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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2019

Quantitative proteomic profiling of tumor-associated vascular endothelial cells in colorectal cancer

SummeryTo investigate the global proteomic profiles of vascular endothelial cells (VECs) in the tumor microenvironment and antiangiogenic therapy for colorectal cancer (CRC), matched pairs of normal (NVECs) and tumor-associated VECs (TVECs) were purified from CRC tissues by laser capture microdissection and subjected to iTRAQ based quantitative proteomics analysis. Here, 216 differentially expressed proteins (DEPs) were identified and performed bioinformatics analysis. Interestingly, these proteins were implicated in epithelial mesenchymal transition (EMT), ECM-receptor interaction, focal adhesion, PI3K-Akt signaling pathway, angiogenesis and HIF-1 signaling pathway, which may play important roles in CRC angiogenesis. Among these DEPs, Tenascin-C (TNC) was found to upregulated in the TVECs of CRC and be correlate with CRC multistage carcinogenesis and metastasis. Furthermore, the reduction of tumor-derived TNC could attenuate human umbilical vein endothelial cell (HUVEC) proliferation, migration and tube formation through ITGB3/FAK/Akt signaling pathway. Based on the present work, we provided a large-scale proteomic profiling of VECs in CRC with quantitative information, a certain number of potential antiangiogenic targets and a novel vision in the angiogenesis bio-mechanism of CRC. Summery statementWe provided large-scale proteomic profiling of vascular endothelial cells in colorectal cancer with quantitative information, a number of potential antiangiogenic targets and a novel vision in the angiogenesis bio-mechanism of CRC.

cancer biology↗

bioRxiv2019

High-coverage, long-read sequencing of Han Chinese trio reference samples.

Single-molecule long-read sequencing datasets were generated for a son-father-mother trio of Han Chinese descent that is part of the Genome In a Bottle (GIAB) consortium portfolio. The dataset was generated using the Pacific Biosciences Sequel System. The son and each parent were sequenced to an average coverage of 60 and 30, respectively, with N50 subread lengths between 16 and 18 kb. Raw reads and reads aligned to both the GRCh37 and GRCh38 are available at the NCBI GIAB ftp site (ftp://ftp-trace.ncbi.nlm.nih.gov/giab/ftp/data/ChineseTrio/) and the raw read data is archived in NCBI SRA (SRX4739017, SRX4739121, and SRX4739122). This dataset is available for anyone to develop and evaluate long-read bioinformatics methods.

genomics↗

bioRxiv2019

MicroRNA-138 negatively regulates the hypoxia-inducible factor 1α to suppress melanoma growth and metastasis

Melanoma with rapid progression towards metastasis becomes the deadliest form of skin cancer. However, the mechanism of melanoma growth and metastasis is still unclear. Here, we found that miRNA-138 was low expression and hypoxia-inducible factor 1 (HIF1) was high expression in the patients melanoma tissue, and they had a significant negative correlation (r=-0.937, P < 0.001). Patients with miRNA-138low/HIF1high signature were predominant in late stage. Further, bioinformatic analysis demonstrated that miRNA-138 directly targeted HIF1. We found that the introduction of miRNA-138 mimics to A375 cells could reduced HIF1 mRNA expression, and suppressed the cell proliferation, migration and invasion. Overexpression of miRNA-138 or inhibition of HIF1 significantly suppressed the growth and metastasis of melanoma in vivo. Our study demonstrates the role and clinical relevance of miRNA-138 and HIF1 in melanoma cell growth and metastasis, providing a novel therapeutic target for suppression of melanoma growth and metastasis.

cancer biology↗

bioRxiv2019

Single-Cell RNA Sequencing Reveals Regulatory Mechanism for Trophoblast Cell-Fate Divergence in Human Peri-Implantation Embryo

