ABSTRACT
HIV-1 remains a global health crisis1, highlighting the need to identify new targets for therapies. Here, given the disproportionate HIV-1 burden and marked human genome diversity in Africa2, we assessed the genetic determinants of control of set-point viral load in 3,879 people of African ancestries living with HIV-1 participating in the international collaboration for the genomics of HIV3. We identify a previously undescribed association signal on chromosome 1 where the peak variant associates with an approximately 0.3 log10-transformed copies per ml lower set-point viral load per minor allele copy and is specific to populations of African descent. The top associated variant is intergenic and lies between a long intergenic non-coding RNA (LINC00624) and the coding gene CHD1L, which encodes a helicase that is involved in DNA repair4. Infection assays in iPS cell-derived macrophages and other immortalized cell lines showed increased HIV-1 replication in CHD1L-knockdown and CHD1L-knockout cells. We provide evidence from population genetic studies that Africa-specific genetic variation near CHD1L associates with HIV replication in vivo. Although experimental studies suggest that CHD1L is able to limit HIV infection in some cell types in vitro, further investigation is required to understand the mechanisms underlying our observations, including any potential indirect effects of CHD1L on HIV spread in vivo that our cell-based assays cannot recapitulate.
Subject(s)
DNA Helicases , DNA-Binding Proteins , Genetic Variation , HIV Infections , HIV-1 , Viral Load , Humans , Cell Line , DNA Helicases/genetics , DNA Helicases/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , HIV Infections/genetics , HIV-1/growth & development , HIV-1/physiology , Viral Load/genetics , Africa , Chromosomes, Human, Pair 1/genetics , Alleles , RNA, Long Noncoding/genetics , Virus ReplicationABSTRACT
MOTIVATION: Identifying and prioritizing disease-related proteins is an important scientific problem to develop proper treatments. Network science has become an important discipline to prioritize such proteins. Multiple sclerosis, an autoimmune disease for which there is still no cure, is characterized by a damaging process called demyelination. Demyelination is the destruction of myelin, a structure facilitating fast transmission of neuron impulses, and oligodendrocytes, the cells producing myelin, by immune cells. Identifying the proteins that have special features on the network formed by the proteins of oligodendrocyte and immune cells can reveal useful information about the disease. RESULTS: We investigated the most significant protein pairs that we define as bridges among the proteins providing the interaction between the two cells in demyelination, in the networks formed by the oligodendrocyte and each type of two immune cells (i.e. macrophage and T-cell) using network analysis techniques and integer programming. The reason, we investigated these specialized hubs was that a problem related to these proteins might impose a bigger damage in the system. We showed that 61%-100% of the proteins our model detected, depending on parameterization, have already been associated with multiple sclerosis. We further observed the mRNA expression levels of several proteins we prioritized significantly decreased in human peripheral blood mononuclear cells of multiple sclerosis patients. We therefore present a model, BriFin, which can be used for analyzing processes where interactions of two cell types play an important role. AVAILABILITY AND IMPLEMENTATION: BriFin is available at https://github.com/BilkentCompGen/brifin.
Subject(s)
Multiple Sclerosis , Humans , Leukocytes, Mononuclear , Oligodendroglia/physiology , Neurons , Myelin SheathABSTRACT
BACKGROUND: Data on intoxication patients with shock and acute organ failure is valuable for the prediction of the tailored scale prognosis of the patients in the emergency department. METHODS: : Our study was designed prospectively as a cross-sectional and observational over the course of four years. The patients over 18 years of age were included and the epidemiological data related to development of shock and acute organ failure, the treatments, and the outcome were recorded. The organic phosphate severity score was also calculated for all patients. RESULTS: A total of 89 patients with shock and/or acute organ failure 72 (80.9%) of the patients were males. Methanol (51 patients, 57.3%) was the most common cause of intoxications followed by cardiovascular agents. Thirty (33.7%) patients died despite all treatments and mortality was found to be higher in patients with hypotension (p = 0.031) at the time of admission to the emergency department and in those with a high organic phosphate poisoning severity index (p = 0.001). High levels of WBC, creatine, lactate, base excess and low bicarbonate and blood pH were associated with mortality. The discharge rates of patients who received extracorporeal treatment were statistically higher than those who did not receive this treatment (p = 0.001). DISCUSSION: The organic phosphate poisoning severity score can partially help us to predict the prognosis in all poisoning patients at the time of the first presentation. Emergency physicians may consider the development of hypotension, high creatine, lactate, base excess, low bicarbonate, and blood pH to be associated with a poor prognosis in the first hours of admission in acute poisoning patients. In these patients, it was predicted that the addition of selected extracorporeal methods without delay, in addition to the treatments that should be applied, may increase the survival rate.
