Ultraconserved cDNA segments in the human transcriptome exhibit resistance to folding and implicate function in translation and alternative splicing

Sathirapongsasuti, J. Fah; Sathira, Nuankanya; Suzuki, Yutaka; Huttenhower, Curtis; Sugano, Sumio

doi:10.1093/nar/gkq949

Cited by 17 publications

(14 citation statements)

References 62 publications

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“…These regions are similar to the previously described HCEs [48, 49]. HCEs are found across the genome in both coding and non-coding regions of genes [48-50, 71]. HCEs are associated with the 3’ UTRs of regulatory genes, and may be involved in post-transcriptional gene regulation, alternative splicing, and polyadenylation [48-51].…”

Section: Discussionsupporting

confidence: 81%

Conserved regions of the DMD 3′ UTR regulate translation and mRNA abundance in cultured myotubes

Larsen

Howard

2014

Neuromuscular Disorders

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Duchenne muscular dystrophy (DMD), a severe muscle-wasting disease, is caused by mutations in the DMD gene, which encodes for the protein dystrophin. Its regulation is of therapeutic interest as even small changes in expression of functional dystrophin can significantly impact the severity of DMD. While tissue-specific distribution and transcriptional regulation of several DMD mRNA isoforms has been well characterized, the post-transcriptional regulation of dystrophin synthesis is not well understood. Here, we utilize qRTPCR and a quantitative dual-luciferase reporter assay to examine the effects of isoform specific DMD 5’ UTRs and the highly conserved DMD 3’ UTR on mRNA abundance and translational control of gene expression in C2C12 cells. The 5’ UTRs were shown to initiate translation with low efficiency in both myoblasts and myotubes. Whereas, two large highly conserved elements in the 3’ UTR, which overlap the previously described Lemaire A and D regions, increase mRNA levels and enhance translation upon differentiation of myoblasts into myotubes. The results presented here implicate an important role for DMD UTRs in dystrophin expression and delineate the cis-acting elements required for the myotube-specific regulation of steady-state mRNA levels and translational enhancer activity found in the DMD 3’ UTR.

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Section: Discussionsupporting

confidence: 81%

Conserved regions of the DMD 3′ UTR regulate translation and mRNA abundance in cultured myotubes

Larsen

Howard

2014

Neuromuscular Disorders

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“…1A). More recently, it has been proposed that these ultraconserved regions have evolved to lack RNA structure (33). To determine the RNA structure of the MBNL1 ultraconserved region and the role of RNA structure if any in MBNL1 binding, structure probing and footprinting experiments were performed.…”

