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Nat Struct Mol Biol. 2008 Jun;15(6):581-90. doi: 10.1038/nsmb.1438. Epub 2008 May 25.

Two distinct mechanisms generate endogenous siRNAs from bidirectional transcription in Drosophila melanogaster.

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Sloan-Kettering Institute, Department of Developmental Biology, 521 Rockefeller Research Laboratories, 1275 York Avenue, Box 252, New York, New York 10065, USA.

Erratum in

  • Nat Struct Mol Biol. 2008 Sep;15(9):998.


Cis-natural antisense transcripts (cis-NATs) have been speculated to be substrates for endogenous RNA interference (RNAi), but little experimental evidence for such a pathway in animals has been reported. Analysis of massive Drosophila melanogaster small RNA data sets now reveals two mechanisms that yield endogenous small interfering RNAs (siRNAs) via bidirectional transcription. First, >100 cis-NATs with overlapping 3' exons generate 21-nt, and, based on previously published small RNA data [corrected] Dicer-2 (Dcr-2)-dependent, 3'-end modified siRNAs. The processing of cis-NATs by RNA interference (RNAi) seems to be actively restricted, and the selected loci are enriched for nucleic acid-based functions and include Argonaute-2 (AGO2) itself. Second, we report that extended intervals of the thickveins and klarsicht genes generate exceptionally abundant siRNAs from both strands. These siRNA clusters derive from atypical cis-NAT arrangements involving introns and 5' or internal exons, but their biogenesis is similarly Dcr-2- and AGO2-dependent. These newly recognized siRNA pathways broaden the scope of regulatory networks mediated by small RNAs.

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