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C-BERST: defining subnuclear proteomic landscapes at genomic elements with dCas9-APEX2.

ABSTRACT: Mapping proteomic composition at distinct genomic loci in living cells has been a long-standing challenge. Here we report that dCas9-APEX2 biotinylation at genomic elements by restricted spatial tagging (C-BERST) allows the rapid, unbiased mapping of proteomes near defined genomic loci, as demonstrated for telomeres and centromeres. C-BERST enables the high-throughput identification of proteins associated with specific sequences, thereby facilitating annotation of these factors and their roles.

SUBMITTER: Gao XD

PROVIDER: S-EPMC6202229 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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C-BERST: defining subnuclear proteomic landscapes at genomic elements with dCas9-APEX2.

Gao Xin D XD Tu Li-Chun LC Mir Aamir A Rodriguez Tomás T Ding Yuehe Y Leszyk John J Dekker Job J Shaffer Scott A SA Zhu Lihua Julie LJ Wolfe Scot A SA Sontheimer Erik J EJ

Nature methods 20180507 6

Mapping proteomic composition at distinct genomic loci in living cells has been a long-standing challenge. Here we report that dCas9-APEX2 biotinylation at genomic elements by restricted spatial tagging (C-BERST) allows the rapid, unbiased mapping of proteomes near defined genomic loci, as demonstrated for telomeres and centromeres. C-BERST enables the high-throughput identification of proteins associated with specific sequences, thereby facilitating annotation of these factors and their roles. ...[more]

PMID: 29735996

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C-BERST: Defining subnuclear proteomic landscapes at genomic elements with dCas9-APEX2

Project description:Mapping proteomic composition at distinct genomic loci and subnuclear landmarks in living cells has been a long-standing challenge. Here we report that dCas9-APEX2 Biotinylation at genomic Elements by Restricted Spatial Tagging (C-BERST) allows the unbiased mapping of proteomes near defined genomic loci, as demonstrated for telomeres and centromeres. C-BERST enables the high-throughput identification of proteins associated with specific sequences, facilitating annotation of these factors and their roles in nuclear and chromosome biology.

2018-05-07 | PXD009216 | Pride

Genomic and proteomic mutation landscapes of SARS-CoV-2.

Project description:The ongoing pandemic caused by a novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), affects thousands of people every day worldwide. Hence, drugs and vaccines effective against all variants of SARS-CoV-2 are crucial today. Viral genome mutations exist commonly which may impact the encoded proteins, possibly resulting to varied effectivity of detection tools and disease treatment. Thus, this study surveyed the SARS-CoV-2 genome and proteome and evaluated its mutation characteristics. Phylogenetic analyses of SARS-CoV-2 genes and proteins show three major clades and one minor clade (P6810S; ORF1ab). The overall frequency and densities of mutations in the genes and proteins of SARS-CoV-2 were observed. Nucleocapsid exhibited the highest mutation density among the structural proteins while the spike D614G was the most common, occurring mostly in genomes outside China and United States. ORF8 protein had the highest mutation density across all geographical areas. Moreover, mutation hotspots neighboring and at the catalytic site of RNA-dependent RNA polymerase were found that might challenge the binding and effectivity of remdesivir. Mutation coldspots may present as conserved diagnostic and therapeutic targets were found in ORF7b, ORF9b, and ORF14. These findings suggest that the virion's genotype and phenotype in a specific population should be considered in developing diagnostic tools and treatment options.

| S-EPMC7537117 | biostudies-literature

Defining the Comprehensive Genomic Landscapes of Pancreatic Ductal Adenocarcinoma Using Real-World Endoscopic Aspiration Samples.

