RNA molecules fold into complex three-dimensional shapes, guided by the pattern of hydrogen bonding between nucleotides. This pattern of base pairing, known as RNA secondary structure, is critical to ...their cellular function. Recently several diverse methods have been developed to assay RNA secondary structure on a transcriptome-wide scale using high-throughput sequencing. Each approach has its own strengths and caveats, however there is no widely available tool for visualizing and comparing the results from these varied methods.
To address this, we have developed Structure Surfer, a database and visualization tool for inspecting RNA secondary structure in six transcriptome-wide data sets from human and mouse ( http://tesla.pcbi.upenn.edu/strucuturesurfer/ ). The data sets were generated using four different high-throughput sequencing based methods. Each one was analyzed with a scoring pipeline specific to its experimental design. Users of Structure Surfer have the ability to query individual loci as well as detect trends across multiple sites.
Here, we describe the included data sets and their differences. We illustrate the database's function by examining known structural elements and we explore example use cases in which combined data is used to detect structural trends.
In total, Structure Surfer provides an easy-to-use database and visualization interface for allowing users to interrogate the currently available transcriptome-wide RNA secondary structure information for mammals.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
TAR DNA-binding protein 43 (TDP-43) is normally a nuclear RNA-binding protein that exhibits a range of functions including regulation of alternative splicing, RNA trafficking, and RNA stability. ...However, in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), TDP-43 is abnormally phosphorylated, ubiquitinated, and cleaved, and is mislocalized to the cytoplasm where it forms distinctive aggregates. We previously developed a mouse model expressing human TDP-43 with a mutation in its nuclear localization signal (ΔNLS-hTDP-43) so that the protein preferentially localizes to the cytoplasm. These mice did not exhibit a significant number of cytoplasmic aggregates, but did display dramatic changes in gene expression as measured by microarray, suggesting that cytoplasmic TDP-43 may be associated with a toxic gain-of-function. Here, we analyze new RNA-sequencing data from the ΔNLS-hTDP-43 mouse model, together with published RNA-sequencing data obtained previously from TDP-43 antisense oligonucleotide (ASO) knockdown mice to investigate further the dysregulation of gene expression in the ΔNLS model. This analysis reveals that the transcriptomic effects of the overexpression of the ΔNLS-hTDP-43 transgene are likely due to a gain of cytoplasmic function. Moreover, cytoplasmic TDP-43 expression alters transcripts that regulate chromatin assembly, the nucleolus, lysosomal function, and histone 3' untranslated region (UTR) processing. These transcriptomic alterations correlate with observed histologic abnormalities in heterochromatin structure and nuclear size in transgenic mouse and human brains.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The poor outcomes in infant acute lymphoblastic leukemia (ALL) necessitate new treatments. Here we discover that EIF4E protein is elevated in most cases of infant ALL and test EIF4E targeting by the ...repurposed antiviral agent ribavirin, which has anticancer properties through EIF4E inhibition, as a potential treatment. We find that ribavirin treatment of actively dividing infant ALL cells on bone marrow stromal cells (BMSCs) at clinically achievable concentrations causes robust proliferation inhibition in proportion with EIF4E expression. Further, we find that ribavirin treatment of KMT2A-rearranged (KMT2A-R) infant ALL cells and the KMT2A-AFF1 cell line RS4:11 inhibits EIF4E, leading to decreases in oncogenic EIF4E-regulated cell growth and survival proteins. In ribavirin-sensitive KMT2A-R infant ALL cells and RS4:11 cells, EIF4E-regulated proteins with reduced levels of expression following ribavirin treatment include MYC, MCL1, NBN, BCL2 and BIRC5. Ribavirin-treated RS4:11 cells exhibit impaired EIF4E-dependent nuclear to cytoplasmic export and/or translation of the corresponding mRNAs, as well as reduced phosphorylation of the p-AKT1, p-EIF4EBP1, p-RPS6 and p-EIF4E signaling proteins. This leads to an S-phase cell cycle arrest in RS4:11 cells corresponding to the decreased proliferation. Ribavirin causes nuclear EIF4E to re-localize to the cytoplasm in KMT2A-AFF1 infant ALL and RS4:11 cells, providing further evidence for EIF4E inhibition. Ribavirin slows increases in peripheral blasts in KMT2A-R infant ALL xenograft-bearing mice. Ribavirin cooperates with chemotherapy, particularly L-asparaginase, in reducing live KMT2A-AFF1 infant ALL cells in BMSC co-cultures. This work establishes that EIF4E is broadly elevated across infant ALL and that clinically relevant ribavirin exposures have preclinical activity and effectively inhibit EIF4E in KMT2A-R cases, suggesting promise in EIF4E targeting using ribavirin as a means of treatment.
