武汉云克隆科技股份有限公司

Abstract:

A subset of long noncoding RNAs (lncRNAs) is spatially correlated with transcription factors (TFs) across the genome, but how these lncRNA-TF gene duplexes regulate tissue development and homeostasis is unclear. We identified a feedback loop within the NANCI (Nkx2.1-associated noncoding intergenic RNA)-Nkx2.1 gene duplex that is essential for buffering Nkx2.1 expression, lung epithelial cell identity, and tissue homeostasis. Within this locus, Nkx2.1 directly inhibits NANCI, while NANCI acts in cis to promote Nkx2.1 transcription. Although loss of NANCI alone does not adversely affect lung development, concurrent heterozygous mutations in both NANCI and Nkx2.1 leads to persistent Nkx2.1 deficiency and reprogramming of lung epithelial cells to a posterior endoderm fate. This disruption in the NANCI-Nkx2.1 gene duplex results in a defective perinatal innate immune response, tissue damage, and progressive degeneration of the adult lung. These data point to a mechanism in which lncRNAs act as rheostats within lncRNA-TF gene duplex loci that buffer TF expression, thereby maintaining tissue-specific cellular identity during development and postnatal homeostasis.

摘要：

长链非编码RNA(IncRNAs)的一个片段与整个基因组中的转录因子(TFs)在空间上关联，但是lncRNA-TF是如何调节组织发育和稳态的内在机制尚不清楚。我们发现在NANCI(Nkx2.1相关的IncRNAs)-Nkx2.1中存在一个反馈回路，对于缓冲Nkx2.1的表达、肺上皮细胞特征和组织稳态至关重要。在这个反馈回路中Nkx2.1可以直接抑制NANCI，而NANCI表现出顺式作用促进Nkx2.1转录。虽然缺失NANCI对肺发育的不利影响并不显著，但是NANCI和Nkx2.1同时杂合突变，导致Nkx2.1缺乏症和肺上皮细胞重新发育为后内胚层细胞。这将导致围产期先天免疫反应缺陷、组织损伤和成人肺的进行性病变。这些数据表明在lncRNA-TF结构中，lncRNA作为可变体来缓冲TF的表达，从而在发育和产后维持组织特异性细胞特征。

使用试剂原文信息：Serum was collected from 10-wk-old mice and analyzed for TSH levels by ELISA following the manufacturer's instructions (Thyroid-Stimulating Hormone kit, Cloud-Clone Corp., ABIN415519).