Subject(s)
Hypotension , Shock , Male , Humans , Adolescent , Adult , Female , Bicarbonates , Cross-Sectional Studies , Creatine , Lactic AcidABSTRACT
BACKGROUND: CRISPR-Cas9 genome-wide screens are being increasingly performed, allowing systematic explorations of cancer dependencies at unprecedented accuracy and scale. One of the major computational challenges when analysing data derived from such screens is to identify genes that are essential for cell survival invariantly across tissues, conditions, and genomic-contexts (core-fitness genes), and to distinguish them from context-specific essential genes. This is of paramount importance to assess the safety profile of candidate therapeutic targets and for elucidating mechanisms involved in tissue-specific genetic diseases. RESULTS: We have developed CoRe: an R package implementing existing and novel methods for the identification of core-fitness genes (at two different level of stringency) from joint analyses of multiple CRISPR-Cas9 screens. We demonstrate, through a fully reproducible benchmarking pipeline, that CoRe outperforms state-of-the-art tools, yielding more reliable and biologically relevant sets of core-fitness genes. CONCLUSIONS: CoRe offers a flexible pipeline, compatible with many pre-processing methods for the analysis of CRISPR data, which can be tailored onto different use-cases. The CoRe package can be used for the identification of high-confidence novel core-fitness genes, as well as a means to filter out potentially cytotoxic hits while analysing cancer dependency datasets for identifying and prioritising novel selective therapeutic targets.
Subject(s)
CRISPR-Cas Systems , Neoplasms , Benchmarking , Genes, Essential , Humans , Neoplasms/geneticsABSTRACT
Background/aim: Critically ill patients are at risk of developing gastrointestinal (GI) bleeding due to stress causing mucosal damage. Aim of the study was to determine the effect of oral/enteral nutrition with or without concomitant pantoprazole on upper GI bleeding in low risk critically ill patients. Materials and methods: This was a prospective, randomized, open-label, multicenter study conducted with intensive care unit (ICU) patients receiving oral/enteral nutritional support. Patients were randomly assigned into two groups including intervention group (received oral/EN plus pantoprazole) and control group (received only oral/EN). Results: A total of 300 patients (intervention group: 152, control group: 148) participated in the study. Overall, 226 (75%) patients were fed by orally and 74 (25%) patients fed by enteral tube feeding. Median duration of nutritional support 4 (range: 233) days. Overt upper GI bleeding was noted only in one patient (0.65%) who was in the intervention group. The overall length of ICU stay of 4 (2105) days, while ICU stay was significantly longer in the intervention group than in the control group (P = 0.006). Conclusions: Our findings seems to indicate that in patients who are at low risk for GI bleeding and under oral/enteral nutritional support, the use of PPIs may not reduce the risk of bleeding, however these results are imprecise because of low event (GI bleeding) rate and limited power.
Subject(s)
Anti-Ulcer Agents/therapeutic use , Critical Care/methods , Enteral Nutrition/methods , Gastrointestinal Hemorrhage/prevention & control , Pantoprazole/therapeutic use , Aged , Critical Illness , Female , Humans , Male , Middle Aged , Prospective Studies , Risk , Treatment OutcomeABSTRACT
It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes--so-called sporadic or simplex families--we sequenced all coding regions of the genome (the exome) for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 677 individual exomes from 209 families. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected ß-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics.
