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154条结果
  • 机译 免疫基因组学时代的免疫检查点和癌症
    摘要:Immune checkpoints have been the subject of a wave of new studies. Among these checkpoints are tytotoxic T-lymphocyte-associated antigen 4, checkpoints programmed death-1 and programmed death-ligand 1; their blockades have been approved by the Food and Drug Administration for therapy of melanoma and other types of cancers. Immunogenomics, which combines the latest nucleic acid sequencing strategy with immunotherapy, provides precise information about genomic alterations (e.g. mutations) and enables a paradigm shift of immune checkpoint therapy from tumor types to molecular signatures. Studying these critical checkpoints in relation to genomic mutations and neoantigens has produced groundbreaking results. This article examines these studies and delves into the relationships between immune checkpoint blockade and tumors harboring certain genomic mutations. Moreover, this article reviews recent studies on resistance to immune checkpoint therapy.
  • 机译 miRNA与宿主基因之间的相互作用及其在癌症中的作用
    摘要:MicroRNAs (miRNAs) are small endogenous non-coding functional RNAs that post-transcriptionally regulate gene expression. They play essential roles in nearly all biological processes including cell development and differentiation, DNA damage repair, cell death as well as intercellular communication. They are highly involved in cancer, acting as tumor suppressors and/or promoters to modulate cell proliferation, epithelial-mesenchymal transition and tumor invasion and metastasis. Recent studies have shown that more than half of miRNAs are located within protein-coding or non-coding genes. Intragenic miRNAs and their host genes either share the promoter or have independent transcription. Meanwhile, miRNAs work as partners or antagonists of their host genes by fine-tuning their target genes functionally associated with host genes. This review outlined the complicated relationship between intragenic miRNAs and host genes. Focusing on miRNAs known as oncogenes or tumor suppressors in specific cancer types, it studied co-expression relationships between these miRNAs and host genes in the cancer types using TCGA data sets, which validated previous findings and revealed common, tumor-specific and even subtype-specific patterns. These observations will help understand the function of intragenic miRNAs and further develop miRNA therapeutics in cancer.
  • 机译 下一代测序技术加速了T细胞治疗癌症的进展
    摘要:Next-generation sequencing has produced a large quantity of DNA or RNA sequences related to the processes occurring within tumors and their microenvironment in a reasonable time and cost. These data have been used to guide the identification of neoantigens and to determine their specific T-cell receptors. Furthermore, adoptive T-cell therapy targeting neoantigens is under development for cancer treatment. In this review, we first provide an overview of sequencing technologies and the updated findings concerning neoantigens related to adoptive T-cell therapy and then summarize the methods and principles underlying the development of next-generation sequencing-based neoantigen-reactive T-cell therapy for cancer.
  • 机译 功能基因组学:为更成功的癌症免疫疗法铺平道路
    摘要:Immunotherapies have revolutionized cancer treatment. Immunotherapy is effective for the treatment of a wide range of cancer types and can mediate complete and durable tumor regression. Nonetheless, the field still faces many significant challenges, such as the need for personalized therapeutic strategies and better biomarkers, the difficulty of selecting the right combination therapy, and resistance to currently available immunotherapies. Both cancer and host immunity comprise significantly diverse and complex ecosystems, making immunogenomics an ideal field for functional genomics analysis. In this review, we describe the cancer–immunity cycle, how cancer cells manage to evade immune attack and the current hurdles in the path of cancer immunotherapy. Then, we discuss how functional genomics approaches can pave the way for more successful cancer immunotherapies.
  • 机译 单细胞基因组学
    • 作者:Martin Hemberg
    • 刊名:Briefings in Functional Genomics
    • 2018年第4期
    摘要:
  • 机译 将ChIP-seq与其他功能基因组学数据整合
    摘要:Transcription is regulated by transcription factor (TF) binding at promoters and distal regulatory elements and histone modifications that control the accessibility of these elements. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) has become the standard assay for identifying genome-wide protein–DNA interactions in vitro and in vivo. As large-scale ChIP-seq data sets have been collected for different TFs and histone modifications, their potential to predict gene expression can be used to test hypotheses about the mechanisms of gene regulation. In addition, complementary functional genomics assays provide a global view of chromatin accessibility and long-range cis-regulatory interactions that are being combined with TF binding and histone remodeling to study the regulation of gene expression. Thus, ChIP-seq analysis is now widely integrated with other functional genomics assays to better understand gene regulatory mechanisms. In this review, we discuss advances and challenges in integrating ChIP-seq data to identify context-specific chromatin states associated with gene activity. We describe the overall computational design of integrating ChIP-seq data with other functional genomics assays. We also discuss the challenges of extending these methods to low-input ChIP-seq assays and related single-cell assays.
