Inference of RNA decay rate from transcriptional profiling highlights the regulatory programs of Alzheimer's disease.

The abundance of mRNA is mainly determined by the rates of RNA transcription and decay. Here, we present a method for unbiased estimation of differential mRNA decay rate from RNA-sequencing data by modeling the kinetics of mRNA metabolism. We show that in all primary human tissues tested, and particularly in the central nervous system, many pathways are regulated at the mRNA stability level. We present a parsimonious regulatory model consisting of two RNA-binding proteins and four microRNAs that modulate the mRNA stability landscape of the brain, which suggests a new link between RBFOX proteins and Alzheimer's disease. We show that downregulation of RBFOX1 leads to destabilization of mRNAs encoding for synaptic transmission proteins, which may contribute to the loss of synaptic function in Alzheimer's disease. RBFOX1 downregulation is more likely to occur in older and female individuals, consistent with the association of Alzheimer's disease with age and gender."mRNA abundance is determined by the rates of transcription and decay. Here, the authors propose a method for estimating the rate of differential mRNA decay from RNA-seq data and model mRNA stability in the brain, suggesting a link between mRNA stability and Alzheimer's disease.

Transcriptional Regulation of Gene Expression in \u3cem\u3eTetrahymena thermophila\u3c/em\u3e

The only well-characterized study of gene expression in Tetrahymena thermophila (1) demonstrates that the temperature dependent expression of the Ser H3 gene is regulated at the level of mRNA stability. A run-on transcription assay was developed to determine if regulation of RNA stability was a major mechanism regulating gene expression in Tetrahymena or if transcriptional regulation dominates. The relative transcriptional activities of 14 Tetrahymena genes were determined in different physiological/developmental states (growing, starved and conjugating) in which many of the genes showed striking differences in RNA abundance. In every case except Ser H3, changes in transcription accompanied changes in RNA abundance. Thus differential transcription, not differential RNA degradation, is the major mechanism regulating RNA abundance in Tetrahymena

RNA structure prediction: progress and perspective

Many recent exciting discoveries have revealed the versatility of RNAs and their importance in a variety of cellular functions which are strongly coupled to RNA structures. To understand the functions of RNAs, some structure prediction models have been developed in recent years. In this review, the progress in computational models for RNA structure prediction is introduced and the distinguishing features of many outstanding algorithms are discussed, emphasizing three dimensional (3D) structure prediction. A promising coarse-grained model for predicting RNA 3D structure, stability and salt effect is also introduced briefly. Finally, we discuss the major challenges in the RNA 3D structure modeling.Comment: 23 page

Effects of Nanoparticles on Double-Stranded RNA Stability in Corn Soil

Double-stranded RNA (dsRNA) can potentially be used as a pesticide because these molecules trigger an immune response called RNA interference (RNAi). If the expression of essential genes matching the dsRNA sequence are silenced, then the pest dies. New classes of pesticides, including RNAi-based pesticides, are needed to overcome pesticide resistance and reduce the environmental impacts of pesticides. Unfortunately, dsRNA is easily degraded by enzymes in the environment, particularly those produced by microbes in the soil (Dubelmanet al., 2014),severely limiting delivery of dsRNA to cryptic (soil dwelling) species unless transgenic plants are used. Here we investigate dsRNA stability when incubated in corn soil supernatant ex situ to determine if encapsulation of dsRNA in chitosan-basednanoparticles (CB-NPs) enhances stability in corn soil. Interestingly, dsRNA stability was not affected by soil supernatant, possibly due to the time of year when sampling was performed (Icozet al., 2008). Nonetheless, these findings provide insight into dsRNA stability in soil, and in the future may lead to a method for protecting dsRNA from environmental degradation using CB-NPs

Melting of Branched RNA Molecules

Stability of the branching structure of an RNA molecule is an important condition for its function. In this letter we show that the melting thermodynamics of RNA molecules is very sensitive to their branching geometry for the case of a molecule whose groundstate has the branching geometry of a Cayley Tree and whose pairing interactions are described by the Go model. Whereas RNA molecules with a linear geometry melt via a conventional continuous phase transition with classical exponents, molecules with a Cayley Tree geometry are found to have a free energy that seems smooth, at least within our precision. Yet, we show analytically that this free energy in fact has a mathematical singularity at the stability limit of the ordered structure. The correlation length appears to diverge on the high-temperature side of this singularity.Comment: 4 pages, 3 figure