Project description:PurposeMost patients with pancreatic ductal adenocarcinoma (PDAC) present with surgically unresectable cancer. As a result, endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is the most common biospecimen source available for diagnosis in treatment-naïve patients. Unfortunately, these limited samples are often not considered adequate for genomic analysis, precluding the opportunity for enrollment on precision medicine trials.Experimental designApplying an epithelial cell adhesion molecule (EpCAM)-enrichment strategy, we show the feasibility of using real-world EUS-FNA for in-depth, molecular-barcoded, whole-exome sequencing (WES) and somatic copy-number alteration (SCNA) analysis in 23 patients with PDAC.ResultsPotentially actionable mutations were identified in >20% of patients. Further, an increased mutational burden and higher aneuploidy in WES data were associated with an adverse prognosis. To identify predictive biomarkers for first-line chemotherapy, we developed an SCNA-based complexity score that was associated with response to platinum-based regimens in this cohort.ConclusionsCollectively, these results emphasize the feasibility of real-world cytology samples for in-depth genomic characterization of PDAC and show the prognostic potential of SCNA for PDAC diagnosis.

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Defining baseline epigenetic landscapes in the rat liver.

Project description:AIM:Characterization of the hepatic epigenome following exposure to chemicals and therapeutic drugs provides novel insights into toxicological and pharmacological mechanisms, however appreciation of genome-wide inter- and intra-strain baseline epigenetic variation, particularly in under-characterized species such as the rat is limited. Material & methods: To enhance the utility of epigenomic endpoints safety assessment, we map both DNA modifications (5-methyl-cytosine and 5-hydroxymethyl-cytosine) and enhancer related chromatin marks (H3K4me1 and H3K27ac) across multiple male and female rat livers for two important outbred laboratory rat strains (Sprague-Dawley and Wistar). Results & conclusion: Integration of DNA modification, enhancer chromatin marks and gene expression profiles reveals clear gender-specific chromatin states at genes which exhibit gender-specific transcription. Taken together this work provides a valuable baseline liver epigenome resource for rat strains that are commonly used in chemical and pharmaceutical safety assessment.

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AUD Biomarkers Study (Proteomic and Genomic Analysis of Biospecimens)

Project description:Study purpose: to explore the entire spectrum of proteomic and genomic changes (amongst others) involved in diseases and in healthy/control populations. The Study is designed to discover biomarkers, develop and validate diagnostic assays, instruments and therapeutics as well as other medical research. Specifically, researchers may analyze proteins, RNA, DNA copy number changes, including large and small (1,000-100,000 kb) scale rearrangements, transcription profiles, epigenetic modifications, sequence variation, and sequence in both diseased tissue and case-matched germline DNA from Subjects.

| 62369 | ecrin-mdr-crc

Defining the Rhythmogenic Elements of Mammalian Breathing.

Project description:Breathing's remarkable ability to adapt to changes in metabolic, environmental, and behavioral demands stems from a complex integration of its rhythm-generating network within the wider nervous system. Yet, this integration complicates identification of its specific rhythmogenic elements. Based on principles learned from smaller rhythmic networks of invertebrates, we define criteria that identify rhythmogenic elements of the mammalian breathing network and discuss how they interact to produce robust, dynamic breathing.

| S-EPMC6230551 | biostudies-literature

Addressing the challenge of defining valid proteomic biomarkers and classifiers.

Project description:The purpose of this manuscript is to provide, based on an extensive analysis of a proteomic data set, suggestions for proper statistical analysis for the discovery of sets of clinically relevant biomarkers. As tractable example we define the measurable proteomic differences between apparently healthy adult males and females. We choose urine as body-fluid of interest and CE-MS, a thoroughly validated platform technology, allowing for routine analysis of a large number of samples. The second urine of the morning was collected from apparently healthy male and female volunteers (aged 21-40) in the course of the routine medical check-up before recruitment at the Hannover Medical School.We found that the Wilcoxon-test is best suited for the definition of potential biomarkers. Adjustment for multiple testing is necessary. Sample size estimation can be performed based on a small number of observations via resampling from pilot data. Machine learning algorithms appear ideally suited to generate classifiers. Assessment of any results in an independent test-set is essential.Valid proteomic biomarkers for diagnosis and prognosis only can be defined by applying proper statistical data mining procedures. In particular, a justification of the sample size should be part of the study design.

| S-EPMC3017845 | biostudies-other

Defining functional DNA elements in the human genome.

