ABSTRACT
We are very thankful to the commentator for pointing out the issues in the review article by Satam et al [...].
ABSTRACT
Recent studies suggest that long non-coding RNAs (lncRNAs) contribute to medulloblastoma (MB) formation and progression. We have identified an lncRNA, lnc-HLX-2-7, as a potential therapeutic target in group 3 (G3) MBs. lnc-HLX-2-7 RNA specifically accumulates in the promoter region of HLX, a sense-overlapping gene of lnc-HLX-2-7, which activates HLX expression by recruiting multiple factors, including enhancer elements. RNA sequencing and chromatin immunoprecipitation reveal that HLX binds to and activates the promoters of several oncogenes, including TBX2, LIN9, HOXM1, and MYC. Intravenous treatment with cerium-oxide-nanoparticle-coated antisense oligonucleotides targeting lnc-HLX-2-7 (CNP-lnc-HLX-2-7) inhibits tumor growth by 40%-50% in an intracranial MB xenograft mouse model. Combining CNP-lnc-HLX-2-7 with standard-of-care cisplatin further inhibits tumor growth and significantly prolongs mouse survival compared with CNP-lnc-HLX-2-7 monotherapy. Thus, the lnc-HLX-2-7-HLX-MYC axis is important for regulating G3 MB progression, providing a strong rationale for using lnc-HLX-2-7 as a therapeutic target for G3 MBs.
Subject(s)
Cerebellar Neoplasms , Medulloblastoma , RNA, Long Noncoding , Humans , Mice , Animals , Feedback , Medulloblastoma/genetics , Medulloblastoma/pathology , Oncogenes , Cerebellar Neoplasms/drug therapy , Cerebellar Neoplasms/genetics , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic , Cell Line, Tumor , Transcription Factors/metabolism , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolismABSTRACT
Recent technological advances in sequencing DNA and RNA modifications using high-throughput platforms have generated vast epigenomic and epitranscriptomic datasets whose power in transforming life science is yet fully unleashed. Currently available in silico methods have facilitated the identification, positioning and quantitative comparisons of individual modification sites. However, the essential challenge to link specific 'epi-marks' to gene expression in the particular context of cellular and biological processes is unmet. To fast-track exploration, we generated epidecodeR implemented in R, which allows biologists to quickly survey whether an epigenomic or epitranscriptomic status of their interest potentially influences gene expression responses. The evaluation is based on the cumulative distribution function and the statistical significance in differential expression of genes grouped by the number of 'epi-marks'. This tool proves useful in predicting the role of H3K9ac and H3K27ac in associated gene expression after knocking down deacetylases FAM60A and SDS3 and N6-methyl-adenosine-associated gene expression after knocking out the reader proteins. We further used epidecodeR to explore the effectiveness of demethylase FTO inhibitors and histone-associated modifications in drug abuse in animals. epidecodeR is available for downloading as an R package at https://bioconductor.riken.jp/packages/3.13/bioc/html/epidecodeR.html.
Subject(s)
Epigenomics , Software , Animals , Epigenomics/methods , DNA Methylation , DNA/metabolism , Epigenesis, GeneticABSTRACT
The prognosis of childhood medulloblastoma (MB) is often poor, and it usually requires aggressive therapy that adversely affects quality of life. microRNA-211 (miR-211) was previously identified as an important regulator of cells that descend from neural cells. Since medulloblastomas primarily affect cells with similar ontogeny, we investigated the role and mechanism of miR-211 in MB. Here we showed that miR-211 expression was highly downregulated in cell lines, PDXs, and clinical samples of different MB subgroups (SHH, Group 3, and Group 4) compared to normal cerebellum. miR-211 gene was ectopically expressed in transgenic cells from MB subgroups, and they were subjected to molecular and phenotypic investigations. Monoclonal cells stably expressing miR-211 were injected into the mouse cerebellum. miR-211 forced expression acts as a tumor suppressor in MB both in vitro and in vivo, attenuating growth, promoting apoptosis, and inhibiting invasion. In support of emerging regulatory roles of metabolism in various forms of cancer, we identified the acyl-CoA synthetase long-chain family member (ACSL4) as a direct miR-211 target. Furthermore, lipid nanoparticle-coated, dendrimer-coated, and cerium oxide-coated miR-211 nanoparticles were applied to deliver synthetic miR-211 into MB cell lines and cellular responses were assayed. Synthesizing nanoparticle-miR-211 conjugates can suppress MB cell viability and invasion in vitro. Our findings reveal miR-211 as a tumor suppressor and a potential therapeutic agent in MB. This proof-of-concept paves the way for further pre-clinical and clinical development.
