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LncRNA DEANR1 facilitates human endoderm differentiation by activating FOXA2 expression

ABSTRACT: Long non-coding RNAs (lncRNAs) regulate diverse biological processes including cell lineage specification. Here we report transcriptome profiling of human endoderm and pancreatic cell lineages using purified cell populations. Analysis of the data sets allowed the identification of hundreds of lncRNAs exhibiting differentiation stage-specific expression patterns. As a first step in characterizing these lncRNAs, we focus on an endoderm-specific lncRNA DEANR1 (Definitive Endoderm Associated long Non-coding RNA1) and demonstrate that it plays an important role in human endoderm differentiation. DEANR1 contributes to endoderm differentiation by positively regulating endoderm factor FOXA2 expression. Importantly, overexpression of FOXA2 is able to rescue endoderm differentiation defects caused by DEANR1 depletion. Mechanistically, DEANR1 facilitates FOXA2 activation by helping SMAD2/3 recruitment to the FOXA2 promoter. Thus, our study not only reveals a large set of differentiation stage-specific lncRNAs, but also characterizes a novel lncRNA important for endoderm differentiation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE44875 | GEO | 2014/06/01

SECONDARY ACCESSION(S): PRJNA192215

REPOSITORIES: GEO

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Project description:Background: The Spemann/Mangold organizer is a transient tissue critical for patterning the gastrula stage vertebrate embryo and formation of the three germ layers. Despite its important role during development, there are still relatively few genes with specific expression in the organizer and its derivatives. Foxa2 is a forkhead transcription factor that is absolutely required for formation of the mammalian equivalent of the organizer, the node, the axial mesoderm and the definitive endoderm (DE). However, the targets of Foxa2 during embryogenesis, and the molecular impact of organizer loss on the gastrula embryo, have not been well defined. Results: To identify genes specific to the Spemann/Mangold organizer, we performed a microarray-based screen that compared wild-type and Foxa2 mutant embryos at late gastrulation stage (E7.5). We could detect genes that were consistently down-regulated in replicate pools of mutant embryos versus wild-type, and these included a number of known node and DE markers. We selected 314 genes without previously published data at E7.5 and screened for expression by whole mount in situ hybridization. We identified 10 novel expression patterns in the node and 5 in the definitive endoderm. We also found significant reduction of markers expressed in secondary tissues that require interaction with the organizer and its derivatives, such as cardiac mesoderm, vasculature, primitive streak, and anterior neuroectoderm. Conclusions: The genes identified in this screen represent novel Spemann/Mangold organizer genes as well as potential Foxa2 targets. Further investigation will be needed to define these genes as novel developmental regulatory factors involved in organizer formation and function. We have placed these genes in a Foxa2-dependent genetic regulatory network and we hypothesize how Foxa2 may regulate a molecular program of Spemann/Mangold organizer development. We have also shown how early loss of the organizer and its inductive properties in an otherwise normal embryo, impacts on the molecular profile of surrounding tissues.

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LncRNA DEANR1 facilitates human endoderm differentiation by activating FOXA2 expression

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