Protecting exons from deleterious R-loops: a potential advantage of having introns

BACKGROUND: Accumulating evidence indicates that the nascent RNA can invade and pair with one strand of DNA, forming an R-loop structure that threatens the stability of the genome. In addition, the cost and benefit of introns are still in debate. RESULTS: At least three factors are likely required for the R-loop formation: 1) sequence complementarity between the nascent RNA and the target DNA, 2) spatial juxtaposition between the nascent RNA and the template DNA, and 3) accessibility of the template DNA and the nascent RNA. The removal of introns from pre-mRNA reduces the complementarity between RNA and the template DNA and avoids the spatial juxtaposition between the nascent RNA and the template DNA. In addition, the secondary structures of group I and group II introns may act as spatial obstacles for the formation of R-loops between nearby exons and the genomic DNA. CONCLUSION: Organisms may benefit from introns by avoiding deleterious R-loops. The potential contribution of this benefit in driving intron evolution is discussed. I propose that additional RNA polymerases may inhibit R-loop formation between preceding nascent RNA and the template DNA. This idea leads to a testable prediction: intermittently transcribed genes and genes with frequently prolonged transcription should have higher intron density. REVIEWERS: This article was reviewed by Dr. Eugene V. Koonin, Dr. Alexei Fedorov (nominated by Dr. Laura F Landweber), and Dr. Scott W. Roy (nominated by Dr. Arcady Mushegian)

Exon definition as a potential negative force against intron losses in evolution

<p>Abstract</p> <p>Background</p> <p>Previous studies have indicated that the wide variation in intron density (the number of introns per gene) among different eukaryotes largely reflects varying degrees of intron loss during evolution. The most popular model, which suggests that organisms lose introns through a mechanism in which reverse-transcribed cDNA recombines with the genomic DNA, concerns only one mutational force.</p> <p>Hypothesis</p> <p>Using exons as the units of splicing-site recognition, exon definition constrains the length of exons. An intron-loss event results in fusion of flanking exons and thus a larger exon. The large size of the newborn exon may cause splicing errors, i.e., exon skipping, if the splicing of pre-mRNAs is initiated by exon definition. By contrast, if the splicing of pre-mRNAs is initiated by intron definition, intron loss does not matter. Exon definition may thus be a selective force against intron loss. An organism with a high frequency of exon definition is expected to experience a low rate of intron loss throughout evolution and have a high density of spliceosomal introns.</p> <p>Conclusion</p> <p>The majority of spliceosomal introns in vertebrates may be maintained during evolution not because of potential functions, but because of their splicing mechanism (i.e., exon definition). Further research is required to determine whether exon definition is a negative force in maintaining the high intron density of vertebrates.</p> <p>Reviewers</p> <p>This article was reviewed by Dr. Scott W. Roy (nominated by Dr. John Logsdon), Dr. Eugene V. Koonin, and Dr. Igor B. Rogozin (nominated by Dr. Mikhail Gelfand). For the full reviews, please go to the Reviewers' comments section.</p

Evidence against the energetic cost hypothesis for the short introns in highly expressed genes

<p>Abstract</p> <p>Background</p> <p>In animals, the moss <it>Physcomitrella patens </it>and the pollen of <it>Arabidopsis thaliana</it>, highly expressed genes have shorter introns than weakly expressed genes. A popular explanation for this is selection for transcription efficiency, which includes two sub-hypotheses: to minimize the energetic cost or to minimize the time cost.</p> <p>Results</p> <p>In an individual human, different organs may differ up to hundreds of times in cell number (for example, a liver versus a hypothalamus). Considered at the individual level, a gene specifically expressed in a large organ is actually transcribed tens or hundreds of times more than a gene with a similar expression level (a measure of mRNA abundance per cell) specifically expressed in a small organ. According to the energetic cost hypothesis, the former should have shorter introns than the latter. However, in humans and mice we have not found significant differences in intron length between large-tissue/organ-specific genes and small-tissue/organ-specific genes with similar expression levels. Qualitative estimation shows that the deleterious effect (that is, the energetic burden) of long introns in highly expressed genes is too negligible to be efficiently selected against in mammals.</p> <p>Conclusion</p> <p>The short introns in highly expressed genes should not be attributed to energy constraint. We evaluated evidence for the time cost hypothesis and other alternatives.</p

