The thermodynamic patterns of eukaryotic genes suggest a mechanism for intron–exon recognition

Nedelcheva-Veleva, Marina N.; Sarov, Mihail; Yanakiev, Ivan; Mihailovska, Eva; Ivanov, Miroslav P; Panova, Greta; Stoynov, Stoyno

doi:10.1038/ncomms3101

Cited by 7 publications

(8 citation statements)

References 59 publications

(90 reference statements)

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“…Importantly also, some tRNA genes were enriched over their entire transcribed region, some showed higher levels of enrichment over their 5′ region, and some other showed enrichment over their 3′ region. This heterogeneity in R-loop occupancy between and within tRNA genes is likely to reflect heterogeneity in tRNA transcription rates among isoacceptors [28] , [29] , [30] , as well as differences in the thermodynamic stability of the RNA-DNA hybrids [12] , [13] . It should be noted that the fold enrichment of R-loops at tRNA genes in strains lacking RNase H (or also Top1) relative to input chromatin (or to the WT) in ChIP-Seq data were generally lower than those in ChIP-QPCR data (compare Figs.…”

Section: Resultsmentioning

confidence: 99%

“…compare the different regions in the relatively long ∼12.88 Kb COX1/Q0045 gene with other mt genes in Fig. 4A ), possibly reflecting variations in the transcription initiation and elongation rates of mtRNAP [45] , as well as differences in the thermodynamic stability of the RNA-DNA hybrids [12] , [13] . Reverse transcriptase activity has been reported in mitochondria of S. cerevisiae [46] .…”

Section: Resultsmentioning

confidence: 99%

“…the G.C content of the inherent sequence. In particular, R-loop formation can be favoured by a high guanine (G) density in the non-template DNA strand (property known as positive GC skew, see [9] , [10] ), and this is specifically due to the higher thermodynamic stability of RNA-DNA hybrid sequences endowed with “G-rich purine RNA”/“C-rich pyrimidine DNA” duplexes [9] , [10] , [11] , [12] , [13] , [14] . Importantly, R-loops rich in G-clusters have been linked to immunoglobulin class switch recombination and CpG methylation in mammals [9] , [10] , [14] , [15] .…”

Section: Introductionmentioning

confidence: 99%

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Genome-Wide Distribution of RNA-DNA Hybrids Identifies RNase H Targets in tRNA Genes, Retrotransposons and Mitochondria

et al. 2014

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During transcription, the nascent RNA can invade the DNA template, forming extended RNA-DNA duplexes (R-loops). Here we employ ChIP-seq in strains expressing or lacking RNase H to map targets of RNase H activity throughout the budding yeast genome. In wild-type strains, R-loops were readily detected over the 35S rDNA region, transcribed by Pol I, and over the 5S rDNA, transcribed by Pol III. In strains lacking RNase H activity, R-loops were elevated over other Pol III genes, notably tRNAs, SCR1 and U6 snRNA, and were also associated with the cDNAs of endogenous TY1 retrotransposons, which showed increased rates of mobility to the 5′-flanking regions of tRNA genes. Unexpectedly, R-loops were also associated with mitochondrial genes in the absence of RNase H1, but not of RNase H2. Finally, R-loops were detected on actively transcribed protein-coding genes in the wild-type, particularly over the second exon of spliced ribosomal protein genes.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genome-Wide Distribution of RNA-DNA Hybrids Identifies RNase H Targets in tRNA Genes, Retrotransposons and Mitochondria

et al. 2014

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“…Indication for weak secondary structure and low GC content adjacent to intronic splice and branch sites It has been shown previously that GC content and thermodynamic patterns affect exon-intron splice site recognition, and that increased pre-mRNA secondary structure promotes AS in multicellular higher eukaryotes including human (Shepard and Hertel 2008;Zhang et al 2011;Amit et al 2012;Nedelcheva-Veleva et al 2013). Yet, evolutionary preference for weak or strong pre-mRNA secondary structure has never been studied systematically in fungi or other organisms.…”

