings expose NFIB and NFIX as crucial rheostats of tissue homeostasis, functioning to safeguard the SC epigenome from a breach in lineage confinement that otherwise triggers irreversible tissue degeneration.

Publication types

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

MeSH terms

  • Alopecia / genetics
  • Alopecia / metabolism
  • Alopecia / pathology*
  • Animals
  • Cell Differentiation*
  • Cells, Cultured
  • Chromatin / genetics
  • Chromatin / metabolism*
  • Female
  • Hair Follicle / cytology*
  • Hair Follicle / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NFI Transcription Factors / physiology*
  • Regeneration
  • Stem Cells / cytology*
  • Stem Cells / metabolism

Substances

  • Chromatin
  • NFI Transcription Factors
  • Nfib protein, mouse
  • Nfix protein, mouse