Why eukaryotic cells use introns to enhance gene expression: Splicing reduces transcription-associated mutagenesis by inhibiting topoisomerase I cutting activity

<p>Abstract</p> <p>Background</p> <p>The costs and benefits of spliceosomal introns in eukaryotes have not been established. One recognized effect of intron splicing is its known enhancement of gene expression. However, the mechanism regulating such splicing-mediated expression enhancement has not been defined. Previous studies have shown that intron splicing is a time-consuming process, indicating that splicing may not reduce the time required for transcription and processing of spliced pre-mRNA molecules; rather, it might facilitate the later rounds of transcription. Because the densities of active RNA polymerase II on most genes are less than one molecule per gene, direct interactions between the splicing apparatus and transcriptional complexes (from the later rounds of transcription) are infrequent, and thus unlikely to account for splicing-mediated gene expression enhancement.</p> <p>Presentation of the hypothesis</p> <p>The serine/arginine-rich protein SF2/ASF can inhibit the DNA topoisomerase I activity that removes negative supercoiling of DNA generated by transcription. Consequently, splicing could make genes more receptive to RNA polymerase II during the later rounds of transcription, and thus affect the frequency of gene transcription. Compared with the transcriptional enhancement mediated by strong promoters, intron-containing genes experience a lower frequency of cut-and-paste processes. The cleavage and religation activity of DNA strands by DNA topoisomerase I was recently shown to account for transcription-associated mutagenesis. Therefore, intron-mediated enhancement of gene expression could reduce transcription-associated genome instability.</p> <p>Testing the hypothesis</p> <p>Experimentally test whether transcription-associated mutagenesis is lower in intron-containing genes than in intronless genes. Use bioinformatic analysis to check whether exons flanking lost introns have higher frequencies of short deletions.</p> <p>Implications of the hypothesis</p> <p>The mechanism of intron-mediated enhancement proposed here may also explain the positive correlation observed between intron size and gene expression levels in unicellular organisms, and the greater number of intron containing genes in higher organisms.</p> <p>Reviewers</p> <p>This article was reviewed by Dr Arcady Mushegian, Dr Igor B Rogozin (nominated by Dr I King Jordan) and Dr Alexey S Kondrashov. For the full reviews, please go to the Reviewer's Reports section.</p

2-[4-(4-Methylphenylsulfonyl)piperazin-1-yl]-1-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)ethanone

In the title thienopyridine derivative, C20H25N3O3S2, the piperazine ring exhibits a chair conformation and the tetra­hydro­pyridine ring exhibits a half-chair conformation. The folded conformation of the mol­ecule is defined by the N—C—C—N torsion angle of −70.20 (2) °. Inter­molecular C—H⋯S and C—H⋯O hydrogen bonds help to establish the packing

1-(4,5,6,7-Tetra­hydro­thieno[3,2-c]pyridin-5-yl)-2-{4-[3-(trifluoro­meth­yl)phen­yl]piperazin-1-yl}ethanone

In the title mol­ecule, C20H22F3N3OS, the piperazine ring has a chair conformation, and the N—C(=O)—C—N torsion angle is −59.42 (14)°. In the crystal, weak C—H⋯O and C—H⋯π inter­actions link the mol­ecules into layers parallel to (101)

Anderson Localization from Berry-Curvature Interchange in Quantum Anomalous Hall System

We theoretically investigate the localization mechanism of the quantum anomalous Hall effect (QAHE) in the presence of spin-flip disorders. We show that the QAHE keeps quantized at weak disorders, then enters a Berry-curvature mediated metallic phase at moderate disorders, and finally goes into the Anderson insulating phase at strong disorders. From the phase diagram, we find that at the charge neutrality point although the QAHE is most robust against disorders, the corresponding metallic phase is much easier to be localized into the Anderson insulating phase due to the \textit{interchange} of Berry curvatures carried respectively by the conduction and valence bands. At the end, we provide a phenomenological picture related to the topological charges to better understand the underlying physical origin of the QAHE Anderson localization.Comment: 6 pages, 4 figure