Section: Resultsmentioning

confidence: 99%

Nucleotide sequence composition adjacent to intronic splice sites improves splicing efficiency via its effect on pre-mRNA local folding in fungi

Zafrir

Tuller

2015

RNA

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RNA splicing is the central process of intron removal in eukaryotes known to regulate various cellular functions such as growth, development, and response to external signals. The canonical sequences indicating the splicing sites needed for intronic boundary recognition are well known. However, the roles and evolution of the local folding of intronic and exonic sequence features adjacent to splice sites has yet to be thoroughly studied. Here, focusing on four fungi (Saccharomyces cerevisiae, Schizosaccharomyces pombe, Aspergillus nidulans, and Candida albicans), we performed for the first time a comprehensive high-resolution study aimed at characterizing the encoding of intronic splicing efficiency in pre-mRNA transcripts and its effect on intron evolution. Our analysis supports the conjecture that pre-mRNA local folding strength at intronic boundaries is under selective pressure, as it significantly affects splicing efficiency. Specifically, we show that in the immediate region of 12-30 nucleotides (nt) surrounding the intronic donor site there is a preference for weak pre-mRNA folding; similarly, in the region of 15-33 nt surrounding the acceptor and branch sites there is a preference for weak pre-mRNA folding. We also show that in most cases there is a preference for strong pre-mRNA folding further away from intronic splice sites. In addition, we demonstrate that these signals are not associated with gene-specific functions, and they correlate with splicing efficiency measurements (r = 0.77, P = 2.98 × 10 −21) and with expression levels of the corresponding genes (P = 1.24 × 10 −19 ). We suggest that pre-mRNA folding strength in the above-mentioned regions has a direct effect on splicing efficiency by improving the recognition of intronic boundaries. These new discoveries are contributory steps toward a broader understanding of splicing regulation and intronic/transcript evolution.

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“…However, Pol II can transiently pause, stall or terminate prematurely 55, 56 . Pol II elongation rate is influenced by a multitude of factors, such as the underlying DNA sequence, nucleosome position and histone modifications, which affect local chromatin structure, the activity of elongation factors, and the folding and processing of the nascent RNA 55, 77 . For example, the balance between histone acetylation and methylation in neuronal cells is a determinant of transcription rate and associated splicing patterns 78 .…”

Section: Transcription and Splicing Interactionsmentioning

confidence: 99%

Splicing and transcription touch base: co-transcriptional spliceosome assembly and function

Herzel

Ottoz

Alpert

et al. 2017

Nat Rev Mol Cell Biol

315

284

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Several macromolecular machines collaborate to produce eukaryotic messenger RNA. RNA polymerase II (Pol II) translocates along genes that are up to millions of base pairs in length and generates a flexible RNA copy of the DNA template. This nascent RNA harbours introns that are removed by the spliceosome, which is a megadalton ribonucleoprotein complex that positions the distant ends of the intron into its catalytic centre. Emerging evidence that the catalytic spliceosome is physically close to Pol II in vivo implies that transcription and splicing occur on similar timescales and that the transcription and splicing machineries may be spatially constrained. In this Review, we discuss aspects of spliceosome assembly, transcription elongation and other co-transcriptional events that allow the temporal coordination of co-transcriptional splicing.

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The thermodynamic patterns of eukaryotic genes suggest a mechanism for intron–exon recognition

Cited by 7 publications

References 59 publications

Genome-Wide Distribution of RNA-DNA Hybrids Identifies RNase H Targets in tRNA Genes, Retrotransposons and Mitochondria

Genome-Wide Distribution of RNA-DNA Hybrids Identifies RNase H Targets in tRNA Genes, Retrotransposons and Mitochondria

Nucleotide sequence composition adjacent to intronic splice sites improves splicing efficiency via its effect on pre-mRNA local folding in fungi

Splicing and transcription touch base: co-transcriptional spliceosome assembly and function

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