Abstract
The majority of variants identified by genome-wide association studies (GWAS) reside in the noncoding genome, affecting regulatory elements including transcriptional enhancers. However, ...characterizing their effects requires the integration of GWAS results with context-specific regulatory activity and linkage disequilibrium annotations to identify causal variants underlying noncoding association signals and the regulatory elements, tissue contexts, and target genes they affect. We propose INFERNO, a novel method which integrates hundreds of functional genomics datasets spanning enhancer activity, transcription factor binding sites, and expression quantitative trait loci with GWAS summary statistics. INFERNO includes novel statistical methods to quantify empirical enrichments of tissue-specific enhancer overlap and to identify co-regulatory networks of dysregulated long noncoding RNAs (lncRNAs). We applied INFERNO to two large GWAS studies. For schizophrenia (36,989 cases, 113,075 controls), INFERNO identified putatively causal variants affecting brain enhancers for known schizophrenia-related genes. For inflammatory bowel disease (IBD) (12,882 cases, 21,770 controls), INFERNO found enrichments of immune and digestive enhancers and lncRNAs involved in regulation of the adaptive immune response. In summary, INFERNO comprehensively infers the molecular mechanisms of causal noncoding variants, providing a sensitive hypothesis generation method for post-GWAS analysis. The software is available as an open source pipeline and a web server.
We implemented a high-throughput identification pipeline for promoter interacting enhancer element to streamline the workflow from mapping raw Hi-C reads, identifying DNA-DNA interacting fragments ...with high confidence and quality control, detecting histone modifications and DNase hypersensitive enrichments in putative enhancer elements, to ultimately extracting possible intra- and inter-chromosomal enhancer-target gene relationships.
This software package is designed to run on high-performance computing clusters with Oracle Grid Engine. The source code is freely available under the MIT license for academic and nonprofit use. The source code and instructions are available at the Wang lab website (http://wanglab.pcbi.upenn.edu/hippie/). It is also provided as an Amazon Machine Image to be used directly on Amazon Cloud with minimal installation.
lswang@mail.med.upenn.edu or bdgregor@sas.upenn.edu
Supplementary Material is available at Bioinformatics online.
In order to improve the measuring accuracy of the Hemispherical Resonator Gyro under variable temperature, aiming at the problem of "external temperature is unavailable and internal temperature is ...unmeasurable," a multiple regression based method is proposed for compensating temperature error in the gyro. The relationship between the internal temperature and the resonant frequency of the gyro is analyzed theoretically. According to a constant temperature experiment, a linear relationship between them is derived based on the least square method. The analysis of a temperature-rising experiment shows that the correlation of the gyro output with the internal temperature is much higher than that with the external temperature. Therefore, taking the resonant frequency as an independent variable, a multiple regression model is established for compensating the temperature error. The compensation effect of the model is verified by temperature-rising and temperature-dropping experiments, which show that the output sequence before compensation is not stable, while it is stable after compensation. After compensation, the drift of the gyro decreases by 62.76% and 48.48%, respectively, and its measuring accuracy becomes equivalent to that at the constant temperature. The experimental results verify the feasibility and effectiveness of the model developed for indirect compensation of temperature error.
Most of the loci identified by genome-wide association studies (GWAS) for late-onset Alzheimer's disease (LOAD) are in strong linkage disequilibrium (LD) with nearby variants all of which could be ...the actual functional variants, often in non-protein-coding regions and implicating underlying gene regulatory mechanisms. We set out to characterize the causal variants, regulatory mechanisms, tissue contexts, and target genes underlying these associations. We applied our INFERNO algorithm to the top 19 non-APOE loci from the IGAP GWAS study. INFERNO annotated all LD-expanded variants at each locus with tissue-specific regulatory activity. Bayesian co-localization analysis of summary statistics and eQTL data was performed to identify tissue-specific target genes. INFERNO identified enhancer dysregulation in all 19 tag regions analyzed, significant enrichments of enhancer overlaps in the immune-related blood category, and co-localized eQTL signals overlapping enhancers from the matching tissue class in ten regions (ABCA7, BIN1, CASS4, CD2AP, CD33, CELF1, CLU, EPHA1, FERMT2, ZCWPW1). In several cases, we identified dysregulation of long noncoding RNA (lncRNA) transcripts and applied the lncRNA target identification algorithm from INFERNO to characterize their downstream biological effects. We also validated the allele-specific effects of several variants on enhancer function using luciferase expression assays. By integrating functional genomics with GWAS signals, our analysis yielded insights into the regulatory mechanisms, tissue contexts, genes, and biological processes affected by noncoding genetic variation associated with LOAD risk.
