Automatic detection of exonic splicing enhancers (ESEs) using SVMs

Mersch, Britta; Gepperth, Alexander; Suhai, Sándor; Hotz‐Wagenblatt, Agnes

doi:10.1186/1471-2105-9-369

Cited by 18 publications

(8 citation statements)

References 36 publications

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“…The AAGAAG ESE motif has been proposed as the second-most common ESE hexamer in vertebrates [15]. Given the importance of ESEs for promoting splicing, we hypothesised that this motif could influence the splicing efficiency of DGAT1 pre-mRNA to influence mRNA expression.…”

Section: Discussionmentioning

confidence: 99%

A new mechanism for a familiar mutation – bovine DGAT1 K232A modulates gene expression through multi-junction exon splice enhancement

et al. 2020

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Background: The DGAT1 gene encodes an enzyme responsible for catalysing the terminal reaction in mammary triglyceride synthesis, and underpins a well-known pleiotropic quantitative trait locus (QTL) with a large influence on milk composition phenotypes. Since first described over 15 years ago, a protein-coding variant K232A has been assumed as the causative variant underlying these effects, following in-vitro studies that demonstrated differing levels of triglyceride synthesis between the two protein isoforms. Results: We used a large RNAseq dataset to reexamine the underlying mechanisms of this large milk production QTL, and hereby report novel expression-based functions of the chr14 g.1802265AA > GC variant that encodes the DGAT1 K232A substitution. Using expression QTL (eQTL) mapping, we demonstrate a highly-significant mammary eQTL for DGAT1, where the K232A mutation appears as one of the top associated variants for this effect. By conducting in vitro expression and splicing experiments in bovine mammary cell culture, we further show modulation of splicing efficiency by this mutation, likely through disruption of an exon splice enhancer as a consequence of the allele encoding the 232A variant. Conclusions: The relative contributions of the enzymatic and transcription-based mechanisms now attributed to K232A remain unclear; however, these results suggest that transcriptional impacts contribute to the diversity of lactation effects observed at the DGAT1 locus.

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Section: Discussionmentioning

confidence: 99%

A new mechanism for a familiar mutation – bovine DGAT1 K232A modulates gene expression through multi-junction exon splice enhancement

et al. 2020

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“…The AAGAAG ESE motif has been proposed as the second-most common ESE hexamer in vertebrates [12]. Given the importance of ESEs for promoting splicing, we hypothesised that this motif could influence the splicing efficiency of DGAT1 pre-mRNA to influence mRNA expression.…”

Section: Discussionmentioning

confidence: 99%

A new mechanism for a familiar mutation – bovineDGAT1K232A modulates gene expression through multi-junction exon splice enhancement

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et al. 2020

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The DGAT1 gene encodes an enzyme responsible for catalysing the terminal reaction in mammary triglyceride synthesis, and underpins a well-known pleiotropic quantitative trait locus (QTL) with a large influence on milk composition phenotypes. Since first described over 15 years ago, a protein-coding variant K232A has been assumed as the causative variant underlying these effects, following in-vitro studies that demonstrated differing levels of triglyceride synthesis between the two protein isoforms. In the current study, we used a large RNAseq dataset to re-examine the underlying mechanisms of this large milk production QTL, and hereby report novel expression-based functions of the chr14 g.1802265AA>GC variant that encodes the DGAT1 K232A substitution. Using expression QTL (eQTL) mapping, we demonstrate a highly-significant mammary eQTL for DGAT1, where the K232A mutation appears as one of the top associated variants for this effect. By conducting in vitro expression and splicing experiments in bovine mammary cell culture, we further show modulation of splicing efficiency by this mutation, likely through disruption of an exon splice enhancer as a consequence of the allele encoding the 232A variant. Although the relative contributions of the enzymatic and transcription-based mechanisms now attributed to K232A remain unclear, these results suggest that transcriptional impacts contribute to the diversity of lactation effects observed at this locus.A lysine to alanine amino acid substitution (K232A) encoded by a mutation in the diacylglyercol O-acyltransferase 1 (DGAT1) gene has major impacts on bovine lactation traits, the most substantial being its impact on milk fat percentage [1,2]. This substitution results from an AA to GC dinucleotide substitution in exon eight of DGAT1, and likely constitutes the most widely studied and validated variant in association analyses of bovine milk characteristics (initially described by Grisart et al (2002), with >1000 Google Scholar citations to date). The DGAT1 gene encodes an enzyme responsible for catalysing the terminal reaction in the mammary triglyceride synthesis pathway [3], and the DGAT1 K allele has been shown [4] to synthesise more triglycerides in vitro when compared to the A allele. Aside from the DGAT1 K232A mutation, an additional polymorphism 5′ of the transcription start site of the gene has also been shown to associate with milk fat percentage [5]. This variant, a variable number tandem repeat (VNTR) expansion, was speculated to play a role in bovine milk composition by increasing the number of putative transcription factor binding sites [5]. However, functional testing of the VNTR variant did not show any differences in DGAT1 expression between QTL genotypes in cell culture [6]. This finding largely put the competing, gene expression-based hypothesis of the DGAT1 milk fat effect to rest, with enzymatic differences deriving from the K232A mutation now widely assumed as the underlying mechanism.Since these initial analyses >10 years ago, further functional charact...

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“…2I). AG-rich binding motifs have been previously observed for SRSF1 and SRSF10 (Ray et al 2013), and the heptamer AAGAAGA is frequently present in exonic splicing enhancer (ESE) motifs in human genes (Tacke and Manley 1995;Mersch et al 2008), indicating that DDX54 binds to or close to the ESEs. This result was further supported by the distribution of ESE motifs, which corresponded to the AAGAAGA heptamer distribution within exons (Supplemental Fig.…”

Section: Many Nucleolar Proteins Exhibit Increased Binding To Polyadementioning

confidence: 92%

DDX54 regulates transcriptome dynamics during DNA damage response

et al. 2017

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The cellular response to genotoxic stress is mediated by a well-characterized network of DNA surveillance pathways. The contribution of post-transcriptional gene regulatory networks to the DNA damage response (DDR) has not been extensively studied. Here, we systematically identified RNA-binding proteins differentially interacting with polyadenylated transcripts upon exposure of human breast carcinoma cells to ionizing radiation (IR). Interestingly, more than 260 proteins, including many nucleolar proteins, showed increased binding to poly(A) + RNA in IR-exposed cells. The functional analysis of DDX54, a candidate genotoxic stress responsive RNA helicase, revealed that this protein is an immediate-to-early DDR regulator required for the splicing efficacy of its target IR-induced pre-mRNAs. Upon IR exposure, DDX54 acts by increased interaction with a well-defined class of pre-mRNAs that harbor introns with weak acceptor splice sites, as well as by proteinprotein contacts within components of U2 snRNP and spliceosomal B complex, resulting in lower intron retention and higher processing rates of its target transcripts. Because DDX54 promotes survival after exposure to IR, its expression and/or mutation rate may impact DDR-related pathologies. Our work indicates the relevance of many uncharacterized RBPs potentially involved in the DDR.

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Automatic detection of exonic splicing enhancers (ESEs) using SVMs

Cited by 18 publications

References 36 publications

A new mechanism for a familiar mutation – bovine DGAT1 K232A modulates gene expression through multi-junction exon splice enhancement

A new mechanism for a familiar mutation – bovine DGAT1 K232A modulates gene expression through multi-junction exon splice enhancement

A new mechanism for a familiar mutation – bovineDGAT1K232A modulates gene expression through multi-junction exon splice enhancement

DDX54 regulates transcriptome dynamics during DNA damage response

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