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The NANCI-Nkx2.1 gene duplex buffers Nkx2.1 expression to maintain lung development and homeostasis

ABSTRACT: A subset of long-noncoding RNAs (lncRNAs) are spatially correlated with transcription factors (TFs) across the genome, but how these lncRNA-TF gene duplexes regulate tissue development and homeostasis is unclear. We have identified a feedback loop within the NANCI-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 where 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE92304 | GEO | 2017/09/08

SECONDARY ACCESSION(S): PRJNA357159

REPOSITORIES: GEO

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Project description:Nkx2.1 is a critical regulator of mammalian lung development. It is expressed in epithelial cells at the initiation of lung organogenesis, becoming progressively restricted during development to bronchiolar and alveolar type II epithelial cells. In humans, it is a common marker of carcinomas of lung and thyroid origin and is highly amplified in 10-15% of lung adenocarcinomas. Despite its key role in development and disease only a few genes directly regulated by Nkx2.1 are known. To identify direct Nkx2.1target genes and pathways controlled by this transcription factor in vivo we analyzed, by chromatin immuno-precipitation (chip)-on-chip method, Nkx2.1 binding to DNA cis-elements in developing mouse lung. We analyzed embryonic day E11.5 lungs, when Nkx2.1 expressing cells are undergoing predominantly proliferation, and day E19.5, when Nkx2.1 expressing cells are undergoing predominantly differentiation. Many highly bound targets are known and well described, such as surfactant proteins and secretoglobins. Unique or common target genes involved in a variety of developmental and tumorigenic pathways were identified at each developmental time point. Positive regulation of cell proliferation was the highest overrepresented biological process at E11.5 while ion transport was the highest overrepresented biological process at E19.5. New identified targets include proliferation related genes such as E2F3, Met, Ccnb1, and Ccnb2. Nkx2.1 downregulation in mouse epithelial and human carcinoma cell lines reduced cell proliferation by arresting cells in the G2/M phase. Reduced expression of Nkx2.1 target genes in both cell lines supports a direct role of Nkx2.1 in regulation of cell proliferation genes. The identification of these transcriptional regulatory pathways in vivo aid us to understand Nkx2.1 function in lung development and link it to disease, since many of the identified targets are aberrantly up regulated in cancer cells. Developing mouse lung, 2 developmental time points E11.5 and E19.5, genomic DNA fragments immunoprecipitated with a-Nkx2.1 (07-601, Upstate-Millipore) vs input, E11.5, 2 biological replicates and E19.5, 3 biological replicates

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The NANCI-Nkx2.1 gene duplex buffers Nkx2.1 expression to maintain lung development and homeostasis

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