Sometimes a perfect match isn’t all it’s cracked up to be – just look at the Hollywood divorce rate. Whether you’re talking relationships or ncRNAs, a few mismatches between partners can still lead to a successful outcome. That seems to be the case for small RNAs that recognize gene promoter regions, as revealed by researchers at the University of Texas Southwestern Medical Center.|
In some earlier work, these scientists and others targeted gene promoter sequences with perfectly complementary duplex RNAs. These small RNAs inhibited mammalian gene expression by recognizing ncRNA transcripts that overlap promoters, thereby recruiting Argonaute proteins.
This time around, the UT crew instead designed synthetic miRNA “mimics” consisting of a natural miRNA sequence and a complementary RNA carrier strand. The miRNA mimics were chosen for their potential to target sites in the promoter region of the human progesterone receptor (PR) gene. Unlike the duplex RNAs, the miRNA mimics had substantial mismatches from their target sequences.
One of the miRNA mimics, called miR-423-5p, showed some interesting effects:
- Reduced PR mRNA levels by more than 70% (even more than a perfectly matched small RNA duplex)
- Recruited Argonaute 2 to a ncRNA transcript overlapping the PR promoter
- Decreased RNA polymerase II occupancy on the PR promoter
- Increased histone H3 lysine 9 dimethylation, a chromatin modification linked to gene silencing
- Silenced expression of the immunoglobulin superfamily member 1, another gene with a predicted target sequence for the miRNA in its promoter
The research team says that miRNA targeting of promoters could be a general mechanism for regulating gene transcription. However, they still don’t know to what extent natural miRNAs silence genes this way – inhibiting endogenous miR-423-5p didn’t affect PR gene expression in the two mammalian cell lines that they studied. Silence your noisy lab mates, and get all the details at Nucleic Acids Research, March 2011