Section: Mbnl1 Binds a Primarily Unstructured Region Between Distant mentioning

confidence: 99%

Autoregulated Splicing of muscleblind-like 1 (MBNL1) Pre-mRNA

Gates

Coonrod

Berglund

2011

Journal of Biological Chemistry

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Muscleblind-like 1 (MBNL1) is a splicing factor whose improper cellular localization is a central component of myotonic dystrophy. In myotonic dystrophy, the lack of properly localized MBNL1 leads to missplicing of many pre-mRNAs. One of these events is the aberrant inclusion of exon 5 within the MBNL1 pre-mRNA. The region of the MBNL1 gene that includes exon 5 and flanking intronic sequence is highly conserved in vertebrate genomes. The 3 -end of intron 4 is noncanonical in that it contains a predicted branch point that is 141 nucleotides from the 3 -splice site and an AAG 3 -splice site. Using a minigene that includes exon 4, intron 4, exon 5, intron 5, and exon 6 of MBNL1, we showed that MBNL1 regulates inclusion of exon 5. Mapping of the intron 4 branch point confirmed that branching occurs primarily at the predicted distant branch point. Structure probing and footprinting revealed that the highly conserved region between the branch point and 3 -splice site is primarily unstructured and that MBNL1 binds within this region of the pre-mRNA. Deletion of the MBNL1 response element eliminated MBNL1 splicing regulation and led to complete inclusion of exon 5, which is consistent with the suppressive effect of MBNL1 on splicing.Splicing of pre-mRNAs is an important event that contributes to a diverse proteome as well as the regulation of gene expression. It is estimated that more than 90% of human genes undergo alternative splicing (1, 2). To produce a functional mRNA, non-coding regions must be accurately removed, and the coding regions must be ligated together. Splicing occurs via two transesterification reactions that result in removal of the intron and ligation of the exons. This splicing mechanism relies on pre-mRNA sequences, proteins, and small nuclear RNAs (snRNAs) that are necessary for intron and exon definition and the two transesterification reactions. Cis-sequences that are important for splicing include the 5Ј-splice site (ss), 2 the branch point sequence, the polypyrimidine (PY) tract, and the 3Ј-ss. These canonical intronic motifs, plus additional regulatory splicing motifs found in exons and introns, are recognized by splicing factors and small nuclear ribonucleoproteins (U1, U2, U4, U5, and U6) to form the spliceosome, which catalyzes intron removal (for a review, see Ref.3).There are many splicing factors that are only involved in a subset of splicing decisions. These include the human muscleblind-like family of RNA-binding proteins: MBNL1/2/3 also known as MBNL/EXP, MBLL/MPL1, and MBXL/CHCR, respectively. The founding member of this family, muscleblind (Mbl), was discovered in Drosophila and was shown to be important for photoreceptor differentiation and terminal differentiation of muscles (4, 5). Subsequently, MBNL proteins were found to associate with expanded CUG repeats (located in the 3Ј-untranslated region of the DMPK gene) that have been shown to act as a toxic RNA and are at least partially responsible for causing myotonic dystrophy (DM) type 1 (for reviews, see Refs. 6 -8). The expanded...

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“…Bioinformatic studies have now shown that about 49% of the human transcriptome contains uORFs, which are mostly conserved among species, suggesting evolutionary selection of functional uORFs [2], [9]–[12]. For example, genes as diverse as CD36 , MDM2 , ERBB2 , SOC1 , and RARB have conserved and experimentally characterized uORFs that regulate translation [10].…”

Section: Introductionmentioning

confidence: 99%

Gene Expression Regulation by Upstream Open Reading Frames and Human Disease

2013

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Upstream open reading frames (uORFs) are major gene expression regulatory elements. In many eukaryotic mRNAs, one or more uORFs precede the initiation codon of the main coding region. Indeed, several studies have revealed that almost half of human transcripts present uORFs. Very interesting examples have shown that these uORFs can impact gene expression of the downstream main ORF by triggering mRNA decay or by regulating translation. Also, evidence from recent genetic and bioinformatic studies implicates disturbed uORF-mediated translational control in the etiology of many human diseases, including malignancies, metabolic or neurologic disorders, and inherited syndromes. In this review, we will briefly present the mechanisms through which uORFs regulate gene expression and how they can impact on the organism's response to different cell stress conditions. Then, we will emphasize the importance of these structures by illustrating, with specific examples, how disturbed uORF-mediated translational control can be involved in the etiology of human diseases, giving special importance to genotype-phenotype correlations. Identifying and studying more cases of uORF-altering mutations will help us to understand and establish genotype-phenotype associations, leading to advancements in diagnosis, prognosis, and treatment of many human disorders.

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Ultraconserved cDNA segments in the human transcriptome exhibit resistance to folding and implicate function in translation and alternative splicing

Cited by 17 publications

References 62 publications

Conserved regions of the DMD 3′ UTR regulate translation and mRNA abundance in cultured myotubes

Conserved regions of the DMD 3′ UTR regulate translation and mRNA abundance in cultured myotubes

Autoregulated Splicing of muscleblind-like 1 (MBNL1) Pre-mRNA

Gene Expression Regulation by Upstream Open Reading Frames and Human Disease

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