Crowding Promotes the Switch from Hairpin to Pseudoknot Conformation in Human Telomerase RNA

Formation of a pseudoknot in the conserved RNA core domain in the ribonucleoprotein human telomerase is required for function. In vitro experiments show that the pseudoknot (PK) is in equilibrium with an extended hairpin (HP) structure. We use molecular simulations of a coarse-grained model, which reproduces most of the salient features of the experimental melting profiles of PK and HP, to show that crowding enhances the stability of PK relative to HP in the wild type and in a mutant associated with dyskeratosis congenita. In monodisperse suspensions, small crowding particles increase the stability of compact structures to a greater extent than larger crowders. If the sizes of crowders in a binary mixture are smaller than the unfolded RNA, the increase in melting temperature due to the two components is additive. In a ternary mixture of crowders that are larger than the unfolded RNA, which mimics the composition of ribosome, large enzyme complexes and proteins in E. coli, the marginal increase in stability is entirely determined by the smallest component. We predict that crowding can restore partially telomerase activity in mutants, which dramatically decrease the PK stability.Comment: File "JACS_MAIN_archive_PDF_from_DOC.pdf" (PDF created from DOC) contains the main text of the paper File JACS_SI_archive.tex + 7 figures are the supplementary inf

Effects of Nanoparticles on Double-Stranded RNA Stability in Corn Soil

Double-stranded RNA (dsRNA) can potentially be used as a pesticide because these molecules trigger an immune response called RNA interference (RNAi). If the expression of essential genes matching the dsRNA sequence are silenced, then the pest dies. New classes of pesticides, including RNAi-based pesticides, are needed to overcome pesticide resistance and reduce the environmental impacts of pesticides. Unfortunately, dsRNA is easily degraded by enzymes in the environment, particularly those produced by microbes in the soil (Dubelmanet al., 2014),severely limiting delivery of dsRNA to cryptic (soil dwelling) species unless transgenic plants are used. Here we investigate dsRNA stability when incubated in corn soil supernatant ex situ to determine if encapsulation of dsRNA in chitosan-basednanoparticles (CB-NPs) enhances stability in corn soil. Interestingly, dsRNA stability was not affected by soil supernatant, possibly due to the time of year when sampling was performed (Icozet al., 2008). Nonetheless, these findings provide insight into dsRNA stability in soil, and in the future may lead to a method for protecting dsRNA from environmental degradation using CB-NPs

Hachimoji DNA and RNA: A genetic system with eight building blocks

Reported here are DNA and RNA-like systems built from eight (hachi-) nucleotide letters (-moji) that form four orthogonal pairs. This synthetic genetic biopolymer meets the structural requirements needed to support Darwinism, including a polyelectrolyte backbone, predictable thermodynamic stability, and stereoregular building blocks that fit a Schrödinger aperiodic crystal. Measured thermodynamic parameters predict the stability of hachimoji duplexes, allowing hachimoji DNA to double the information density of natural terran DNA. Three crystal structures show that the synthetic building blocks do not perturb the aperiodic crystal seen in the DNA double helix. Hachimoji DNA was then transcribed to give hachimoji RNA in the form of a functioning fluorescent hachimoji aptamer. These results expand the scope of molecular structures that might support life, including life throughout the cosmos

The prebiotic evolutionary advantage of transferring genetic information from RNA to DNA.

In the early 'RNA world' stage of life, RNA stored genetic information and catalyzed chemical reactions. However, the RNA world eventually gave rise to the DNA-RNA-protein world, and this transition included the 'genetic takeover' of information storage by DNA. We investigated evolutionary advantages for using DNA as the genetic material. The error rate of replication imposes a fundamental limit on the amount of information that can be stored in the genome, as mutations degrade information. We compared misincorporation rates of RNA and DNA in experimental non-enzymatic polymerization and calculated the lowest possible error rates from a thermodynamic model. Both analyses found that RNA replication was intrinsically error-prone compared to DNA, suggesting that total genomic information could increase after the transition to DNA. Analysis of the transitional RNA/DNA hybrid duplexes showed that copying RNA into DNA had similar fidelity to RNA replication, so information could be maintained during the genetic takeover. However, copying DNA into RNA was very error-prone, suggesting that attempts to return to the RNA world would result in a considerable loss of information. Therefore, the genetic takeover may have been driven by a combination of increased chemical stability, increased genome size and irreversibility