The Integrator complex regulates differential snRNA processing and fate of adult stem cells in the highly regenerative planarian Schmidtea mediterranea

In multicellular organisms, cell type diversity and fate depend on specific sets of transcript isoforms generated by post-transcriptional RNA processing. Here, we used Schmidtea mediterranea, a flatworm with extraordinary regenerative abilities and a large pool of adult stem cells, as an in vivo model to study the role of Uridyl-rich small nuclear RNAs (UsnRNAs), which participate in multiple RNA processing reactions including splicing, in stem cell regulation. We characterized the planarian UsnRNA repertoire, identified stem cell-enriched variants and obtained strong evidence for an increased rate of UsnRNA 3’-processing in stem cells compared to their differentiated counterparts. Consistently, components of the Integrator complex showed stem cell-enriched expression and their depletion by RNAi disrupted UsnRNA processing resulting in global changes of splicing patterns and reduced processing of histone mRNAs. Interestingly, loss of Integrator complex function disrupted both stem cell maintenance and regeneration of tissues. Our data show that the function of the Integrator complex in UsnRNA 3’-processing is conserved in planarians and essential for maintaining their stem cell pool. We propose that cell type-specific modulation of UsnRNA composition and maturation contributes to in vivo cell fate choices, such as stem cell self-renewal in planarians.This work was supported by the Max-Planck-Gesellschaft, the Deutsche Forschungsgemeinschaft (German Research Foundation) (BA4044/3-1) and the European Research Council (ERC-2016-StG 716894-IniReg). MI was supported by the European Research Council under the European Union's Horizon 2020 program (ERC-StG-LS2-637591), the Spanish Ministerio de Economía y Competitividad (BFU2017-89201-P) and the ‘Centro de Excelencia Severo Ochoa 2013-2017’(SEV-2012-0208). We acknowledge the support of the CERCA Programme/Generalitat de Catalunya and of the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership. The Bartscherer lab is part of the Cells-in-Motion Cluster of Excellence (EXC 1003-CiM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript