MicroRNAs (miRNAs) are short, noncoding RNAs that regulate gene expression by targeting messenger RNAs (mRNAs) for degradation as part of the RNA-induced silencing complex. MiRNAs are transcribed as primary miRNAs (pri-miRNAs), which are processed to precursor miRNAs (pre-miRNAs) in the nucleus by the enzyme Drosha. Pre-miRNAs are processed to generate mature miRNAs by the enzyme Dicer in the cytoplasm. Davis et al. previously showed that Smad proteins, which are activated by transforming growth factor–β (TGF-β) and bone morphogenetic protein (BMP) signaling, promote the processing of specific miRNAs, but the mechanism involved was unclear. Here, the authors performed array analysis to identify miRNAs in human primary pulmonary smooth muscle cells (PASMCs) whose abundance was increased in response to TGF-β or BMP4. They identified 20 miRNAs, 17 of which contained a sequence (R-SBE) similar to the consensus sequence found in the promoters of Smad target genes. Mutation of this sequence prevented the TGF-β– and BMP-dependent processing of pri-miRNAs to pre-miRNAs. The increased abundance of R-SBE–containing miRNAs was not due to Smad-dependent induction of pri-miRNA transcription. Smad1 bound to the R-SBE sequence in vitro through its MH1 domain, which is used to bind to DNA in target genes. Knockdown of Smad1 or Smad5 in PASMCs inhibited the TGF-β– or BMP-dependent recruitment of Drosha to R-SBE–containing pri-miRNAs, thus preventing their processing. Together, these data indicate a role for Smad proteins in promoting the processing of a specific subset of miRNAs. As Treiber and Meister suggest in commentary, these findings should stimulate investigation of the potential ability of other DNA-binding proteins to regulate miRNA expression.
B. N. Davis, A. C. Hilyard, P. H. Nguyen, G. Lagna, A. Hata, Smad proteins bind a conserved RNA sequence to promote microRNA maturation by Drosha. Mol. Cell 39, 373–384 (2010). [PubMed]
T. Treiber, G. Meister, SMADs stimulate miRNA processing. Mol. Cell 39, 315–316 (2010). [PubMed]