Subject(s)
Autistic Disorder/genetics , Exome/genetics , Exons/genetics , Point Mutation/genetics , Protein Interaction Maps/genetics , DNA-Binding Proteins/genetics , GPI-Linked Proteins/genetics , Genetic Predisposition to Disease/genetics , Humans , Laminin/genetics , NAV1.1 Voltage-Gated Sodium Channel , Nerve Tissue Proteins/genetics , Netrins , Parents , Receptors, N-Methyl-D-Aspartate/genetics , Reproducibility of Results , Siblings , Signal Transduction , Sodium Channels/genetics , Stochastic Processes , Transcription Factors/genetics , Tumor Suppressor Protein p53/metabolism , beta Catenin/metabolismABSTRACT
Two African apes are the closest living relatives of humans: the chimpanzee (Pan troglodytes) and the bonobo (Pan paniscus). Although they are similar in many respects, bonobos and chimpanzees differ strikingly in key social and sexual behaviours, and for some of these traits they show more similarity with humans than with each other. Here we report the sequencing and assembly of the bonobo genome to study its evolutionary relationship with the chimpanzee and human genomes. We find that more than three per cent of the human genome is more closely related to either the bonobo or the chimpanzee genome than these are to each other. These regions allow various aspects of the ancestry of the two ape species to be reconstructed. In addition, many of the regions that overlap genes may eventually help us understand the genetic basis of phenotypes that humans share with one of the two apes to the exclusion of the other.
Subject(s)
Evolution, Molecular , Genetic Variation/genetics , Genome, Human/genetics , Genome/genetics , Pan paniscus/genetics , Pan troglodytes/genetics , Animals , DNA Transposable Elements/genetics , Gene Duplication/genetics , Genotype , Humans , Molecular Sequence Data , Phenotype , Phylogeny , Species SpecificityABSTRACT
Gorillas are humans' closest living relatives after chimpanzees, and are of comparable importance for the study of human origins and evolution. Here we present the assembly and analysis of a genome sequence for the western lowland gorilla, and compare the whole genomes of all extant great ape genera. We propose a synthesis of genetic and fossil evidence consistent with placing the human-chimpanzee and human-chimpanzee-gorilla speciation events at approximately 6 and 10 million years ago. In 30% of the genome, gorilla is closer to human or chimpanzee than the latter are to each other; this is rarer around coding genes, indicating pervasive selection throughout great ape evolution, and has functional consequences in gene expression. A comparison of protein coding genes reveals approximately 500 genes showing accelerated evolution on each of the gorilla, human and chimpanzee lineages, and evidence for parallel acceleration, particularly of genes involved in hearing. We also compare the western and eastern gorilla species, estimating an average sequence divergence time 1.75 million years ago, but with evidence for more recent genetic exchange and a population bottleneck in the eastern species. The use of the genome sequence in these and future analyses will promote a deeper understanding of great ape biology and evolution.
Subject(s)
Evolution, Molecular , Genetic Speciation , Genome/genetics , Gorilla gorilla/genetics , Animals , Female , Gene Expression Regulation , Genetic Variation/genetics , Genomics , Humans , Macaca mulatta/genetics , Molecular Sequence Data , Pan troglodytes/genetics , Phylogeny , Pongo/genetics , Proteins/genetics , Sequence Alignment , Species Specificity , Transcription, GeneticABSTRACT
OBJECTIVE: Our aim in this retrospective study was to determine the factors affecting poor prognosis and mortality of organophosphate (OP) poisoning by reviewing patient data. We also reviewed present knowledge to make conclusions on certain longstanding debates in light of the literature. METHODS: In this retrospective descriptive study, patients who were admitted to and hospitalized in the emergency department (ED) or intensive care unit (ICU) of a university hospital with the diagnosis of OP poisoning between December 2010 and December 2015 were evaluated. All the data were obtained from electronic and manual patient files. A total of 80 patients were included in the study. RESULTS: The mean age of the study patients was 32.4±15.0 (13-94). Forty-nine (61.2%) patients were female. Twenty-two (27.5%) patients were seriously poisoned and needed mechanical ventilation (MV) support. Low pseudocholinesterase (PChE), high creatinine (Cr), low Glasgow Coma Scale (GCS) scores and long hospitalization durations were all found to be poor prognostics in MV patients. Low PChE and high Cr levels were found to be independent predictors of the hospitalization duration and high Cr was found to be an independent predictor of the intubation duration of MV patients in regression analyses. Ten (45.5%) of the MV patients were unresponsive to medical treatment and Therapeutic plasma exchange (TPE) was performed. Seven patients were discharged healthy. Three patients with low PChE levels and comorbidities died. CONCLUSIONS: Prolongation of respiratory depression necessitating MV support, comorbidities, long hospital stay, elevated creatinine, low GCS scores and low PcHE levels without regeneration in the first 48 hours of admission are all found to be poor prognostic factors for organophosphate (OP) poisoning.
