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

Modic, Miha; Grosch, Markus; Rot, Gregor; Schirge, Silvia; Lepko, Tjasa; Yamazaki, Tomohiro; Lee, Flora C Y; Rusha, Ejona; Shaposhnikov, Dmitry; Palo, Michael; Merl-Pham, Juliane; Cacchiarelli, Davide; Rogelj, Boris; Hauck, Stefanie M; von Mering, Christian; Meissner, Alexander; Lickert, Heiko; Hirose, Tetsuro; Ule, Jernej; Drukker, Micha

doi:10.1016/j.molcel.2019.03.041

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Modic, M., Grosch, M., Rot, G., Schirge, S., Lepko, T., Yamazaki, T., Lee, F. C. Y., Rusha, E., Shaposhnikov, D., Palo, M., Merl-Pham, J., Cacchiarelli, D., Rogelj, B., Hauck, S. M., von Mering, C., Meissner, A., Lickert, H., Hirose, T., Ule, J., & Drukker, M. (2019). Cross-Regulation between TDP-43 and Paraspeckles Promotes Pluripotency-Differentiation Transition. Molecular Cell, 74(5), 951-965.e13. https://doi.org/10.1016/j.molcel.2019.03.041

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