Project description:With the completion of the human genome sequence, attention turned to identifying and annotating its functional DNA elements. As a complement to genetic and comparative genomics approaches, the Encyclopedia of DNA Elements Project was launched to contribute maps of RNA transcripts, transcriptional regulator binding sites, and chromatin states in many cell types. The resulting genome-wide data reveal sites of biochemical activity with high positional resolution and cell type specificity that facilitate studies of gene regulation and interpretation of noncoding variants associated with human disease. However, the biochemically active regions cover a much larger fraction of the genome than do evolutionarily conserved regions, raising the question of whether nonconserved but biochemically active regions are truly functional. Here, we review the strengths and limitations of biochemical, evolutionary, and genetic approaches for defining functional DNA segments, potential sources for the observed differences in estimated genomic coverage, and the biological implications of these discrepancies. We also analyze the relationship between signal intensity, genomic coverage, and evolutionary conservation. Our results reinforce the principle that each approach provides complementary information and that we need to use combinations of all three to elucidate genome function in human biology and disease.

| S-EPMC4035993 | biostudies-literature

Molecular genomic landscapes of hepatobiliary cancer.

Project description:Hepatocellular carcinoma (HCC) and biliary tract cancer are more frequent in East Asia including Japan than in Europe or North America. A compilation of 1340 multi-ethnic HCC genomes, the largest cohort ever reported, identified a comprehensive landscape of HCC driver genes, comprised of three core drivers (TP53, TERT, and WNT signaling) and combinations of infrequent alterations in various cancer pathways. In contrast, five core driver genes (TP53, ARID1A, KRAS, SMAD4, and BAP1) with characteristic molecular alterations including fusion transcripts involving fibroblast growth factor receptor 2 and the protein kinase A pathway, and IDH1/2 mutation constituted the biliary tract cancer genomes. Consistent with their heterogeneous epidemiological backgrounds, mutational signatures and combinations of non-core driver genes within these cancer genomes were found to be complex. Integrative analyses of multi-omics data identified molecular classifications of these tumors that are associated with clinical outcome and enrichments of potential therapeutic targets, including immune checkpoint molecules. Translating comprehensive molecular-genomic analysis together with further basic research and international collaborations are highly anticipated for developing precise and better treatments, diagnosis, and prevention of these tumor types.

| S-EPMC5980207 | biostudies-literature

A next generation sequencing (NGS) analysis to reveal genomic and proteomic mutation landscapes of SARS-CoV-2 in South Asia.

Project description:Counts for SARS-CoV-2 associated infections and fatalities are on the rise globally even in regions which contained the spread momentarily. The pattern of infections has been found to be controlled by the distinctive selection pressures exerted by fluctuating environmental nature and hosts. A total of 410 whole-genome sequences submitted by the South Asian countries were retrieved from the GISAID database and analyzed to assess the impact and pattern of mutations in this region. Most common and frequent mutations in the South Asian countries are 241C > T, 3037C > T, 14408C > T, and 23403A > G and about 85% SNPs are localized in ORF1ab, spike protein, and nucleocapsid. Among the identified mutations, the proportion of missense type (54.17%) was highest, followed by the synonymous (41.66%) and the non-coding types (4.17%). While analyzing transmission source in terms of geolocation, the largest clustered group from the South Asian countries was based on the G-clade (D614G) (81.7%; 335/410 samples), tracing the inception and transmission of SARS-CoV-2 infections in the South Asian countries from European regions. Phylogenetic analysis also revealed that the South Asian strains are highly related to the South American and European strains. We found that G-clade mutations are more prevalent (96.19%) in the samples of Bangladesh which were also prevalent in the European isolates. Surprisingly, one missense mutation (1163A > T) in ORF1ab gene became dominant only in Bangladesh (78.8%), which led to debates regarding effects on the pathogenicity and transmissibility of the virus. Overall, the findings of this study highlight the frequently mutated SARS-CoV-2 variants among the COVID-19 patients in the South Asian countries which might ease containment of the disease in this region through investigating the virulence reducing factors as the identified mutations are strongly correlated with low infection and mortality rate.

| S-EPMC8610355 | biostudies-literature

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