Transgenic overexpression of miR-133a in skeletal muscle

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRNAs) are a class of non-coding regulatory RNAs of ~22 nucleotides in length. miRNAs regulate gene expression post-transcriptionally, primarily by associating with the 3' untranslated region (UTR) of their regulatory target mRNAs. Recent work has begun to reveal roles for miRNAs in a wide range of biological processes, including cell proliferation, differentiation and apoptosis. Many miRNAs are expressed in cardiac and skeletal muscle, and dysregulated miRNA expression has been correlated with muscle-related disorders. We have previously reported that the expression of muscle-specific miR-1 and miR-133 is induced during skeletal muscle differentiation and miR-1 and miR-133 play central regulatory roles in myoblast proliferation and differentiation in vitro.</p> <p>Methods</p> <p>In this study, we measured the expression of miRNAs in the skeletal muscle of mdx mice, an animal model for human muscular dystrophy. We also generated transgenic mice to overexpress miR-133a in skeletal muscle.</p> <p>Results</p> <p>We examined the expression of miRNAs in the skeletal muscle of <it>mdx </it>mice. We found that the expression of muscle miRNAs, including miR-1a, miR-133a and miR-206, was up-regulated in the skeletal muscle of <it>mdx </it>mice. In order to further investigate the function of miR-133a in skeletal muscle in vivo, we have created several independent transgenic founder lines. Surprisingly, skeletal muscle development and function appear to be unaffected in miR-133a transgenic mice.</p> <p>Conclusions</p> <p>Our results indicate that miR-133a is dispensable for the normal development and function of skeletal muscle.</p

Observation of ηc→ωω\eta_c\to\omega\omega in J/ψ→γωωJ/\psi\to\gamma\omega\omega

Using a sample of $(1310.6\pm7.0)\times10^6$ $J/\psi$ events recorded with the BESIII detector at the symmetric electron positron collider BEPCII, we report the observation of the decay of the $(1^1 S_0)$ charmonium state $\eta_c$ into a pair of $\omega$ mesons in the process $J/\psi\to\gamma\omega\omega$. The branching fraction is measured for the first time to be $\mathcal{B}(\eta_c\to\omega\omega)= (2.88\pm0.10\pm0.46\pm0.68)\times10^{-3}$, where the first uncertainty is statistical, the second systematic and the third is from the uncertainty of $\mathcal{B}(J/\psi\to\gamma\eta_c)$. The mass and width of the $\eta_c$ are determined as $M=(2985.9\pm0.7\pm2.1)\,$MeV/$c^2$ and $\Gamma=(33.8\pm1.6\pm4.1)\,$MeV.Comment: 13 pages, 6 figure

Observation and study of the decay J/ψ→ϕηη′J/\psi\rightarrow\phi\eta\eta'

We report the observation and study of the decay $J/\psi\rightarrow\phi\eta\eta'$ using $1.3\times{10^9}$ $J/\psi$ events collected with the BESIII detector. Its branching fraction, including all possible intermediate states, is measured to be $(2.32\pm0.06\pm0.16)\times{10^{-4}}$. We also report evidence for a structure, denoted as $X$, in the $\phi\eta'$ mass spectrum in the $2.0-2.1$ GeV/$c^2$ region. Using two decay modes of the $\eta'$ meson ($\gamma\pi^+\pi^-$ and $\eta\pi^+\pi^-$), a simultaneous fit to the $\phi\eta'$ mass spectra is performed. Assuming the quantum numbers of the $X$ to be $J^P = 1^-$, its significance is found to be 4.4$\sigma$, with a mass and width of $(2002.1 \pm 27.5 \pm 21.4)$ MeV/$c^2$ and $(129 \pm 17 \pm 9)$ MeV, respectively, and a product branching fraction $\mathcal{B}(J/\psi\rightarrow\eta{}X)\times{}\mathcal{B}(X\rightarrow\phi\eta')=(9.8 \pm 1.2 \pm 1.7)\times10^{-5}$. Alternatively, assuming $J^P = 1^+$, the significance is 3.8$\sigma$, with a mass and width of $(2062.8 \pm 13.1 \pm 7.2)$ MeV/$c^2$ and $(177 \pm 36 \pm 35)$ MeV, respectively, and a product branching fraction $\mathcal{B}(J/\psi\rightarrow\eta{}X)\times{}\mathcal{B}(X\rightarrow\phi\eta')=(9.6 \pm 1.4 \pm 2.0)\times10^{-5}$. The angular distribution of $J/\psi\rightarrow\eta{}X$ is studied and the two $J^P$ assumptions of the $X$ cannot be clearly distinguished due to the limited statistics. In all measurements the first uncertainties are statistical and the second systematic.Comment: 10 pages, 6 figures and 4 table