ABSTRACT
Allele sharing between modern and archaic hominin genomes has been variously interpreted to have originated from ancestral genetic structure or through non-African introgression from archaic hominins. However, evolution of polymorphic human deletions that are shared with archaic hominin genomes has yet to be studied. We identified 427 polymorphic human deletions that are shared with archaic hominin genomes, approximately 87% of which originated before the Human-Neandertal divergence (ancient) and only approximately 9% of which have been introgressed from Neandertals (introgressed). Recurrence, incomplete lineage sorting between human and chimp lineages, and hominid-specific insertions constitute the remaining approximately 4% of allele sharing between humans and archaic hominins. We observed that ancient deletions correspond to more than 13% of all common (>5% allele frequency) deletion variation among modern humans. Our analyses indicate that the genomic landscapes of both ancient and introgressed deletion variants were primarily shaped by purifying selection, eliminating large and exonic variants. We found 17 exonic deletions that are shared with archaic hominin genomes, including those leading to three fusion transcripts. The affected genes are involved in metabolism of external and internal compounds, growth and sperm formation, as well as susceptibility to psoriasis and Crohn's disease. Our analyses suggest that these "exonic" deletion variants have evolved through different adaptive forces, including balancing and population-specific positive selection. Our findings reveal that genomic structural variants that are shared between humans and archaic hominin genomes are common among modern humans and can influence biomedically and evolutionarily important phenotypes.
Subject(s)
Evolution, Molecular , Genome , Hominidae/genetics , Sequence Deletion , Alleles , Animals , Genetic Variation , HumansABSTRACT
We searched for disruptive, genic rare copy-number variants (CNVs) among 411 families affected by sporadic autism spectrum disorder (ASD) from the Simons Simplex Collection by using available exome sequence data and CoNIFER (Copy Number Inference from Exome Reads). Compared to high-density SNP microarrays, our approach yielded â¼2× more smaller genic rare CNVs. We found that affected probands inherited more CNVs than did their siblings (453 versus 394, p = 0.004; odds ratio [OR] = 1.19) and that the probands' CNVs affected more genes (921 versus 726, p = 0.02; OR = 1.30). These smaller CNVs (median size 18 kb) were transmitted preferentially from the mother (136 maternal versus 100 paternal, p = 0.02), although this bias occurred irrespective of affected status. The excess burden of inherited CNVs among probands was driven primarily by sibling pairs with discordant social-behavior phenotypes (p < 0.0002, measured by Social Responsiveness Scale [SRS] score), which contrasts with families where the phenotypes were more closely matched or less extreme (p > 0.5). Finally, we found enrichment of brain-expressed genes unique to probands, especially in the SRS-discordant group (p = 0.0035). In a combined model, our inherited CNVs, de novo CNVs, and de novo single-nucleotide variants all independently contributed to the risk of autism (p < 0.05). Taken together, these results suggest that small transmitted rare CNVs play a role in the etiology of simplex autism. Importantly, the small size of these variants aids in the identification of specific genes as additional risk factors associated with ASD.