Multipotent trophoblasts undergo dynamic morphological movement and cellular differentiation after embryonic implantation to generate placenta. However, the mechanism controlling trophoblast development and differentiation during peri-implantation development remains elusive. In this study, we modeled human embryo peri-implantation development from blastocyst to early post-implantation stages by using an in vitro coculture system, and profiled the transcriptome of individual trophoblast cells from these embryos. We revealed the genetic networks regulating peri-implantation trophoblast development. While determining when trophoblast differentiation happens, our bioinformatic analysis identified T-box transcription factor 3 (TBX3) as a key regulator for the differentiation of cytotrophoblast into syncytiotrophoblast. The function of TBX3 in trophoblast differentiation is then validated by a loss-of-function experiment. In conclusion, our results provided a valuable resource to study the regulation of trophoblasts development and differentiation during human peri-implantation development.

cell biology↗

bioRxiv2019

Pulcherrimin formation controls growth arrest of the Bacillus subtilis biofilm

Biofilm formation by Bacillus subtilis is a communal process that culminates in the formation of architecturally complex multicellular communities. Here we reveal that the transition of the biofilm into a non-expanding phase constitutes a distinct step in the process of biofilm development. Using genetic analysis we show that B. subtilis strains lacking the ability to synthesize pulcherriminic acid form biofilms that sustain the expansion phase, thereby linking pulcherriminic acid to growth arrest. However, production of pulcherriminic acid is not sufficient to block expansion of the biofilm. It needs to be secreted into the extracellular environment where it chelates Fe3+ from the growth medium in a non-enzymatic reaction. Utilizing mathematical modelling and a series of experimental methodologies we show that when the level of freely available iron in the environment drops below a critical threshold, expansion of the biofilm stops. Bioinformatics analysis allows us to identify the genes required for pulcherriminic acid synthesis in other Firmicutes but the patchwork presence both within and across closely related species suggests loss of these genes through multiple independent recombination events. The seemingly counterintuitive self-restriction of growth led us to explore if there were any benefits associated pulcherriminic acid production. We identified that pulcherriminic acid producers can prevent invasion from neighbouring communities through the generation of an \"iron free\" zone thereby addressing the paradox of pulcherriminic acid production by B. subtilis.\n\nSignificanceUnderstanding the processes that underpin the mechanism of biofilm formation, dispersal, and inhibition are critical to allow exploitation and to understand how microbes thrive in the environment. Here, we reveal that the formation of an extracellular iron chelate restricts the expansion of a biofilm. The countering benefit to self-restriction of growth is protection of an environmental niche. These findings highlight the complex options and outcomes that bacteria need to balance in order to modulate their local environment to maximise colonisation, and therefore survival.

microbiology↗

bioRxiv2019

Identification and characterization of putative Aeromonas spp. T3SS effectors

The genetic determinants of bacterial pathogenicity are highly variable between species and strains. However, a factor that is commonly associated with virulent Gram-negative bacteria, including many Aeromonas spp., is the type 3 secretion system (T3SS), which is used to inject effector proteins into target eukaryotic cells. In this study, we developed a bioinformatics pipeline to identify T3SS effector proteins, applied this approach to the genomes of 105 Aeromonas strains isolated from environmental, mutualistic, or pathogenic contexts and evaluated the cytotoxicity of the identified effectors through their heterologous expression in yeast. The developed pipeline uses a two-step approach, where candidate families are initially selected using HMM profiles with minimal similarity scores against the Virulence Factors DataBase (VFDB), followed by strict comparisons against positive and negative control datasets, greatly reducing the number of false positives. Using our approach, we identified 21 Aeromonas T3SS likely effector groups, of which 8 represented known or characterized effectors, while the remaining 13 had not previously been described in Aeromonas. We experimentally validated our in silico findings by assessing the cytotoxicity of representative effectors in Saccharomyces cerevisiae BY4741, with 15 out of 21 assayed proteins eliciting a cytotoxic effect in yeast. The results of this study demonstrate the utility of our approach, combining a novel in silico search method with in vivo experimental validation, and will be useful in future research aimed at identifying and authenticating bacterial effector proteins from other genera.

microbiology↗

bioRxiv2019

An ancient lineage of highly divergent parvoviruses infects both vertebrate and invertebrate hosts.

