Cross-regulation between TDP-43 and paraspeckles promotes pluripotency-differentiation transition.
journal contributionposted on 2020-01-08, 16:50 authored by Miha Modic, Markus Grosch, Gregor Rot, Silvia Schirge, Tjasa Lepko, Tomohiro Yamazaki, Flora CY Lee, Ejona Rusha, Dmitry Shaposhnikov, Michael Palo, Juliane Merl-Pham, Davide Cacchiarelli, Boris Rogelj, Stefanie M Hauck, Christian von Mering, Alexander Meissner, Heiko Lickert, Tetsuro Hirose, Jernej Ule, Micha Drukker
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.