Subject(s)
Cerebellar Neoplasms , Medulloblastoma , MicroRNAs , Animals , Humans , Mice , Cell Line, Tumor , Cell Proliferation , Cerebellar Neoplasms/metabolism , Gene Expression Regulation, Neoplastic , Homeostasis , Ligases/genetics , Ligases/metabolism , Medulloblastoma/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Quality of LifeABSTRACT
The advent of next-generation sequencing (NGS) has brought about a paradigm shift in genomics research, offering unparalleled capabilities for analyzing DNA and RNA molecules in a high-throughput and cost-effective manner. This transformative technology has swiftly propelled genomics advancements across diverse domains. NGS allows for the rapid sequencing of millions of DNA fragments simultaneously, providing comprehensive insights into genome structure, genetic variations, gene expression profiles, and epigenetic modifications. The versatility of NGS platforms has expanded the scope of genomics research, facilitating studies on rare genetic diseases, cancer genomics, microbiome analysis, infectious diseases, and population genetics. Moreover, NGS has enabled the development of targeted therapies, precision medicine approaches, and improved diagnostic methods. This review provides an insightful overview of the current trends and recent advancements in NGS technology, highlighting its potential impact on diverse areas of genomic research. Moreover, the review delves into the challenges encountered and future directions of NGS technology, including endeavors to enhance the accuracy and sensitivity of sequencing data, the development of novel algorithms for data analysis, and the pursuit of more efficient, scalable, and cost-effective solutions that lie ahead.
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Circular RNAs (circRNAs) are a class of RNA with a stable cyclic structure. They are expressed in various tissues and cells with conserved, specific characteristics. CircRNAs have been found to play critical roles in a wide range of cellular processes by regulating gene expression at the epigenetic, transcriptional, and posttranscriptional levels. There is an accumulation of evidence on newly discovered circRNAs, their molecular interactions, and their roles in the development and progression of human brain tumors, including cell proliferation, cell apoptosis, invasion, and chemoresistance. Here we summarize the current state of knowledge of the circRNAs that have been implicated in brain tumor pathogenesis, particularly in gliomas and medulloblastomas. In providing a comprehensive overview of circRNA studies, we highlight how different circRNAs have oncogenic or tumor-suppressive roles in brain tumors, making them attractive therapeutic targets and biomarkers for personalized therapy and precision diagnostics. This review article discusses circRNAs' functional roles and the prospect of using them as diagnostic biomarkers and therapeutic targets in patients with brain tumors.
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Pyrrolizidine alkaloids (PAs) are among the most significant hepatotoxins widely distributed in plant species. Incidence of liver injuries caused by PAs has been reported worldwide, and the reactive metabolites of PAs are known to play a critical role in causing the hepatotoxicity. To better understand the toxicity-induction mechanisms, we explored the interactions of PA metabolites with cellular RNA molecules, and examined their effects on the biochemical and metabolic properties of hepatic RNAs. After exposure to retrorsine, adduction on adenosine and guanosine were detected in mouse liver microsomal incubations, cultured mouse primary hepatocytes, and mouse liver tissues. NMR analysis showed that the exocyclic amino group participated in the adduction. We found drastically altered properties and metabolism of the adducted RNA such as reverse-transcriptability, translatability, and RNase-susceptibility. In addition, endogenous modification of N6-methyladenosine (m6A) was remarkably reduced.