Chapparvoviruses are a highly divergent group of parvoviruses (family Parvoviridae) first identified in 2013. Interest in these poorly characterized viruses has been raised by recent studies indicating that they are the cause of chronic kidney disease that arises spontaneously in laboratory mice. In this study, we investigate the biological and evolutionary characteristics of chapparvoviruses via comparative analysis of genome sequence data. Our analysis, which incorporates sequences derived from endogenous viral elements (EVEs) as well as exogenous viruses, reveals that chapparvoviruses are an ancient lineage within the family Parvoviridae, clustering separately from members of both currently established parvoviral subfamilies. Consistent with this, they exhibit a number of characteristic genomic and structural features, i.e. a large number of putative auxiliary protein-encoding genes, capsid protein genes non-homologous to any hitherto parvoviral cap, as well as a putative capsid structure lacking the canonical fifth strand of the ABIDG sheet comprising the luminal side of the jelly roll. Our findings demonstrate that the chapparvovirus lineage infects an exceptionally broad range of host species, including both vertebrates and invertebrates. Furthermore, we observe that chapparvoviruses found in fish are more closely related to those from invertebrates than they are to those that infect amniote vertebrates. This suggests that transmission between distantly related host species may have occurred in the past. Our study provides the first integrated overview of the chapparvovirus group, and revises current views of parvovirus evolution\n\nAUTHOR SUMMARYChapparvoviruses are a recently identified group of viruses about which relatively little is known. However, recent studies have shown that these viruses cause disease in laboratory mice and are prevalent in the fecal virome of pigs and poultry, raising interest in their potential impact as pathogens, and utility as experimental tools. We examined the genomes of chapparvoviruses and endogenous viral elements ( fossilized virus sequences derived from ancestral viruses) using a variety of bioinformatics-based approaches. We show that the chapparvoviruses have an ancient origin and are evolutionarily distinct from all other related viruses. Accordingly, their genomes and virions exhibit a range of distinct characteristic features. We examine the distribution of these features in the light of chapparvovirus evolutionary history (which we can also infer from genomic data), revealing new insights into chapparvovirus biology.

evolutionary biology↗

bioRxiv2019

CRISPR disruption and UK Biobank analysis of a highly conserved polymorphic enhancer suggests its role in anxiety and male alcohol intake.

Excessive alcohol intake is associated with 5.9% of global deaths. However, this figure is especially acute in men such that 7.6% of deaths can be attributed to alcohol intake. Previous studies identified a significant interaction between genotypes of the galanin (GAL) gene with anxiety and alcohol abuse in different male populations but were unable to define a mechanism. To address these issues the current study analysed the human UK Biobank cohort and identified a significant interaction (n=115,865; p=0.0007) between allelic variation (GG or CA genotypes) in the highly conserved human GAL5.1 enhancer, alcohol intake (AUDIT questionnaire scores) and anxiety in men that was consistent with these previous studies. Critically, disruption of GAL5.1 in mice using CRISPR genome editing significantly reduced GAL expression in the amygdala and hypothalamus whilst producing a corresponding reduction in ethanol intake in KO mice. Intriguingly, we also found evidence of reduced anxiety-like behaviour in male GAL5.1KO animals mirroring that seen in humans. Using bioinformatic analysis and co-transfection studies we further identified the EGR1 transcription factor, that is co expressed with GAL in amygdala and hypothalamus, as being important in the protein kinase C (PKC) supported activity of the GG genotype of GAL5.1 but less so in the CA genotype. Our unique study uses a novel combination of human association analysis, CRISPR genome editing in mice, animal behavioural analysis and cell culture studies to identify a highly conserved regulatory mechanism linking anxiety and alcohol intake that might contribute to increased susceptibility to anxiety and alcohol abuse in men.

