Functionally distinct regulatory RNAs generated by bidirectional transcription and processing of microRNA loci.
Many microRNA (miRNA) loci exhibit compelling hairpin structures on both sense and antisense strands; however, the possibility that a miRNA gene might produce functional species from its antisense strand has not been examined. We report here that antisense transcription of the Hox miRNA locus mir-iab-4 generates the novel pre-miRNA hairpin mir-iab-8, which is then processed into endogenous mature miRNAs. Sense and antisense iab-4/iab-8 miRNAs are functionally distinguished by their distinct domains of expression and targeting capabilities. We find that miR-iab-8-5p, like miR-iab-4-5p, is also relevant to Hox gene regulation. Ectopic mir-iab-8 can strongly repress the Hox genes Ultrabithorax and abdominal-A via extensive arrays of conserved target sites, and can induce a dramatic homeotic transformation of halteres into wings. We generalize the antisense miRNA principle by showing that several other loci in both invertebrates and vertebrates are endogenously processed on their antisense strands into mature miRNAs with distinct seeds. These findings demonstrate that antisense transcription and processing contributes to the functional diversification of miRNA genes.
Tyler
David M
DM
Department of Developmental Biology, Sloan-Kettering Institute, New York, New York 10021, USA;
Okamura
Katsutomo
K
Chung
Wei-Jen
WJ
Hagen
Joshua W
JW
Berezikov
Eugene
E
Hannon
Gregory J
GJ
Lai
Eric C
EC
D000818:Animals; D001483:Base Sequence; D019521:Body Patterning; D004330:Drosophila / Q000196:embryology / Q000235:genetics / Q000254:growth & development; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox; D017344:Genes, Insect; D017403:In Situ Hybridization; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D038621:Regulatory Sequences, Ribonucleic Acid; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D029721:Drosophila Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins; D038621:Regulatory Sequences, Ribonucleic Acid; D014157:Transcription Factors; C066591:abd-A protein, Drosophila