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  Cross-Regulation between TDP-43 and Paraspeckles Promotes Pluripotency-Differentiation Transition

Modic, M., Grosch, M., Rot, G., Schirge, S., Lepko, T., Yamazaki, T., et al. (2019). Cross-Regulation between TDP-43 and Paraspeckles Promotes Pluripotency-Differentiation Transition. Molecular Cell, 74: e13, pp. 1-15. doi:10.1016/j.molcel.2019.03.041.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-906C-1 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-906D-0
Genre: Journal Article

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 Creators:
Modic, Miha , Author
Grosch, Markus , Author
Rot, Gregor, Author
Schirge, Silvia , Author
Lepko, Tjasa , Author
Yamazaki, Tomohiro , Author
Lee, Flora C. Y. , Author
Rusha, Ejona , Author
Shaposhnikov, Dmitry , Author
Palo, Michael, Author
Merl-Pham, Juliane , Author
Cacchiarelli, Davide , Author
Rogelj, Boris , Author
Hauck, Stefanie M. , Author
von Mering, Christian, Author
Meissner, Alexander1, 2, Author              
Lickert, Heiko, Author
Hirose, Tetsuro , Author
Drukker, Micha , Author
Affiliations:
1Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              
2Broad Institute of Harvard University/MIT, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA, ou_persistent22              

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 Abstract: RNA-binding proteins (RBPs) and long non-coding RNAs (lncRNAs) are key regulators of gene expression, but their joint functions in coordinating cell fate decisions are poorly understood. Here we show that the expression and activity of the RBP TDP-43 and the long isoform of the lncRNA Neat1, the scaffold of the nuclear compartment "paraspeckles," are reciprocal in pluripotent and differentiated cells because of their cross-regulation. In pluripotent cells, TDP-43 represses the formation of paraspeckles by enhancing the polyadenylated short isoform of Neat1. TDP-43 also promotes pluripotency by regulating alternative polyadenylation of transcripts encoding pluripotency factors, including Sox2, which partially protects its 3' UTR from miR-21-mediated degradation. Conversely, paraspeckles sequester TDP-43 and other RBPs from mRNAs and promote exit from pluripotency and embryonic patterning in the mouse. We demonstrate that cross-regulation between TDP-43 and Neat1 is essential for their efficient regulation of a broad network of genes and, therefore, of pluripotency and differentiation.

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Language(s): eng - English
 Dates: 2019-03-282019-04-292019-06-06
 Publication Status: Published in print
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 Rev. Method: -
 Identifiers: DOI: 10.1016/j.molcel.2019.03.041
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Title: Molecular Cell
Source Genre: Journal
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Publ. Info: Cambridge, Mass. : Cell Press
Pages: - Volume / Issue: 74 Sequence Number: e13 Start / End Page: 1 - 15 Identifier: ISSN: 1097-2765
CoNE: https://pure.mpg.de/cone/journals/resource/954925610929