genetics↗

bioRxiv2019

Genetic analysis of TP53 gene mutations in exon 4 and exon 8 among esophageal cancer patients in Sudan

BackgroundEsophageal carcinoma (EC) represents the 1st rank among all gastrointestinal cancers in Sudan. Despite little publications, there is a deep absence of literature about the molecular pathogenesis of EC considering TP53 gene from Sudanese population.\n\nAimsIn this study, we performed the expression analysis on p53 protein level by immunohistochemical staining and examined its overexpression with p53 mutations in exons 4 and 8 among esophageal cancer patients in Sudan.\n\nMaterial and MethodsFixed tissue with 10% buffered formalin was stained by Hematoxlin and Eosin (H&E), Alcian blue-Periodic Acid Schiff (PAS) and Immunohistochemistry stain. PCR-RFLP was used to study the frequencies of p53 codon 72 R/P polymorphism. Conventional PCR and sanger sequencing were applied for exon 4 and exon 8. Then detection and functional analysis of SNPs and mutations were performed using various in bioinformatics tools.\n\nResultNuclear accumulations for p53 protein was detected in all of the esophageal carcinomas examined while no accumulations were observed in normal control sections. Four patients with immune-positive for p53 showed no mutations in p53 gene (exon4 and exon8). The incidence of the homozygous mutant variant Pro/Pro was higher in esophageal cancerous patients comparing to healthy control subject 20(71. 4%) vs. 1(10%), respectively (p=0.0026). In exon 4, no mutation was detected other than NG_017013.2:g. 16397C>G. While in exon 8, g.18783-18784AG>TT, g.18803A>C, g.18860A>C, g.18845A>T and g.18863_ 18864 InsT were observed.\n\nConclusionwe found a significant association between the overexpression of TP53 protein and mutation in exon 4 and 8. A silent mutation P301P was detected in all of examined cases. Two patients who diagnosed with small cell sarcoma have shared the same mutations in exon8. Further studies with large sample size are required to demonstrate the usefulness of these mutations in the screening of EC especially SCCE.

cancer biology↗

bioRxiv2019

De-novo variants in XIRP1 associated with polydactyly and polysyndactyly in Holstein cattle

Congenital polydactylous cattle are sporadically observed. Impairment of the limb patterning process due to altered control of the zone of polarizing activity (ZPA) was associated in several species with preaxial polydactyly and syndactyly. In cattle, the role of ZPA and other genes involved in limb patterning for polydactyly was not yet elucidated. Herein, we report on a preaxial type II polydactyly and a praeaxial type II+V polysyndactyly in two Holstein calves and screen whole genome sequencing data for associated variants. Using whole genome sequencing data of both affected calves did not show mutations in the candidate regions of ZRS and pZRS or in candidate genes associated with polydactyly, syndactyly and polysyndactyly in other species. Two indels, which are located in XIRP1 within a common haplotype, were highly associated with the two phenotypes. Bioinformatic analyses retrieved an interaction between XIRP1 and FGFR1, CTNNB1 and CTNND1 supporting a link between the XIRP1 variants and embryonic limb patterning. The heterozygous haplotype was highly associated with the present polydactylous phenotypes due to dominant mode of inheritance with an incomplete penetrance in Holstein cattle.

genetics↗

bioRxiv2019

A validated workflow for rapid taxonomic assignment and monitoring of a national fauna of bees (Apiformes) using high throughput barcoding

