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00925njm 22002777a 4500 dc Barberán-Soler, Sergio author Fontrodona, Laura author Ribó Rubio, Anna author Lamm, Ayelet T. author Iannone, Camilla, 1984- author Cerón, Julián author Lehner, Ben, 1978- author Valcárcel, J. (Juan) author 2023-06-27T06:07:33Z 2023-06-27T06:07:33Z 2014 Includes supplementary materials for the online appendix. Many eukaryotic genes contain embedded antisense transcripts and repetitive sequences of unknown function. We report that male germline-specific expression of an antisense transcript contained in an intron of C. elegans Target of Rapamycin (TOR, let-363) is associated with (1) accumulation of endo-small interfering RNAs (siRNAs) against an embedded Helitron transposon and (2) activation of an alternative 3′ splice site of TOR. The germline-specific Argonaute proteins PRG-1 and CSR-1, which participate in self/nonself RNA recognition, antagonistically regulate the generation of these endo-siRNAs, TOR mRNA levels, and 3′ splice-site selection. Supply of exogenous double-stranded RNA against the region of sense/antisense overlap reverses changes in TOR expression and splicing and suppresses the progressive multigenerational sterility phenotype of prg-1 mutants. We propose that recognition of a “nonself” intronic transposon by endo-siRNAs/the piRNA system provides physiological regulation of expression and alternative splicing of a host gene that, in turn, contributes to the maintenance of germline function across generations. We thank A. Fire, S. Ahmed, and E. Miska for sharing information and helpful discussions, members of our laboratories for critical feedback, the Caenorhabditis Genetics Center (CGC) for providing strains, Matthew Ragle for collection of sperm samples, Alan Zahler for assistance and critical feedback, and Montserrat Porta de la Riva for technical assistance. S.B.-S. was supported by an EMBO postdoctoral fellowship. A.T.L. is a Taub Fellow, supported by the Taub Foundation. J.C. is a Miguel Servet Junior Investigator. Work in J.V.’s lab is supported by Fundación Botín, Consolider RNAREG and Ministerio de Economía y Competitividad (MINECO). Work in B.L.’s lab is supported by the European Research Council (ERC), MINECO Plan Nacional grants BFU2008-00365 and BFU2011-26206, ERASysBio+ ERANET project EUI2009-04059 GRAPPLE, the EMBO Young Investigator Program, EU Framework 7 project 277899 4DCellFate, the AXA Research Fund, and the EMBL/CRG Systems Biology Program. Support from the CRG Genomics Facility is also acknowledged. Cromatina Citoplasma Cèl·lules Cèl·lules humanes -- Cultius Co-option of the piRNA pathway for germline-specific alternative splicing of C. elegans TOR