MicroRNAs are short, noncoding RNAs that play critical roles in regulating gene expression in normal physiology and disease. Despite having tightly controlled expression levels, little is known about how miRNAs themselves are regulated because their genes are poorly defined. In a study published online on August 19, 2015 in Genome Research, researchers devised a strategy for genome-wide annotation of primary miRNA transcripts, providing extensive new annotations in human and mouse, and shedding light on mechanisms of regulation of microRNA gene expression. The article is titled “Genome-Wide Annotation of MicroRNA Primary Transcript Structures Reveals Novel Regulatory Mechanisms.” Although mature miRNAs are only ~22 nucleotides, their transcripts are up to hundreds of kilobases long. Primary miRNA transcripts, or pri-miRNAs, are quickly processed into mature miRNAs from hairpin structures located in the exons or introns of pri-miRNA transcripts. Because processing occurs very quickly, standard methods such as RT-PCR or RNA sequencing detect full-length pri-miRNAs with poor sensitivity. Many miRNA genes, therefore, lack annotated features such as a promoter or splice sites, hindering progress in understanding their transcriptional and post-transcriptional regulation. To overcome this, researchers from the University of Texas Southwestern Medical Center and Johns Hopkins University stabilized pri-miRNAs by expressing a dominant negative form of DROSHA, the RNase III enzyme responsible for pri-miRNA cleavage, in a variety of human and mouse cell lines. By deeply sequencing nuclear RNAs and applying the computational tool StringTie to assemble transcripts, the researchers were able to annotate 69% of human miRNAs and 75% of mouse miRNAs.
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