生物
重编程
细胞生物学
转录因子
基因
基因表达
基因表达调控
平衡
遗传学
作者
Michael J. Herriges,David J. Tischfield,Zheng Cui,Michael P. Morley,Yumiao Han,Apoorva Babu,Li Su,MinMin Lu,Isis Cendan,Benjamin A. García,Stewart A. Anderson,Edward E. Morrisey
出处
期刊:Genes & Development
[Cold Spring Harbor Laboratory Press]
日期:2017-05-01
卷期号:31 (9): 889-903
被引量:37
标识
DOI:10.1101/gad.298018.117
摘要
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.
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