A human ESC-based screen identifies a role for the translated lncRNA LINC00261 in pancreatic endocrine differentiation

Long noncoding RNAs (lncRNAs) are a heterogenous group of RNAs, which can encode small proteins. The extent to which developmentally regulated lncRNAs are translated and whether the produced microproteins are relevant for human development is unknown. Using a human embryonic stem cell (hESC)-based p...

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Published in:eLife 2020-08, Vol.9
Main Authors: Gaertner, Bjoern, van Heesch, Sebastiaan, Schneider-Lunitz, Valentin, Schulz, Jana Felicitas, Witte, Franziska, Blachut, Susanne, Nguyen, Steven, Wong, Regina, Matta, Ileana, Hübner, Norbert, Sander, Maike
Format: Article
Language:English
Subjects:
Cell differentiation
Cell Differentiation - physiology
Cells, Cultured
Clonal deletion
Computational and Systems Biology
CRISPR-Cas Systems
Developmental Biology
DNA binding proteins
Embryogenesis
Embryonic stem cells
endocrine development
endoderm
Gene Deletion
Gene Expression Regulation, Developmental
Gene Knockout Techniques
Genes
HEK293 Cells
Human Embryonic Stem Cells
Humans
Insulin
Islets of Langerhans - cytology
Islets of Langerhans - embryology
lncRNA
Male
microproteins
Open reading frames
ORF detection
Pancreas
Protein Biosynthesis
Proteins
Regulation
Ribonucleic acid
RNA
RNA, Long Noncoding - genetics
RNA, Long Noncoding - physiology
Roles
Stem cells
Transcription factors
Transcription Factors - metabolism
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Summary:Long noncoding RNAs (lncRNAs) are a heterogenous group of RNAs, which can encode small proteins. The extent to which developmentally regulated lncRNAs are translated and whether the produced microproteins are relevant for human development is unknown. Using a human embryonic stem cell (hESC)-based pancreatic differentiation system, we show that many lncRNAs in direct vicinity of lineage-determining transcription factors (TFs) are dynamically regulated, predominantly cytosolic, and highly translated. We genetically ablated ten such lncRNAs, most of them translated, and found that nine are dispensable for pancreatic endocrine cell development. However, deletion of diminishes insulin cells, in a manner independent of the nearby TF . One-by-one disruption of each of 's open reading frames suggests that the RNA, rather than the produced microproteins, is required for endocrine development. Our work highlights extensive translation of lncRNAs during hESC pancreatic differentiation and provides a blueprint for dissection of their coding and noncoding roles.
ISSN:2050-084X
2050-084X
DOI:10.7554/ELIFE.58659