title: Long noncoding RNAs are spatially correlated with transcription factors and regulate lung development.
abstract: Long noncoding RNAs (lncRNAs) are thought to play important roles in regulating gene transcription, but few have well-defined expression patterns or known biological functions during mammalian development. Using a conservative pipeline to identify lncRNAs that have important biological functions, we identified 363 lncRNAs in the lung and foregut endoderm. Importantly, we show that these lncRNAs are spatially correlated with transcription factors across the genome. In-depth expression analyses of lncRNAs with genomic loci adjacent to the critical transcription factors Nkx2.1, Gata6, Foxa2 (forkhead box a2), and Foxf1 mimic the expression patterns of their protein-coding neighbor. Loss-of-function analysis demonstrates that two lncRNAs, LL18/NANCI (Nkx2.1-associated noncoding intergenic RNA) and LL34, play distinct roles in endoderm development by controlling expression of critical developmental transcription factors and pathways, including retinoic acid signaling. In particular, we show that LL18/NANCI acts upstream of Nkx2.1 and downstream from Wnt signaling to regulate lung endoderm gene expression. These studies reveal that lncRNAs play an important role in foregut and lung endoderm development by regulating multiple aspects of gene transcription, often through regulation of transcription factor expression.
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Herriges
authors.affiliation: Division of Neonatology, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Swarr
authors.affiliation: Department of Medicine.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Morley
authors.affiliation: Department of Medicine.
authors.forename: Komal S
authors.initials: KS
authors.lastname: Rathi
authors.affiliation: Department of Medicine.
authors.forename: Tien
authors.initials: T
authors.lastname: Peng
authors.affiliation: Department of Medicine.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Stewart
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine, Institute for Regenerative Medicine, Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Morrisey
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D004707:Endoderm / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D016678:Genome; D057809:HEK293 Cells; D006801:Humans; D008168:Lung / Q000196:embryology / Q000254:growth & development*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D062085:RNA, Long Noncoding; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors
keywords: Nkx2.1; Wnt signaling; development; lncRNA; lung; retinoic acid