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Mol Cell. 2019 Apr 29. pii: S1097-2765(19)30270-9. doi: 10.1016/j.molcel.2019.03.041. [Epub ahead of print]

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

Author information

1
Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; The Francis Crick Institute, London NW1 1AT, UK; Department for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
2
Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
3
Institute of Molecular Life Sciences of the University of Zurich and Swiss Institute of Bioinformatics, 8057 Zurich, Switzerland.
4
Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
5
Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
6
The Francis Crick Institute, London NW1 1AT, UK; Department for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
7
Research Unit Protein Science, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 80939 Munich, Germany.
8
Broad Institute of Harvard University/MIT, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Telethon Institute of Genetics and Medicine (TIGEM), NA 80078 Pozzuoli, Italy.
9
Department of Biotechnology, Jožef Stefan Institute, 1000 Ljubljana, Slovenia; Faculty of Chemistry and Chemical Technology, University of Ljubljana, 1000 Ljubljana, Slovenia; Biomedical Research Institute BRIS, 1000 Ljubljana, Slovenia.
10
Broad Institute of Harvard University/MIT, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Department of Genome Regulation, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
11
The Francis Crick Institute, London NW1 1AT, UK; Department for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK. Electronic address: jernej.ule@crick.ac.uk.
12
Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Comprehensive Pneumology Center (CPC-M), Ludwig-Maximilians-Universität München, Asklepios Fachkliniken München-Gauting und Helmholtz Zentrum München, Max-Lebsche-Platz 31, 81377 Munich, Germany. Electronic address: micha.drukker@helmholtz-muenchen.de.

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.

PMID:
31047794
DOI:
10.1016/j.molcel.2019.03.041
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