Improved taxonomic methods are needed to quantify declining populations of insect pollinators. This study devises a high-throughput DNA barcoding protocol for a regional fauna (United Kingdom) of bees (Apiformes), consisting of reference library construction, a proof-of-concept monitoring scheme, and the deep barcoding of individuals to assess potential artefacts and organismal associations. A reference database of Cytochrome Oxidase subunit 1 (cox1) sequences including 92.4% of 278 bee species known from the UK showed high congruence with morphological taxon concepts, but molecular species delimitations resulted in numerous split and (fewer) lumped entities within the Linnaean species. Double tagging permitted deep illumina sequencing of 762 separate individuals of bees from a UK-wide survey. Extracting the target barcode from the amplicon mix required a new protocol employing read abundance and phylogenetic position, which revealed 180 molecular entities of Apiformes identifiable to species. An additional 72 entities were ascribed to mitochondrial pseudogenes based on patterns of read abundance and phylogenetic relatedness to the reference set. Clustering of reads revealed a range of secondary Operational Taxonomic Units (OTUs) in almost all samples, resulting from traces of insect species caught in the same traps, organisms associated with the insects including a known mite parasite of bees, and the common detection of human DNA, besides evidence for low-level cross-contamination in pan traps and laboratory steps. Custom scripts were generated to conduct critical steps of the bioinformatics protocol. The resources built here will greatly aid DNA-based monitoring to inform management and conservation policies for the protection of pollinators.

molecular biology↗

bioRxiv2019

Nanopore sequencing of the pharmacogene CYP2D6 allows simultaneous haplotyping and detection of duplications

BackgroundThe accurate genotyping of CYP2D6 is hindered by the very polymorphic nature of the gene, high homology with its pseudogene CYP2D7, and the occurrence of structural variations. Long read sequencing offers the promise of overcoming some of these challenges, along with the advantage of straightforward variant phasing. We have established methods for sequencing and analysis of DNA amplicons containing the whole CYP2D6 gene, using the GridION nanopore sequencer.\n\nMaterials and methodsSeven reference and 25 clinical samples covering various haplotypes including gene duplication were barcoded and sequenced over two sequencing runs. Sequenced raw reads were analyzed using a pipeline of bioinformatics tools including two mapping tools and two variant calling tools.\n\nResultsUsing minimap2 and nanopolish (mapping and variant calling tools respectively) resulted in the most accurate variant detection. Haplotypes of 52 alleles could be matched accurately to known alleles or subvariants, while the remaining 12 alleles being assigned as novel star (*) allele of novel subvariants of known alleles in the PharmVar CYP2D6 haplotype database. Allele duplication could be detected by analyzing the allelic balance between the sample haplotypes.\n\nConclusionNanopore sequencing of CYP2D6 offers a high throughput method for genotyping, accurate haplotyping, and detection of new variants and duplicated alleles.

genetics↗

bioRxiv2019

Unbiased metagenomic sequencing for pediatric meningitis in Bangladesh reveals neuroinvasive Chikungunya virus outbreak and other unrealized pathogens

The disease burden due to meningitis in low and middle-income countries remains significant and failure to determine an etiology impedes appropriate treatment for patients and evidence-based policy decisions for populations. Broad-range pathogen surveillance using metagenomic next-generation sequencing (mNGS) of RNA isolated from cerebral spinal fluid (CSF) provides an unbiased assessment for possible infectious etiologies. In this study, our objective was to use mNGS to identify etiologies of pediatric meningitis in Bangladesh.\n\nWe conducted a retrospective case-control mNGS study on CSF from patients with known neurologic infections (n=36), idiopathic meningitis (n=25), without infection (n=30) and six environmental samples collected between 2012-2018. Using an open-access, cloud-based bioinformatics pipeline (IDseq) and machine learning, we identified potential pathogens which were confirmed through qPCR and Sanger sequencing. These cases were followed-up through phone/home-visits. The CSF samples were collected from children with WHO-defined meningeal signs during prospective meningitis surveillance at the largest pediatric referral hospital in Bangladesh.\n\nThe 91 participants (42% female) ranged in age from 0-160 months (median: 9 months). In samples with known infectious causes of meningitis and without infections (n=66), there was 83% concordance between mNGS and conventional testing. In idiopathic cases (n=25), mNGS identified a potential etiology in 40% (n=10), including bacterial and viral pathogens. There were three instances of neuroinvasive Chikungunya virus (CHIKV). The CHIKV genomes were >99% identical to each other and to a Bangladeshi strain only previously recognized to cause systemic illness in 2017. CHIKV qPCR of all remaining stored CSF samples from children who presented with idiopathic meningitis in 2017 at the same hospital (n=472) revealed 17 additional CHIKV meningitis cases. Orthogonal molecular confirmation of each mNGS-identified infection, case-based clinical data, and follow-up of patients substantiated the key findings.\n\nUsing mNGS, we obtained a microbiological diagnosis for 40% of idiopathic meningitis cases and identified a previous unappreciated pediatric CHIKV meningitis outbreak. Case-control CSF mNGS surveys can complement conventional diagnostic methods to identify etiologies of meningitis and facilitate informed policy decisions.