Subject(s)
Pyrrolizidine Alkaloids , RNA , Activation, Metabolic , Animals , Liver , Mice , Microsomes, Liver/metabolism , Pyrrolizidine Alkaloids/metabolism , Pyrrolizidine Alkaloids/toxicity , RNA/metabolismABSTRACT
BACKGROUND: Autoinflammatory disorders are the group of inherited inflammatory disorders caused due to the genetic defect in the genes that regulates innate immune systems. These have been clinically characterized based on the duration and occurrence of unprovoked fever, skin rash, and patient's ancestry. There are several autoinflammatory disorders that are found to be prevalent in a specific population and whose disease genetic epidemiology within the population has been well understood. However, India has a limited number of genetic studies reported for autoinflammatory disorders till date. The whole genome sequencing and analysis of 1029 Indian individuals performed under the IndiGen project persuaded us to perform the genetic epidemiology of the autoinflammatory disorders in India. RESULTS: We have systematically annotated the genetic variants of 56 genes implicated in autoinflammatory disorder. These genetic variants were reclassified into five categories (i.e., pathogenic, likely pathogenic, benign, likely benign, and variant of uncertain significance (VUS)) according to the American College of Medical Genetics and Association of Molecular pathology (ACMG-AMP) guidelines. Our analysis revealed 20 pathogenic and likely pathogenic variants with significant differences in the allele frequency compared with the global population. We also found six causal founder variants in the IndiGen dataset belonging to different ancestry. We have performed haplotype prediction analysis for founder mutations haplotype that reveals the admixture of the South Asian population with other populations. The cumulative carrier frequency of the autoinflammatory disorder in India was found to be 3.5% which is much higher than reported. CONCLUSION: With such frequency in the Indian population, there is a great need for awareness among clinicians as well as the general public regarding the autoinflammatory disorder. To the best of our knowledge, this is the first and most comprehensive population scale genetic epidemiological study being reported from India.
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BACKGROUND: Evidence suggests specialist eating disorders services for children and adolescents with anorexia nervosa have the potential to improve outcomes and reduce costs through reduced hospital admissions. This study aimed to evaluate the cost-effectiveness of assessment and diagnosis in community-based specialist child and adolescent mental health services (CAMHS) compared to generic CAMHS for children and adolescents with anorexia nervosa. METHOD: Observational, surveillance study of children and adolescents aged 8 to 17, in contact with community-based CAMHS in the UK or Republic of Ireland for a first episode of anorexia nervosa. Data were reported by clinicians at baseline, 6 and 12-months follow-up. Outcomes included the Children's Global Assessment Scale (CGAS) and percentage of median expected body mass for age and sex (%mBMI). Service use data included paediatric and psychiatric inpatient admissions, outpatient and day-patient attendances. A joint distribution of incremental mean costs and effects for each group was generated using bootstrapping to explore the probability that each service is the optimal choice, subject to a range of values a decision-maker might be willing to pay for outcome improvements. Uncertainty was explored using cost-effectiveness acceptability curves. RESULTS: Two hundred ninety-eight children and adolescents met inclusion criteria. At 12-month follow-up, there were no significant differences in total costs or outcomes between specialist eating disorders services and generic CAMHS. However, adjustment for pre-specified baseline covariates resulted in observed differences favouring specialist services, due to significantly poorer clinical status of the specialist group at baseline. Cost-effectiveness analysis using CGAS suggests that the probability of assessment in a specialist service being cost-effective compared to generic CAMHS ranges from 90 to 50%, dependent on willingness to pay for improvements in outcome. CONCLUSIONS: Assessment in a specialist eating disorders service for children and adolescents with anorexia nervosa may have a higher probability of being cost-effective than assessment in generic CAMHS. TRIAL REGISTRATION: ISRCTN12676087 . Date of registration 07/01/2014.