  • 机译 单细胞RNA测序对了解免疫系统功能组织的影响
    摘要:Application of single-cell genomics technologies has revolutionized our approach to study the immune system. Unravelling the functional diversity of immune cells and their coordinated response is key to understanding immunity. Single-cell transcriptomics technologies provide high-dimensional assessment of the transcriptional states of immune cells and have been successfully applied to discover new immune cell types, reveal haematopoietic lineages, identify gene modules dictating immune responses and investigate lymphocyte antigen receptor diversity. In this review, we discuss the impact and applications of single-cell RNA sequencing technologies in immunology.
  • 机译 聚集单细胞:高和低深度单细胞RNA序列数据方法综述
    • 作者:Vilas Menon
    • 刊名:Briefings in Functional Genomics
    • 2018年第4期
    摘要:Advances in single-cell RNA-sequencing technology have resulted in a wealth of studies aiming to identify transcriptomic cell types in various biological systems. There are multiple experimental approaches to isolate and profile single cells, which provide different levels of cellular and tissue coverage. In addition, multiple computational strategies have been proposed to identify putative cell types from single-cell data. From a data generation perspective, recent single-cell studies can be classified into two groups: those that distribute reads shallowly over large numbers of cells and those that distribute reads more deeply over a smaller cell population. Although there are advantages to both approaches in terms of cellular and tissue coverage, it is unclear whether different computational cell type identification methods are better suited to one or the other experimental paradigm. This study reviews three cell type clustering algorithms, each representing one of three broad approaches, and finds that PCA-based algorithms appear most suited to low read depth data sets, whereas gene clustering-based and biclustering algorithms perform better on high read depth data sets. In addition, highly related cell classes are better distinguished by higher-depth data, given the same total number of reads; however, simultaneous discovery of distinct and similar types is better served by lower-depth, higher cell number data. Overall, this study suggests that the depth of profiling should be determined by initial assumptions about the diversity of cells in the population, and that the selection of clustering algorithm(s) subsequently based on the depth of profiling will allow for better identification of putative transcriptomic cell types.
  • 机译 以接近碱基对的分辨率解析蛋白质-DNA相互作用的见解
    • 作者:Bryan J Venters
    • 刊名:Briefings in Functional Genomics
    • 2018年第2期
    摘要:One of the central goals in molecular biology is to understand how cell-type-specific expression patterns arise through selective recruitment of RNA polymerase II (Pol II) to a subset of gene promoters. Pol II needs to be recruited to a precise genomic position at the proper time to produce messenger RNA from a DNA template. Ostensibly, transcription is a relatively simple cellular process; yet, experimentally measuring and then understanding the combinatorial possibilities of transcriptional regulators remain a daunting task. Since its introduction in 1985, chromatin immunoprecipitation (ChIP) has remained a key tool for investigating protein–DNA contacts in vivo. Over 30 years of intensive research using ChIP have provided numerous insights into mechanisms of gene regulation. As functional genomic technologies improve, they present new opportunities to address key biological questions. ChIP-exo is a refined version of ChIP-seq that significantly reduces background signal, while providing near base-pair mapping resolution for protein–DNA interactions. This review discusses the evolution of the ChIP assay over the years; the methodological differences between ChIP-seq, ChIP-exo and ChIP-nexus; and highlight new insights into epigenetic and transcriptional mechanisms that were uniquely enabled with the near base-pair resolution of ChIP-exo.