Subject(s)
Child Development Disorders, Pervasive/genetics , DNA Copy Number Variations , Linkage Disequilibrium , Child , Exome , Female , Gene Expression , Genetic Predisposition to Disease , Humans , Male , Phenotype , Polymorphism, Single Nucleotide , Risk , Risk Factors , SiblingsABSTRACT
We report a novel gene for a parkinsonian disorder. X-linked parkinsonism with spasticity (XPDS) presents either as typical adult onset Parkinson's disease or earlier onset spasticity followed by parkinsonism. We previously mapped the XPDS gene to a 28 Mb region on Xp11.2-X13.3. Exome sequencing of one affected individual identified five rare variants in this region, of which none was missense, nonsense or frame shift. Using patient-derived cells, we tested the effect of these variants on expression/splicing of the relevant genes. A synonymous variant in ATP6AP2, c.345C>T (p.S115S), markedly increased exon 4 skipping, resulting in the overexpression of a minor splice isoform that produces a protein with internal deletion of 32 amino acids in up to 50% of the total pool, with concomitant reduction of isoforms containing exon 4. ATP6AP2 is an essential accessory component of the vacuolar ATPase required for lysosomal degradative functions and autophagy, a pathway frequently affected in Parkinson's disease. Reduction of the full-size ATP6AP2 transcript in XPDS cells and decreased level of ATP6AP2 protein in XPDS brain may compromise V-ATPase function, as seen with siRNA knockdown in HEK293 cells, and may ultimately be responsible for the pathology. Another synonymous mutation in the same exon, c.321C>T (p.D107D), has a similar molecular defect of exon inclusion and causes X-linked mental retardation Hedera type (MRXSH). Mutations in XPDS and MRXSH alter binding sites for different splicing factors, which may explain the marked differences in age of onset and manifestations.
Subject(s)
Chromosomes, Human, X , Genetic Diseases, X-Linked/genetics , Genetic Variation , Muscle Spasticity/genetics , Parkinsonian Disorders/genetics , Receptors, Cell Surface/genetics , Vacuolar Proton-Translocating ATPases/genetics , Aged , Binding Sites/genetics , Cells, Cultured , Codon, Nonsense , Exome , Female , Frameshift Mutation , Gene Expression Regulation , Gene Knockdown Techniques , Genetic Diseases, X-Linked/metabolism , Genetic Linkage , HEK293 Cells , Humans , Male , Mental Retardation, X-Linked/genetics , Mental Retardation, X-Linked/metabolism , Muscle Spasticity/metabolism , Mutation, Missense , Parkinsonian Disorders/metabolism , Receptors, Cell Surface/chemistry , Receptors, Cell Surface/metabolism , Sequence Analysis, RNA , Vacuolar Proton-Translocating ATPases/chemistry , Vacuolar Proton-Translocating ATPases/metabolismABSTRACT
MOTIVATION: RNA-Seq technology is promising to uncover many novel alternative splicing events, gene fusions and other variations in RNA transcripts. For an accurate detection and quantification of transcripts, it is important to resolve the mapping ambiguity for those RNA-Seq reads that can be mapped to multiple loci: >17% of the reads from mouse RNA-Seq data and 50% of the reads from some plant RNA-Seq data have multiple mapping loci. In this study, we show how to resolve the mapping ambiguity in the presence of novel transcriptomic events such as exon skipping and novel indels towards accurate downstream analysis. We introduce ORMAN ( O ptimal R esolution of M ultimapping A mbiguity of R N A-Seq Reads), which aims to compute the minimum number of potential transcript products for each gene and to assign each multimapping read to one of these transcripts based on the estimated distribution of the region covering the read. ORMAN achieves this objective through a combinatorial optimization formulation, which is solved through well-known approximation algorithms, integer linear programs and heuristics. RESULTS: On a simulated RNA-Seq dataset including a random subset of transcripts from the UCSC database, the performance of several state-of-the-art methods for identifying and quantifying novel transcripts, such as Cufflinks, IsoLasso and CLIIQ, is significantly improved through the use of ORMAN. Furthermore, in an experiment using real RNA-Seq reads, we show that ORMAN is able to resolve multimapping to produce coverage values that are similar to the original distribution, even in genes with highly non-uniform coverage. AVAILABILITY: ORMAN is available at http://orman.sf.net
Subject(s)
Gene Expression Profiling/methods , RNA Isoforms/metabolism , Sequence Analysis, RNA/methods , Software , Algorithms , Alternative Splicing , Exons , Humans , RNA Isoforms/chemistry , Sequence AlignmentABSTRACT
INTRODUCTION AND AIM: This study examined the extracorporeal methods for the elimination of toxic substances in poisoned patients that are used by clinicians taking care of such patients. Here we present our experience in the use of therapeutic plasma exchange (TPE). To the best of our knowledge, this is the largest number of poisoning cases ever reported in a study. PATIENTS AND METHODS: This is a retrospective study conducted at the Çukurova University Faculty of Medicine, Department of Emergency Medicine, with the permission of the ethical committee of the medical faculty. The study includes patients who had undergone TPE because of poisoning between January 2007 and May 2015. We summarize the clinical data and outcomes of the patients with available files. RESULTS: A total of 36 cases among the 42 patients who underwent TPE in this 8-year period were included in the study. More than 20 identified toxic substances, most of which were pesticides, were found to be the causes of poisoning. Twenty-three healthy discharges and 12 deaths are discussed in the study. CONCLUSION: We believe that our study reports the largest ever number of poisoning cases treated with TPE in the literature. When applicable, TPE may be a promising extracorporeal elimination and treatment technique in poisoned patients when performed in selected cases.