Specialist eating disorders services may improve outcomes and reduce hospitalisations for children and adolescents with anorexia nervosa. Reductions in hospitalisation could save money for the NHS and are better for young people because hospitalisation disrupts their home life, social life and education. This study evaluated outcomes and costs of specialist eating disorders services compared to general child and adolescent mental health services (CAMHS) for children and adolescents with anorexia nervosa.Children and adolescents were identified by contacting child and adolescent psychiatrists in the UK and Ireland and asking them to report any new cases of anorexia nervosa. These psychiatrists identified 298 young people aged 8 to 17 with an anorexia nervosa diagnosis for the first time. The psychiatrists provided information on the health services these young people used and how they were doing when they were first diagnosed and 6 months and 1 year later.Children and adolescents in specialist services were more severely ill than those in CAMHS when they were first diagnosed. Despite this, care for the young people in specialist services cost about the same as for those diagnosed in CAMHS, and their outcomes after 1 year were similar. This work showed that specialist services may be better value for money than CAMHS.
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Aim: Numerous drugs are being widely prescribed for COVID-19 treatment without any direct evidence for the drug safety/efficacy in patients across diverse ethnic populations. Materials & methods: We analyzed whole genomes of 1029 Indian individuals (IndiGen) to understand the extent of drug-gene (pharmacogenetic), drug-drug and drug-drug-gene interactions associated with COVID-19 therapy in the Indian population. Results: We identified 30 clinically significant pharmacogenetic variants and 73 predicted deleterious pharmacogenetic variants. COVID-19-associated pharmacogenes were substantially overlapped with those of metabolic disorder therapeutics. CYP3A4, ABCB1 and ALB are the most shared pharmacogenes. Fifteen COVID-19 therapeutics were predicted as likely drug-drug interaction candidates when used with four CYP inhibitor drugs. Conclusion: Our findings provide actionable insights for future validation studies and improved clinical decisions for COVID-19 therapy in Indians.
Subject(s)
COVID-19 Drug Treatment , COVID-19/genetics , Antiviral Agents/therapeutic use , Asian People , Drug Interactions/genetics , Genome/genetics , Genotype , Humans , India , Pharmacogenetics/methods , Pharmacogenomic Testing/methods , Pharmacogenomic Variants/genetics , SARS-CoV-2/drug effectsABSTRACT
With the advent of next-generation sequencing, large-scale initiatives for mining whole genomes and exomes have been employed to better understand global or population-level genetic architecture. India encompasses more than 17% of the world population with extensive genetic diversity, but is under-represented in the global sequencing datasets. This gave us the impetus to perform and analyze the whole genome sequencing of 1029 healthy Indian individuals under the pilot phase of the 'IndiGen' program. We generated a compendium of 55,898,122 single allelic genetic variants from geographically distinct Indian genomes and calculated the allele frequency, allele count, allele number, along with the number of heterozygous or homozygous individuals. In the present study, these variants were systematically annotated using publicly available population databases and can be accessed through a browsable online database named as 'IndiGenomes' http://clingen.igib.res.in/indigen/. The IndiGenomes database will help clinicians and researchers in exploring the genetic component underlying medical conditions. Till date, this is the most comprehensive genetic variant resource for the Indian population and is made freely available for academic utility. The resource has also been accessed extensively by the worldwide community since it's launch.
