The NANCI-Nkx2.1 gene duplex buffers Nkx2.1 expression to maintain lung development and homeostasis.
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.
['Herriges|Michael J|MJ|', 'Tischfield|David J|DJ|', 'Cui|Zheng|Z|', 'Morley|Michael P|MP|', 'Han|Yumiao|Y|', 'Babu|Apoorva|A|', 'Li|Su|S|', 'Lu|MinMin|M|', 'Cendan|Isis|I|', 'Garcia|Benjamin A|BA|', 'Anderson|Stewart A|SA|', 'Morrisey|Edward E|EE|']
D000818:Animals D004847:Epithelial Cells D018507:Gene Expression Regulation, Developmental D006706:Homeostasis D006801:Humans D007111:Immunity, Cellular D008168:Lung D051379:Mice D009687:Nuclear Proteins D062085:RNA, Long Noncoding D000074482:Thyroid Nuclear Factor 1 D014157:Transcription Factors
lung development lncRNAs transcription factors