Transcription factors (TFs) are dosage-sensitive master regulators of gene expression, with haploinsufficiency frequently leading to life-threatening disease. Numerous mechanisms have evolved to tightly regulate the expression and activity of TFs at the transcriptional, translational, and posttranslational levels. A subset of long noncoding RNAs (lncRNAs) is spatially correlated with transcription factors in the genome, but the regulatory relationship between these lncRNAs and their neighboring TFs is unclear. We identified a regulatory feedback loop between the TF Foxa2 and a downstream lncRNA, Falcor (Foxa2-adjacent long noncoding RNA). Foxa2 directly represses Falcor expression by binding to its promoter, while Falcor functions in cis to positively regulate the expression of Foxa2. In the lung, loss of Falcor is sufficient to lead to chronic inflammatory changes and defective repair after airway epithelial injury. Moreover, disruption of the Falcor-Foxa2 regulatory feedback loop leads to altered cell adhesion and migration, in turn resulting in chronic peribronchial airway inflammation and goblet cell metaplasia. These data reveal that the lncRNA Falcor functions within a regulatory feedback loop to fine-tune the expression of Foxa2, maintain airway epithelial homeostasis, and promote regeneration.

中文翻译：

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长的非编码RNA Falcor调节Foxa2表达，以维持肺上皮稳态和促进再生。

转录因子（TFs）是基因表达的剂量敏感性主调节剂，单倍剂量不足经常导致威胁生命的疾病。已经发展出许多机制来在转录，翻译和翻译后水平上紧密调节TF的表达和活性。长非编码RNA（lncRNA）的一个子集与基因组中的转录因子在空间上相关，但这些lncRNA及其相邻TF之间的调节关系尚不清楚。我们确定了TF Foxa2和下游lncRNA Falcor（Foxa2相邻的长非编码RNA）之间的调控反馈环。Foxa2通过与其启动子结合直接抑制Falcor的表达，而Falcor在顺式中起作用以正向调节Foxa2的表达。在肺里 Falcor的丧失足以导致气道上皮损伤后引起慢性炎症变化和修复不良。此外，Falcor-Foxa2调节反馈回路的破坏导致细胞粘附和迁移的改变，进而导致慢性支气管周围气道炎症和杯状细胞化生。这些数据表明，lncRNA Falcor在调节性反馈回路中发挥功能，以微调Foxa2的表达，维持气道上皮稳态和促进再生。