To better capture the polygenic architecture of Alzheimer's disease (AD), we developed a joint genetic score, MetaGRS. We incorporated genetic variants for AD and 24 other traits from two independent ...cohorts, NACC (
= 3,174, training set) and UPitt (
= 2,053, validation set). One standard deviation increase in the MetaGRS is associated with about 57% increase in the AD risk hazard ratio (HR) = 1.577,
= 7.17 E-56, showing little difference from the HR for AD GRS alone (HR = 1.579,
= 1.20E-56), suggesting similar utility of both models. We also conducted APOE-stratified analyses to assess the role of the e4 allele on risk prediction. Similar to that of the combined model, our stratified results did not show a considerable improvement of the MetaGRS. Our study showed that the prediction power of the MetaGRS significantly outperformed that of the reference model without any genetic information, but was effectively equivalent to the prediction power of the AD GRS.
The North Qilian Orogen is considered to represent an oceanic suture zone formed by closure of the North Qilian Ocean, which formed the northern part of the Proto-Tethys Ocean along the northern ...margin of the eastern Gondwana during the Early Paleozoic. However, the Early Paleozoic subduction system remains controversial, especially along the southeastern margin where it is connected to the Qinling Orogen. Here we present zircon U-Pb geochronology and whole-rock elemental and Sr-Nd-Pb-Hf isotopic data on a suite of andesitic–dacitic volcanic rocks from the Chenjiahe Group and basalts–basaltic andesites from the Hongtubao Formation in the southeast margin of the North Qilian Orogen. SHRIMP and LA-ICP-MS zircon U-Pb dating of dacite and basaltic andesite sample yield crystallization ages of ca. 443Ma and 438Ma. The andesitic–dacitic volcanic rocks exhibit calc-alkaline feature, with LREE- and LILE-enrichment, Nb–Ta depletion, moderate whole-rock (87Sr/86Sr)i (0.7055–0.7071), εNd(t) (−4.5 to 0.3) and εHf(t) (−0.3 to 5.6) values, and enriched Pb-isotopic compositions. Our data suggest magma derivation from ancient crustal sources involving juvenile materials by magmatic underplating, followed by MASH processes under a continental arc setting. The basalts–basaltic andesites are characterized by medium- to low-K tholeiitic, LREE- and LILE-enrichment and Nb-Ta depletion. Their whole-rock Sr-Nd-Pb-Hf isotopes show depleted mantle features with lower (87Sr/86Sr)i (0.7044–0.7047), positive εNd(t) (3.0–5.9) and εHf(t) (11.1–11.3) values, and Nd-Pb-Hf isotopic features that exhibit affinity with the Tethyan tectonic domain. These features could reflect partial melting of an asthenospheric mantle that witnessed recent subduction-related metasomatism and experienced fractional crystallization in an initial back-arc setting. We suggest that the Early Paleozoic arc–back-arc system was formed during the southward oceanic subduction beneath the Qilian Block in the southeastern margin of the North Qilian Orogen and that the Early Paleozoic subduction system might be inconsistent in different parts of the North Qilian Orogen.
Display omitted
•Ca. 443Ma volcanics derived through partial melting of heterogeneous lower crust sources•Ca. 438Ma volcanic suite formed through partial melting of metasomatized asthenospheric mantle•Continental arc-back arc system related to subduction of the North Qilian oceanic slab
The tectonic affinity of the Ama Drime Massif in central Himalaya remains a subject of debate. We provide evidences of the metamorphic conditions and new geochronological data for orthogneiss and ...paragneiss in the Riwu area, eastern side of Ama Drime Massif. The peak P–T conditions for garnet gneiss is 13–14 kbar and 750–765 °C using phase equilibria modelling. The zircon U–Pb dating results reveal that the orthogneiss has a crystallization age of 1,848 ± 12 Ma and zircon rims age of 1,767 ± 18 Ma. Three major age peaks characterize all detrital zircons from the paragneisses: 975, 1,161, and 1,749 Ma. These new data integrated with previous literature data indicate that (a) the Ama Drime Massif might be ascribed to the Greater Himalayan Series; and (b) the Himalayan terrane may have been located closer to both the India and Lhasa terranes during the amalgamation of the supercontinent Columbia.
PDF