Subject(s)
Databases, Genetic , Genetic Variation , Genome, Human , Human Genome Project , Software , Adult , Exome , Female , Genetics, Population/statistics & numerical data , Humans , India , Internet , Male , Molecular Sequence Annotation , Whole Genome SequencingABSTRACT
Long noncoding RNAs (lncRNAs) are a recently discovered class of noncoding functional RNAs encoded by metazoan genomes. Recent studies suggest a larger regulatory role for lncRNAs in critical biological and disease processes. Mounting evidence on the role of lncRNAs in regulating key processes of the immune system prompted us to hypothesize the role of lncRNAs as key regulators of the pathophysiology of Sjögren's syndrome (SS). We used two similar approaches based on reanalysis of microarray expression datasets and curation of lncRNA-protein coding gene interactions from literature to derive support for our hypothesis. We also discuss potential caveats to our approach and suggest approaches to validate the hypothesis. Our analysis suggests the potential larger and hitherto unknown role of lncRNA regulatory networks in modulating the expression of key genes involved in the pathogenesis of SS and thereby modulating the pathophysiology of SS.
Subject(s)
RNA, Long Noncoding/genetics , Salivary Glands/metabolism , Sjogren's Syndrome/genetics , Computational Biology , Databases, Genetic , Gene Expression Profiling/methods , Gene Expression Regulation , Genetic Association Studies , Genetic Markers , Genetic Predisposition to Disease , Humans , Oligonucleotide Array Sequence Analysis , Phenotype , Risk Factors , Salivary Glands/immunology , Salivary Glands/physiopathology , Sjogren's Syndrome/diagnosis , Sjogren's Syndrome/immunology , Sjogren's Syndrome/physiopathologyABSTRACT
The human mitochondrial genome has been reported to have a very high mutation rate as compared with the nuclear genome. A large number of mitochondrial mutations show significant phenotypic association and are involved in a broad spectrum of diseases. In recent years, there has been a remarkable progress in the understanding of mitochondrial genetics. The availability of next-generation sequencing (NGS) technologies have not only reduced sequencing cost by orders of magnitude but has also provided us good quality mitochondrial genome sequences with high coverage, thereby enabling decoding of a number of human mitochondrial diseases. In this study, we report a computational and experimental pipeline to decipher the human mitochondrial DNA variations and examine them for their clinical correlation. As a proof of principle, we also present a clinical study of a patient with Leigh disease and confirmed maternal inheritance of the causative allele. The pipeline is made available as a user-friendly online tool to annotate variants and find haplogroup, disease association, and heteroplasmic sites. The "mit-o-matic" computational pipeline represents a comprehensive cloud-based tool for clinical evaluation of mitochondrial genomic variations from NGS datasets. The tool is freely available at http://genome.igib.res.in/mitomatic/.
Subject(s)
Computational Biology/methods , Genetic Variation , Genome, Mitochondrial , Genomics/methods , Mitochondria/genetics , Software , High-Throughput Nucleotide Sequencing , Humans , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/genetics , Molecular Sequence Annotation , Sequence Analysis, DNA/methodsABSTRACT
UNLABELLED: Accurate identification and characterization of infectious agent and its subtype is essential for efficient treatment of infectious diseases on a target population of patients. Comparative biology of microbial populations in vitro and in vivo can identify signatures that may be used to develop and improve diagnostic procedures. Here we report Genomic Signature Identification Tool (GSIT) a web based tool for identification and validation of genomic signatures in a group of similar DNA sequences of microorganisms. GSIT uses multiple sequence alignment to identify the unique base sites and scores them for inclusion as genomic signature for the particular strain. GSIT is a web based tool where the front-end in designed using HTML/CSS and Javascript, while back-end is run using CGI-Perl. AVAILABILITY: The server is freely available at the http://genome-sign.net/gsit.
