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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; Lee, FCY; ... Drukker, M; + view all (2019) Cross-Regulation between TDP-43 and Paraspeckles Promotes Pluripotency-Differentiation Transition. Molecular Cell , 74 (5) pp. 951-956. 10.1016/j.molcel.2019.03.041. Green open access

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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.

Type: Article
Title: Cross-Regulation between TDP-43 and Paraspeckles Promotes Pluripotency-Differentiation Transition
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.molcel.2019.03.041
Publisher version: https://doi.org/10.1016/j.molcel.2019.03.041
Language: English
Additional information: © 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10074171
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