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

Rene C. Adam, Hanseul Yang, Yejing Ge, Nicole R. Infarinato, Shiri Gur-Cohen, Yuxuan Miao, Ping Wang, Yilin Zhao, Catherine P. Lu, Jeong E. Kim, Joo Y. Ko, Seung S. Paik, Richard M. Gronostajski, Jaehwan Kim, James G. Krueger, Deyou Zheng, Elaine Fuchs

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)640-650
Number of pages11
JournalNature Cell Biology
Volume22
Issue number6
DOIs
StatePublished - Jun 1 2020

ASJC Scopus subject areas

  • Cell Biology

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    Adam, R. C., Yang, H., Ge, Y., Infarinato, N. R., Gur-Cohen, S., Miao, Y., Wang, P., Zhao, Y., Lu, C. P., Kim, J. E., Ko, J. Y., Paik, S. S., Gronostajski, R. M., Kim, J., Krueger, J. G., Zheng, D., & Fuchs, E. (2020). NFI transcription factors provide chromatin access to maintain stem cell identity while preventing unintended lineage fate choices. Nature Cell Biology, 22(6), 640-650. https://doi.org/10.1038/s41556-020-0513-0