Subject(s)
Extracorporeal Circulation , Plasma Exchange/methods , Poisoning/therapy , Adolescent , Adult , Aged , Aged, 80 and over , Female , Hospitals, University , Humans , Male , Medical Records , Middle Aged , Outcome Assessment, Health Care/statistics & numerical data , Retrospective Studies , Turkey , Young AdultABSTRACT
We report an algorithm to detect structural variation and indels from 1 base pair (bp) to 1 Mbp within exome sequence data sets. Splitread uses one end-anchored placements to cluster the mappings of subsequences of unanchored ends to identify the size, content and location of variants with high specificity and sensitivity. The algorithm discovers indels, structural variants, de novo events and copy number-polymorphic processed pseudogenes missed by other methods.
Subject(s)
Exome , Algorithms , PseudogenesABSTRACT
A cancer mass is composed of a heterogeneous group of cells, a small part of which constitutes the cancer stem cells since they are less differentiated and have a high capacity to develop cancer. Versican is an extracellular matrix protein located in many human tissues. The mRNA of versican has been shown to have "splicing patterns" as detected by RT-PCR, northern blot analysis, and cDNA sequencing. Based on this knowledge this study aims to reveal the splice variants of versican molecules, which are thought to be involved in the pathogenesis of the DU-145 human prostatic carcinoma cell line and prostatic cancer stem cells isolated from this cell line. In this study, RWPE-1 normal prostatic and DU-145 human prostate cancer cell lines have been used. Prostatic cancer stem cells and the remaining group of non-prostatic-cancer stem cells (bulk population) were isolated according to their CD133+/CD44+. RNA was isolated in all groups, and sequence analysis was accomplished for splicing variants by Illumina NextSeq 500 sequencing system. The results were analyzed by bioinformatic evaluation. As five isoforms of the versican gene in the differential transcript expression are analyzed, it was observed that a significant change was only found in the isoforms Versican 0 and Versican 1. In this study, we explored the function of this molecule which we think to be effective in cancer progression, and suggested that more valuable results can be obtained after the accomplishment of in vivo experiments.
