biostudies-literatureModic MIMPRS Max Planck SocietyFrancis Crick InstituteCancer Research UKEuropean Research CouncilTelethonSlovenian Research AgencyThe Francis Crick InstituteMedical Research CouncilWellcome TrustUHU Network951-965.e13https://www.ebi.ac.uk/biostudies/studies/S-EPMC6561722biostudies-literatureUnknown74(5)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 seqMolecular cellCross-Regulation between TDP-43 and Paraspeckles Promotes Pluripotency-Differentiation Transition.PMC6561722P4-0127617837206726J3-9263JS-6789617837-TranslateJ3-8201TGM16GM02FC00100210002206726-CLIPLepko TSchirge SRogelj BRusha EGrosch MRot GHauck SMCacchiarelli DPalo Mvon Mering CMeissner AModic MMerl-Pham JDrukker MShaposhnikov DUle JLee FCYHirose TLickert HYamazaki TfalseCross-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 seq2019-01-01T00:00:00Z2019 Jun2026-05-07T01:39:57.891Z2019-07-24T07:15:47ZS-EPMC65617223104779410.1016/j.molcel.2019.03.041