  • 机译 使用杂交捕获方法在染色质上捕获RNA
    摘要:The growing appreciation of the importance of long noncoding RNAs (lncRNAs), together with the awareness that some of these RNAs are associated with chromatin, has inspired the development of methods to detect their sites of interaction on a genome-wide scale at high resolution. Hybridization capture methods combine antisense oligonucleotide hybridization with enrichment of RNA from cross-linked chromatin extracts. These techniques have provided insight into lncRNA localization and the interactions of lncRNAs with protein to better understand biological roles of lncRNAs. Here, we review the core principles of hybridization capture methods, focusing on the three most commonly used protocols: capture hybridization analysis of RNA targets (CHART), chromatin isolation by RNA purification (ChIRP) and RNA affinity purification (RAP). We highlight the general principles of these techniques and discuss how differences in experimental procedures present distinct challenges to help researchers using these protocols or, more generally, interpreting the results of hybridization capture experiments.
  • 机译 单细胞测序在人类癌症中的应用
    摘要:Precision medicine is emerging as a cornerstone of future cancer care with the objective of providing targeted therapies based on the molecular phenotype of each individual patient. Traditional bulk-level molecular phenotyping of tumours leads to significant information loss, as the molecular profile represents an average phenotype over large numbers of cells, while cancer is a disease with inherent intra-tumour heterogeneity at the cellular level caused by several factors, including clonal evolution, tissue hierarchies, rare cells and dynamic cell states. Single-cell sequencing provides means to characterize heterogeneity in a large population of cells and opens up opportunity to determine key molecular properties that influence clinical outcomes, including prognosis and probability of treatment response. Single-cell sequencing methods are now reliable enough to be used in many research laboratories, and we are starting to see applications of these technologies for characterization of human primary cancer cells. In this review, we provide an overview of studies that have applied single-cell sequencing to characterize human cancers at the single-cell level, and we discuss some of the current challenges in the field.
  • 机译 全局和有针对性的单细胞转录组表征方法
    摘要:Analysing transcriptomes of cell populations is a standard molecular biology approach to understand how cells function. Recent methodological development has allowed performing similar experiments on single cells. This has opened up the possibility to examine samples with limited cell number, such as cells of the early embryo, and to obtain an understanding of heterogeneity within populations such as blood cell types or neurons. There are two major approaches for single-cell transcriptome analysis: quantitative reverse transcription PCR (RT-qPCR) on a limited number of genes of interest, or more global approaches targeting entire transcriptomes using RNA sequencing. RT-qPCR is sensitive, fast and arguably more straightforward, while whole-transcriptome approaches offer an unbiased perspective on a cell’s expression status.
  • 机译 线虫寄生虫的基因组基础
    • 作者:Mark Viney
    • 刊名:Briefings in Functional Genomics
    • 2018年第1期
    摘要:Nematodes are highly abundant animals, and many species have a parasitic lifestyle. Nematode parasites are important pathogens of humans and other animals, and there is considerable interest in understanding their molecular and genomic adaptations to nematode parasitism. This has been approached in three main ways: comparing the genomes of closely related parasitic and free-living taxa, comparing the gene expression of parasitic and free-living life cycle stages of parasitic nematode species, and analysing the molecules that parasitic nematodes excrete and secrete. To date, these studies show that many species of parasitic nematodes have genomes that have large gene families coding for proteases/peptidases, protease inhibitors, SCP/TAPS proteins and acetylcholinesterases, and in many cases there is evidence that these appear to be used by parasitic stages inside hosts, and are often secreted. Many parasitic nematodes have taxa-restricted gene families that also appear to be involved in parasitism, emphasizing that there is still much to be discovered about what it takes to be a parasitic nematode.
  • 机译 共享生物样本时的法律和道德合规
    摘要:When obtaining samples from biobanks, resolving ethical and legal concerns is a time-consuming task where researchers need to balance the needs of privacy, trust and scientific progress. The Biobanking and Biomolecular Resources Research Infrastructure-Large Prospective Cohorts project has resolved numerous such issues through intense communication between involved researchers and experts in its mission to unite large prospective study sets in Europe. To facilitate efficient communication, it is useful for nonexperts to have an at least basic understanding of the regulatory system for managing biological samples.Laws regulating research oversight are based on national law and normally share core principles founded on international charters. In interview studies among donors, chief concerns are privacy, efficient sample utilization and access to information generated from their samples. Despite a lack of clear evidence regarding which concern takes precedence, scientific as well as public discourse has largely focused on privacy concerns and the right of donors to control the usage of their samples.It is therefore important to proactively deal with ethical and legal issues to avoid complications that delay or prevent samples from being accessed. To help biobank professionals avoid making unnecessary mistakes, we have developed this basic primer covering the relationship between ethics and law, the concept of informed consent and considerations for returning findings to donors.
