Dataset Information

Genetic variation and RNA structure regulate microRNA biogenesis.

ABSTRACT: MiRNA biogenesis is highly regulated at the post-transcriptional level; however, the role of sequence and secondary RNA structure in this process has not been extensively studied. A single G to A substitution present in the terminal loop of pri-mir-30c-1 in breast and gastric cancer patients had been previously described to result in increased levels of mature miRNA. Here, we report that this genetic variant directly affects Drosha-mediated processing of pri-mir-30c-1 in vitro and in cultured cells. Structural analysis of this variant revealed an altered RNA structure that facilitates the interaction with SRSF3, an SR protein family member that promotes pri-miRNA processing. Our results are compatible with a model whereby a genetic variant in pri-mir-30c-1 leads to a secondary RNA structure rearrangement that facilitates binding of SRSF3 resulting in increased levels of miR-30c. These data highlight that primary sequence determinants and RNA structure are key regulators of miRNA biogenesis.

SUBMITTER: Fernandez N

PROVIDER: S-EPMC5418625 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Genetic variation and RNA structure regulate microRNA biogenesis.

Fernandez Noemi N Cordiner Ross A RA Young Robert S RS Hug Nele N Macias Sara S Cáceres Javier F JF

Nature communications 20170503

MiRNA biogenesis is highly regulated at the post-transcriptional level; however, the role of sequence and secondary RNA structure in this process has not been extensively studied. A single G to A substitution present in the terminal loop of pri-mir-30c-1 in breast and gastric cancer patients had been previously described to result in increased levels of mature miRNA. Here, we report that this genetic variant directly affects Drosha-mediated processing of pri-mir-30c-1 in vitro and in cultured ce ...[more]

PMID: 28466845

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Project description:Disease-associated variants (DAVs) are commonly considered either through a genomic lens that describes variant function at the DNA level, or at the protein function level if the variant is translated. Although the genomic and proteomic effects of variation are well-characterized, genetic variants disrupting post-transcriptional regulation is another mechanism of disease that remains understudied. Specific RNA sequence motifs mediate post-transcriptional regulation both in the nucleus and cytoplasm of eukaryotic cells, often by binding to RNA-binding proteins or other RNAs. However, many DAVs map far from these motifs, which suggests deeper layers of post-transcriptional mechanistic control. Here, we consider a transcriptomic framework to outline the importance of post-transcriptional regulation as a mechanism of disease-causing single-nucleotide variation in the human genome. We first describe the composition of the human transcriptome and the importance of abundant yet overlooked components such as introns and untranslated regions (UTRs) of messenger RNAs (mRNAs). We present an analysis of Human Gene Mutation Database variants mapping to mRNAs and examine the distribution of causative disease-associated variation across the transcriptome. Although our analysis confirms the importance of post-transcriptional regulatory motifs, a majority of DAVs do not directly map to known regulatory motifs. Therefore, we review evidence that regions outside these well-characterized motifs can regulate function by RNA structure-mediated mechanisms in all four elements of an mRNA: exons, introns, 5' and 3' UTRs. To this end, we review published examples of riboSNitches, which are single-nucleotide variants that result in a change in RNA structure that is causative of the disease phenotype. In this review, we present the current state of knowledge of how DAVs act at the transcriptome level, both through altering post-transcriptional regulatory motifs and by the effects of RNA structure.

Dataset Information

Genetic variation and RNA structure regulate microRNA biogenesis.

Publications

Genetic variation and RNA structure regulate microRNA biogenesis.

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