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.

中文翻译：

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NFI 转录因子提供染色质通路以维持干细胞身份，同时防止意外的谱系命运选择。

组织稳态和再生依赖于常驻干细胞（SC），其行为通过生态位依赖性串扰进行调节。SC 身份的潜在机制仍在不断发展。在这里，我们利用小鼠毛囊中的时空基因消融，发现了转录因子 (TF)、核因子 IB (NFIB) 和 IX (NFIX) 在维持 SC 身份方面的关键作用。如果没有 NFI TF，SC 就会失去毛发再生能力，并产生与不可逆转的人类脱发惊人相似的皮肤，这也表现出 NFI 的减少。通过单细胞转录组学、ATAC-Seq 和 ChIP-Seq 分析，我们揭示了 NFIB 和 NFIX 在控制关键毛囊 SC 特异性 TF 基因的超级增强子维持中的关键作用。当 NFIB 和 NFIX 被基因去除后，干性表观遗传景观就会消失。驱动 SC 身份的超级增强子被停用，而不需要的谱系则被异位抑制。总之，我们的研究结果表明 NFIB 和 NFIX 是组织稳态的关键变阻器，其作用是保护 SC 表观基因组免受谱系限制的破坏，否则会引发不可逆的组织退化。