Intron Retention Controls Localization of lncRNAs PURPL and MALAT1 to Promote Cell Proliferation and Migration

Abstract

Intron retention (IR) is increasingly recognized as a feature of long noncoding RNAs (lncRNAs), yet the mechanisms that shape IR in lncRNAs and the functional consequences of this process remain largely unexplored. To investigate how IR contributes to lncRNA regulation, we performed a genome-wide screen to identify factors controlling IR in the lncRNA PURPL. This approach uncovered a prominent role for U2AF2, which promotes retention of a specific intron in PURPL through a weak polypyrimidine tract. IR of this intron drives nuclear enrichment of PURPL and enhances cell proliferation, revealing biological relevance. Transcriptome-wide analyses showed that although U2AF2 broadly supports canonical splicing consistent with its well-established function in promoting splicing, it also facilitates IR within a distinct subset of RNAs, including the nuclear speckle-associated lncRNA MALAT1. Loss of U2AF2 disrupts MALAT1 speckle localization and using MALAT1 knockout cells reconstituted with wild-type or intron deleted variants, we identified a single intron critical for MALAT1s speckle localization. Deletion of this intron from endogenous MALAT1 impaired speckle localization and reduced cell migration, phenocopying the loss of MALAT1. Together, these findings reveal IR as a key regulatory mechanism governing lncRNA localization and function and uncover an unexpected role for U2AF2 in promoting IR within specific lncRNA contexts.