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

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. Modic et al. uncover opposing roles of TDP-43 and paraspeckles in pluripotency and differentiation that are further enhanced by their cross-regulation. TDP-43 represses paraspeckles through processing of the scaffolding lncRNA Neat1, whereas paraspeckles partially sequester TDP-43. This reciprocal relationship promotes coordinated changes in alternative polyadenylation essential for efficient exit from pluripotency.