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A functional screen of translated pancreatic lncRNAs identifies a microprotein-independent role for LINC00261 in endocrine cell differentiation

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Title:A functional screen of translated pancreatic lncRNAs identifies a microprotein-independent role for LINC00261 in endocrine cell differentiation
Creators Name:Gaertner, B. and van Heesch, S. and Schneider-Lunitz, V. and Schulz, J.F. and Witte, F. and Blachut, S. and Nguyen, S. and Wong, R. and Matta, I. and Hubner, N. and Sander, M.
Abstract: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. Here, we show that many lncRNAs in direct vicinity of lineage-determining transcription factors (TFs) are dynamically regulated, predominantly cytosolic, and highly translated during pancreas development. We genetically ablated ten such lncRNAs, most of them translated, and found that nine are dispensable for endocrine cell differentiation. However, deletion of LINC00261 diminishes generation of insulin+ endocrine cells, in a manner independent of the nearby TF FOXA2. Systematic deletion of each of LINC00261’s seven poorly conserved microproteins shows that the RNA, rather than the microproteins, is required for endocrine development. Our work highlights extensive translation of lncRNAs into recently evolved microproteins during human pancreas development and provides a blueprint for dissection of their coding and noncoding roles.
Keywords:ORF Detection, CRISPR, Endocrine Development, Endoderm, hESC, Insulin, lncRNAs, Microproteins, Pancreas Development, Ribosome Profiling, Short ORFs, Translational Regulation, Translatome
Source:bioRxiv
Publisher:Cold Spring Harbor Laboratory Press
Article Number:2020.04.28.062679
Date:29 April 2020
Official Publication:https://doi.org/10.1101/2020.04.28.062679
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https://edoc.mdc-berlin.de/19198/Final version

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