Long noncoding RNA CR46040 is essential for injury-stimulated regeneration of intestinal stem cells in Drosophila

Long noncoding RNAs (lncRNAs) play important regulatory roles in stem cell self-renewal, pluripotency maintenance, and differentiation. Till now, there is very limited knowledge about how lncRNAs regulate intestinal stem cells (ISCs), and lncRNAs mediating ISC regeneration in Drosophila have yet been characterized. Here, we identify a lncRNA, CR46040, that is essential for the injury-induced ISC regeneration in Drosophila. Loss of CR46040 greatly impairs ISC proliferation in response to tissue damage caused by dextran sulfate sodium (DSS) treatment. We demonstrate that CR46040 is a genuine lncRNA that has two isoforms transcribed from the same transcription start site and works in trans to regulate intestinal stem cells. Mechanistically, CR46040 knock-out flies failed to fully activate JNK, JAK/STAT, and HIPPO signaling pathways after tissue damage, which are required for ISC proliferation after intestinal injury. Moreover, CR46040 knock-out flies are highly susceptible to DSS treatment and enteropathogenic bacteria Erwinia carotovora ssp. carotovora 15 (Ecc15) infection. Our findings characterize, for the first time, a lncRNA that mediates damage-induced ISC proliferation in Drosophila and provide new insights into the functional links among the long noncoding RNAs, ISC proliferation, and tissue homeostasis.