genomics↗

bioRxiv2019

An evaluation of pool-sequencing transcriptome-based exon capture for population genomics of non-model species

AO_SCPLOWBSTRACTC_SCPLOWExon capture coupled to high-throughput sequencing constitutes a cost-effective technical solution for addressing specific questions in evolutionary biology by focusing on expressed regions of the genome preferentially targeted by selection. Transcriptome-based capture, a process that can be used to capture the exons of non-model species, is use in phylogenomics. However, its use in population genomics remains rare due to the high costs of sequencing large numbers of indexed individuals across multiple populations. We evaluated the feasibility of combining transcriptome-based capture and the pooling of tissues from numerous individuals for DNA extraction as a cost-effective, generic and robust approach to estimating the variant allele frequencies of any species at the population level. We designed capture probes for [~]5 Mb of chosen de novo transcripts from the Asian ladybird Harmonia axyridis (5,717 transcripts). We called [~]300,000 bi-allelic SNPs for a pool of 36 non-indexed individuals. Capture efficiency was high, and pool-seq was as effective and accurate as individual-seq for detecting variants and estimating allele frequencies. Finally, we also evaluated an approach for simplifying bioinformatic analyses by mapping genomic reads directly to targeted transcript sequences to obtain coding variants. This approach is effective and does not affect the estimation of SNP allele frequencies, except for a small bias close to some exon ends. We demonstrate that this approach can also be used to predict the intron-exon boundaries of targeted de novo transcripts, making it possible to abolish genotyping biases near exon ends.

genomics↗

bioRxiv2019

Characterization of genes and alleles involved in the control of flowering time in grapevine

Grapevine (Vitis vinifera) is one of the most important perennial crop plants in worldwide. Understanding of developmental processes like flowering, which impact quality and quantity of yield in this species is therefore of high interest. This gets even more important when considering some of the expected consequences of climate change. Earlier bud burst and flowering, for example, may result in yield loss due to spring frost. Berry ripening under higher temperatures will impact wine quality. Knowledge of interactions between a genotype or allele combination and the environment can be used for the breeding of genotypes that are better adapted to new climatic conditions. To this end, we have generated a list of more than 500 candidate genes that may play a role in the timing of flowering. The grapevine genome was exploited for flowering time control gene homologs on the basis of functional data from model organisms like A. thaliana. In a previous study, a mapping population derived from early flowering GF.GA-47-42 and late flowering Villard Blanc was analyzed for flowering time QTLs. In a second step we have now established a workflow combining amplicon sequencing and bioinformatics to follow alleles of selected candidate genes in the F1 individuals and the parental genotypes. Allele combinations of these genes in individuals of the mapping population were correlated with early or late flowering phenotypes. Specific allele combinations of flowering time candidate genes within and outside of the QTL regions for flowering time on chromosome 1, 4, 14, 17, and 18 were found to be associated with an early flowering phenotype. In addition, expression of many of the flowering candidate genes was analyzed over consecutive stages of bud and inflorescence development indicating functional roles of these genes in the flowering control network.