Subject(s)
AC133 Antigen , Hyaluronan Receptors , Neoplastic Stem Cells , Prostatic Neoplasms , Versicans , Humans , Versicans/genetics , Versicans/metabolism , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Prostatic Neoplasms/metabolism , Male , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Hyaluronan Receptors/metabolism , Hyaluronan Receptors/genetics , AC133 Antigen/metabolism , AC133 Antigen/genetics , Cell Line, Tumor , Alternative Splicing , Protein IsoformsABSTRACT
Yin yang 1 (YY1), a transcription factor, plays crucial roles in cell fate specification, differentiation, and pluripotency during embryonic development. It is also involved in tumorigenesis, drug resistance, metastasis, and relapse caused by cancer stem cells (CSCs), particularly in prostate cancer (PCa). Targeting YY1 could potentially eliminate prostate CSCs (PCSCs) and provide novel therapeutic approaches. PCa tissues often exhibit elevated YY1 expression levels, especially in high-grade cases. Notably, high-grade PCa tissues from 58 PCa patients and CD133high/CD44high PCSCs isolated from DU145 PCa cell line by FACS both showed significantly increased YY1 expression as observed through immunofluorescence staining, respectively. To investigate the embryonic microenvironment impact on YY1 expression in CSC populations, firstly PCSCs were microinjected into the inner cell mass of blastocysts and then PCSCs were co-cultured with blastocysts. Next Generation Sequencing was used to analyze alterations in YY1 and related gene expressions. Interestingly, exposure to the embryonic microenvironment significantly reduced the expressions of YY1, YY2, and other relevant genes in PCSCs. These findings emphasize the tumor-suppressing effects of the embryonic environment by downregulating YY1 and YY1-related genes in PCSCs, thus providing promising strategies for PCa therapy. Through elucidating the mechanisms involved in embryonic reprogramming and its effects on YY1 expression, this research offers opportunities for further investigation into focused therapies directed against PCSCs, therefore enhancing the outcomes of PCa therapy. As a result, PCa tumors may benefit from YY1 and associated genes as a novel therapeutic target.
Subject(s)
Neoplastic Stem Cells , Prostatic Neoplasms , YY1 Transcription Factor , YY1 Transcription Factor/genetics , YY1 Transcription Factor/metabolism , Humans , Male , Prostatic Neoplasms/pathology , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Neoplastic Stem Cells/pathology , Neoplastic Stem Cells/metabolism , Gene Expression Regulation, Neoplastic/genetics , Tumor Microenvironment , Cell Line, Tumor , AnimalsABSTRACT
Genetic screens in cancer cell lines inform gene function and drug discovery. More comprehensive screen datasets with multi-omics data are needed to enhance opportunities to functionally map genetic vulnerabilities. Here, we construct a second-generation map of cancer dependencies by annotating 930 cancer cell lines with multi-omic data and analyze relationships between molecular markers and cancer dependencies derived from CRISPR-Cas9 screens. We identify dependency-associated gene expression markers beyond driver genes, and observe many gene addiction relationships driven by gain of function rather than synthetic lethal effects. By combining clinically informed dependency-marker associations with protein-protein interaction networks, we identify 370 anti-cancer priority targets for 27 cancer types, many of which have network-based evidence of a functional link with a marker in a cancer type. Mapping these targets to sequenced tumor cohorts identifies tractable targets in different cancer types. This target prioritization map enhances understanding of gene dependencies and identifies candidate anti-cancer targets for drug development.
Subject(s)
Genetic Testing , Neoplasms , Humans , Phenotype , Drug Discovery , Neoplasms/genetics , Neoplasms/pathology , Cell Line, Tumor , CRISPR-Cas SystemsABSTRACT
How human genetic variation contributes to vaccine effectiveness in infants is unclear, and data are limited on these relationships in populations with African ancestries. We undertook genetic analyses of vaccine antibody responses in infants from Uganda (n = 1391), Burkina Faso (n = 353) and South Africa (n = 755), identifying associations between human leukocyte antigen (HLA) and antibody response for five of eight tested antigens spanning pertussis, diphtheria and hepatitis B vaccines. In addition, through HLA typing 1,702 individuals from 11 populations of African ancestry derived predominantly from the 1000 Genomes Project, we constructed an imputation resource, fine-mapping class II HLA-DR and DQ associations explaining up to 10% of antibody response variance in our infant cohorts. We observed differences in the genetic architecture of pertussis antibody response between the cohorts with African ancestries and an independent cohort with European ancestry, but found no in silico evidence of differences in HLA peptide binding affinity or breadth. Using immune cell expression quantitative trait loci datasets derived from African-ancestry samples from the 1000 Genomes Project, we found evidence of differential HLA-DRB1 expression correlating with inferred protection from pertussis following vaccination. This work suggests that HLA-DRB1 expression may play a role in vaccine response and should be considered alongside peptide selection to improve vaccine design.