Pulmonary disease is the number three cause of morbidity and mortality in the Western world. Intense investigation over the last two decades has shown that many of the pathways critical for lung development are reactivated in adult disease states. Recently, non-coding RNAs have been demonstrated to play key roles in regulating lung development. Moreover, expression of many miRNAs is disregulated in adult disease states suggesting a potential role in repair/regeneration/diseases progression. This has led to the hypothesis that the non-coding RNA transcriptome may constitute a core set of regulatory factors that promote both development and proper repair/regeneration after injury and during disease remodeling in the lung. Long non-coding RNAs (lncRNAs) are thought to play key roles in regulating gene expression and, in recent studies, have been shown to regulate various developmental processes from maintaining pluripotency to regulating neural, eye, and cardiac development. LncRNAs are generally defined as RNA transcripts greater than 200 basepairs that do not encode for a polypeptide. Many lncRNAs are polyadenylated and contain multiple exon-intron structures. Some lncRNAs overlap with protein coding genes while others exists as independent transcripts between genes. The mechanism by which lncRNAs function is unclear but several studies suggest they can act either in cis or trans to either repress or enhance gene expression, possibly through interactions with chromatin remodeling complexes such as polycomb repressor complex 2 (PRC2). This suggests a role for lncRNAs in defining and modulating the epigenetic landscape to control gene expression. We have recently performed a high throughout genomic screen for lncRNAs expressed in the embryonic and adult lung using RNAseq and ChIPseq analysis. In this screen, we have chosen to focus on intergenic lncRNAs given their previously reported importance in regulating gene transcription. We have used these data to identify a lung lncRNA transcriptome containing 363 lncRNAs that likely play critical roles in lung biology. This database of lung lncRNAs provides a novel resource to identify and characterize new and important regulators of lung gene transcription and development. Our preliminary data shows that lung lncRNAs are often transcribed near transcription factors and signaling molecules critically important for lung development and homeostasis including Nkx2.1, Foxf1, and Foxa2 and are expressed in patterns similar to these genes. In particular, we show that a novel lncRNA associated with Nkx2.1 (NANCI) acts upstream of Nkx2.1 to regulate lung gene expression. These findings will have a broad impact on our understanding of the non-coding transcriptome in pulmonary development, disease and repair/regeneration.

Public Health Relevance

This proposal will examine the role of long non-coding RNAs in lung development and regeneration. The information gained form these studies will provide novel and important information regarding the role of this species of RNA in regulating gene expression in the lung and the affects that disruption of these genes have on normal lung development. These are some of the first studies to explore this type of control on lung gene expression and will provide a platform of knowledge that can be used by other researchers to explore the importance of these genes in human lung biology.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL122993-01A1
Application #
8831997
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lin, Sara
Project Start
2015-08-01
Project End
2019-02-28
Budget Start
2015-08-01
Budget End
2016-02-29
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Herriges, Michael J; Tischfield, David J; Cui, Zheng et al. (2017) The NANCI-Nkx2.1 gene duplex buffers Nkx2.1 expression to maintain lung development and homeostasis. Genes Dev 31:889-903