genetics↗

bioRxiv2019

microRNA mir-598-3p mediates susceptibility to stress-enhancement of remote fear memory

microRNAs (miRNAs) have emerged as potent regulators of learning, recent memory and extinction. However, our understanding of miRNAs directly involved in regulating complex psychiatric conditions perpetuated by aberrant memory, such as in posttraumatic stress disorder (PTSD), remains limited. To begin to address the role of miRNAs in persistent memory, we performed small-RNA sequencing on basolateral amygdala (BLA) tissue to identify miRNAs altered by auditory fear conditioning (FC) one month after training. mir-598-3p, a highly conserved miRNA previously unstudied in the brain, was downregulated in the BLA. Further decreasing BLA mir-598-3p levels did not alter the expression or extinction of the remote fear memory. Given that stress is a critical component in PTSD, we next assessed the impact of stress-enhanced fear learning (SEFL) on mir-598-3p levels, finding the miRNA is elevated in the BLA of male, but not female, mice susceptible to the effects of stress in SEFL. Accordingly, intra-BLA inhibition of mir-598-3p interfered with expression and extinction of the remote fear memory in male, but not female, mice. This effect could not be attributed to an anxiolytic effect of miRNA inhibition. Finally, bioinformatic analysis following quantitative proteomics on BLA tissue collected 30 days post-SEFL training identified putative mir-598-3p targets and related pathways mediating the differential susceptibility, with evidence for regulation of the actin cytoskeleton.

neuroscience↗

bioRxiv2019

MS Atlas - A molecular map of brain lesion stages in progressive multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disorder of the central nervous system with an untreatable late progressive phase in a high percentage of patients. Molecular maps of different stages of brain lesion evolution in patients with progressive MS (PMS) are missing but critical for understanding disease development and to identify novel targets to halt progression. We introduce the first MS brain lesion atlas (msatlas.dk), developed to address the current challenges of understanding mechanisms driving the fate of PMS on lesion basis. The MS Atlas gives means for testing research hypotheses, validating candidate biomarkers and drug targets. The MS Atlas data base comprises comprehensive high-quality transcriptomic profiles of 73 brain white matter lesions at different stages of lesion evolution from 10 PMS patients and 25 control white matter samples from five patients with non-neurological disease. The MS Atlas was assembled from next generation RNA sequencing of post mortem samples using strict, conservative preprocessing as well as advanced statistical data analysis. It comes with a user-friendly web interface, which allows for querying and interactively analyzing the PMS lesion evolution. It fosters bioinformatics methods for de novo network enrichment to extract mechanistic markers for specific lesion types and pathway-based lesion type comparison. We describe examples of how the MS Atlas can be used to extract systems medicine signatures. We also demonstrate how its interface can interactively condense and visualize the atlas content. This compendium of mechanistic PMS white matter lesion profiles is an invaluable resource to fuel future multiple sclerosis research and a new basis for treatment development.

systems biology↗

bioRxiv2019

Circular RNA profiling in the oocyte and cumulus cells reveals that circARMC4 is essential for porcine oocyte maturation

Thousands of circular RNAs (circRNAs) have been recently discovered in cumulus cells and oocytes from several species. However, the expression and function of circRNA during porcine oocyte meiotic maturation have been never examined. Here, we separately identified 7,067 and 637 circRNAs in both the cumulus cell and the oocyte via deep sequencing and bioinformatic analysis. Further analysis revealed that a faction of circRNAs is differentially expressed (DE) in a developmental stage-specific manner. The host genes of DE circRNAs are markedly enriched to multiple signaling pathways associated with cumulus cell function and oocyte maturation. Additionally, most DE circRNAs harbor several miRNA targets, suggesting that these DE circRNAs potentially act as miRNA sponge. Importantly, we found that maternal circARMC4 knockdown by siRNA microinjection caused a severely impaired chromosome alignment, and significantly inhibited first polar body extrusion and early embryo development. Taken together, these results demonstrate for the first time that circRNAs are abundantly and dynamically expressed in a developmental stage-specific manner in cumulus cells and oocytes, and maternally expressed circARMC4 is essential for porcine oocyte meiotic maturation and early embryo development.

developmental biology↗