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A large repertoire of gene-centric data has been generated in the field of zebrafish biology. Although the bulk of these data are available in the public domain, most of them are not readily accessible or available in nonstandard formats. One major challenge is to unify and integrate these widely scattered data sources. We tested the hypothesis that active community participation could be a viable option to address this challenge. We present here our approach to create standards for assimilation and sharing of information and a system of open standards for database intercommunication. We have attempted to address this challenge by creating a community-centric solution for zebrafish gene annotation. The Zebrafish GenomeWiki is a 'wiki'-based resource, which aims to provide an altruistic shared environment for collective annotation of the zebrafish genes. The Zebrafish GenomeWiki has features that enable users to comment, annotate, edit and rate this gene-centric information. The credits for contributions can be tracked through a transparent microattribution system. In contrast to other wikis, the Zebrafish GenomeWiki is a 'structured wiki' or rather a 'semantic wiki'. The Zebrafish GenomeWiki implements a semantically linked data structure, which in the future would be amenable to semantic search. Database URL: http://genome.igib.res.in/twiki.
Subject(s)
Crowdsourcing/methods , Genome/genetics , Internet , Molecular Sequence Annotation/methods , Zebrafish/genetics , Animals , Databases, GeneticABSTRACT
We describe here the draft genome sequence of Sporosarcina pasteurii, a urease-producing bacterium with potential applications in biocement production.
ABSTRACT
Mycobacterium tuberculosis, along with closely related species, commonly known as M. tuberculosis complex (MTBC), causes tuberculosis in humans and other organisms. Tuberculosis is a disease with high morbidity and mortality, especially in the third world. The genetic variability between clinical isolates of MTBC has been poorly understood, although recent years have seen the re-sequencing of a large number of clinical isolates of MTBC from around the world. The availability of genomic data of multiple isolates in public domain would potentially offer a unique opportunity toward understanding the variome of the organism and the functional consequences of the variations. This nevertheless has been limited by the lack of systematic curation and analysis of data sets available in public domain. In this report, we have re-analyzed re-sequencing data sets corresponding to >450 isolates of MTBC available in public domain to create a comprehensive variome map of MTBC comprising >29 000 single nucleotide variations. Using a systematic computational pipeline, we have annotated potential functional variants and drug-resistance-associated variants from the variome. We have made available this data set as a searchable database. Apart from a user-friendly interface, the database also has a novel option to annotate variants from clinical re-sequencing data sets of MTBC. To the best of our knowledge, tbvar is the largest and most comprehensive genome variation resources for MTBC. Database URL: http://genome.igib.res.in/tbvar/
Subject(s)
Databases, Genetic , Genetic Variation , Genome, Bacterial/genetics , Mycobacterium tuberculosis/genetics , Software , Humans , Internet , Molecular Sequence Annotation , Statistics as TopicABSTRACT
BACKGROUND: With a higher throughput and lower cost in sequencing, second generation sequencing technology has immense potential for translation into clinical practice and in the realization of pharmacogenomics based patient care. The systematic analysis of whole genome sequences to assess patient to patient variability in pharmacokinetics and pharmacodynamics responses towards drugs would be the next step in future medicine in line with the vision of personalizing medicine. METHODS: Genomic DNA obtained from a 55 years old, self-declared healthy, anonymous male of Malay descent was sequenced. The subject's mother died of lung cancer and the father had a history of schizophrenia and deceased at the age of 65 years old. A systematic, intuitive computational workflow/pipeline integrating custom algorithm in tandem with large datasets of variant annotations and gene functions for genetic variations with pharmacogenomics impact was developed. A comprehensive pathway map of drug transport, metabolism and action was used as a template to map non-synonymous variations with potential functional consequences. PRINCIPAL FINDINGS: Over 3 million known variations and 100,898 novel variations in the Malay genome were identified. Further in-depth pharmacogenetics analysis revealed a total of 607 unique variants in 563 proteins, with the eventual identification of 4 drug transport genes, 2 drug metabolizing enzyme genes and 33 target genes harboring deleterious SNVs involved in pharmacological pathways, which could have a potential role in clinical settings. CONCLUSIONS: The current study successfully unravels the potential of personal genome sequencing in understanding the functionally relevant variations with potential influence on drug transport, metabolism and differential therapeutic outcomes. These will be essential for realizing personalized medicine through the use of comprehensive computational pipeline for systematic data mining and analysis.