College of Basic Medical Medicine, Dalian Medical University, Dalian, 116044, China.
School of Medicine, Nantong University, Nantong, 226001, China.
Genetics. 2023 May 4;224(1). doi: 10.1093/genetics/iyad040.
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.
长链非编码 RNA（lncRNA）在干细胞自我更新、多能性维持和分化中发挥重要的调控作用。直到现在，人们对 lncRNA 如何调控肠道干细胞（ISCs）知之甚少，也尚未对调控果蝇 ISC 再生的 lncRNA 进行鉴定。在这里，我们鉴定了一个 lncRNA，CR46040，它对果蝇损伤诱导的 ISC 再生是必需的。缺失 CR46040 会极大地损害 ISC 对葡聚糖硫酸钠（DSS）处理引起的组织损伤的增殖反应。我们证明 CR46040 是一种真正的 lncRNA，它有两个从相同转录起始位点转录的异构体，以反式作用调控肠道干细胞。在机制上，组织损伤后，CR46040 敲除果蝇不能完全激活 JNK、JAK/STAT 和 HIPPO 信号通路，而这些信号通路是 ISC 增殖所必需的。此外，CR46040 敲除果蝇对 DSS 处理和肠道致病菌欧文氏菌 15（Ecc15）感染高度敏感。我们的研究首次描述了一个 lncRNA，它介导了果蝇损伤诱导的 ISC 增殖，并为长链非编码 RNA、ISCs 增殖和组织稳态之间的功能联系提供了新的见解。
