1. Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA
2. Harvard Medical School, Department of Genetics, Howard Hughes Medical Institute, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA
3. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02141, USA
4. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
5. Department of Biological Chemistry, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA
6. These authors contributed equally to this work.

Correspondence to: Gregory J. Hannon¹Julius Brennecke¹ Correspondence and requests for materials should be addressed to G.J.H. (Email: hannon@cshl.edu) or J.B. (Email: brenneck@cshl.edu).

Abstract

Drosophila endogenous small RNAs are categorized according to their mechanisms of biogenesis and the Argonaute protein to which they bind. MicroRNAs are a class of ubiquitously expressed RNAs of 22 nucleotides in length, which arise from structured precursors through the action of Drosha–Pasha and Dicer-1–Loquacious complexes^{1, 2, 3, 4, 5, 6, 7}. These join Argonaute-1 to regulate gene expression^{8, 9}. A second endogenous small RNA class, the Piwi-interacting RNAs, bind Piwi proteins and suppress transposons^{10, 11}. Piwi-interacting RNAs are restricted to the gonad, and at least a subset of these arises by Piwi-catalysed cleavage of single-stranded RNAs^{12, 13}. Here we show that Drosophila generates a third small RNA class, endogenous small interfering RNAs, in both gonadal and somatic tissues. Production of these RNAs requires Dicer-2, but a subset depends preferentially on Loquacious^{1, 4, 5} rather than the canonical Dicer-2 partner, R2D2 (ref. 14). Endogenous small interfering RNAs arise both from convergent transcription units and from structured genomic loci in a tissue-specific fashion. They predominantly join Argonaute-2 and have the capacity, as a class, to target both protein-coding genes and mobile elements. These observations expand the repertoire of small RNAs in Drosophila, adding a class that blurs distinctions based on known biogenesis mechanisms and functional roles.

1. Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA
2. Harvard Medical School, Department of Genetics, Howard Hughes Medical Institute, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA
3. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02141, USA
4. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
5. Department of Biological Chemistry, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA
6. These authors contributed equally to this work.

Correspondence to: Gregory J. Hannon¹Julius Brennecke¹ Correspondence and requests for materials should be addressed to G.J.H. (Email: hannon@cshl.edu) or J.B. (Email: brenneck@cshl.edu).

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