  • 机译 在风湿性疾病中翻译GWAS:建立与强直性脊柱炎遗传关联的机制和功能的方法
    摘要:Ankylosing spondylitis (AS) is a highly heritable chronic inflammatory arthritis characterized by osteoproliferation, fusion of affected joints and systemic manifestations. Many disease associations for AS have been reported through genome-wide association studies; however, identifying modulated genes and functional mechanism remains challenging. This review summarizes current genetic associations involving AS and describes strategic approaches for functional follow-up of disease-associated variants. Fine mapping using methods leveraging Bayesian approaches are outlined. Evidence highlighting the importance of context specificity for regulatory variants is reviewed, noting current evidence in AS for the relevant cell and tissue type to conduct such analyses. Technological advances for understanding the regulatory landscape within which functional variants may act are discussed using exemplars. Approaches include defining regulatory elements based on chromatin accessibility, effects of variants on genes at a distance through evidence of physical interactions (chromatin conformation capture), expression quantitative trait loci mapping and single-cell methodologies. Opportunities for mechanistic studies to investigate the function of specific variants, regulatory elements and genes enabled by genome editing using clustered regularly interspaced short palindromic repeats/Cas9 are also described. Further progress in our understanding of the genetics of AS through functional genomic and epigenomic approaches offers new opportunities to understand mechanism and develop innovative treatments.
  • 机译 基因组学在促进基因库植物遗传资源利用中的作用
    摘要:Global efforts have seen the world’s plant genetic resources (PGRs) conserved in about 1625 germ plasm repositories. Utility of these resources is important in increasing the resilience and productivity of agricultural production systems. However, despite their importance, utility of these resources has been poor. This article reviews the real and potential application of the current advances in genomic technologies in improving the utilization of these resources. The actual and potential application of these genomic approaches in plant identification, phylogenetic analysis, analysing the genetic value of germ plasm, facilitating germ plasm selection in genebanks as well as instilling confidence in international germ plasm exchange system is discussed. We note that if genebanks are to benefit from this genomic revolution, there is need for fundamental changes in the way genebanks are managed, perceived, organized and funded. Increased collaboration between genebank managers and the user community is also recommended
  • 机译 定量单细胞转录组学
    摘要:Single-cell RNA sequencing (scRNA-seq) is currently transforming our understanding of biology, as it is a powerful tool to resolve cellular heterogeneity and molecular networks. Over 50 protocols have been developed in recent years and also data processing and analyzes tools are evolving fast. Here, we review the basic principles underlying the different experimental protocols and how to benchmark them. We also review and compare the essential methods to process scRNA-seq data from mapping, filtering, normalization and batch corrections to basic differential expression analysis. We hope that this helps to choose appropriate experimental and computational methods for the research question at hand.
  • 机译 通过全基因组重复的痕迹推断祖先脊椎动物的表型
    摘要:Inferring the phenotype of the last common ancestor of living vertebrates is a challenging problem because of several unresolvable factors. They include the lack of reliable out-groups of living vertebrates, poor information about less fossilizable organs and specialized traits of phylogenetically important species, such as lampreys and hagfishes (e.g. secondary loss of vertebrae in adult hagfishes). These factors undermine the reliability of ancestral reconstruction by traditional character mapping approaches based on maximum parsimony. In this article, we formulate an approach to hypothesizing ancestral vertebrate phenotypes using information from the phylogenetic and functional properties of genes duplicated by genome expansions in early vertebrate evolution. We named the conjecture as ‘chronological reconstruction of ohnolog functions (CHROF)’. This CHROF conjecture raises the possibility that the last common ancestor of living vertebrates may have had more complex traits than currently thought.
  • 机译 修剪树枝:功能基因组学和真核基因调控的进化
    摘要:Advances in the methods for detecting protein–DNA interactions have played a key role in determining the directions of research into the mechanisms of transcriptional regulation. The most recent major technological transformation happened a decade ago, with the move from using tiling arrays [chromatin immunoprecipitation (ChIP)-on-Chip] to high-throughput sequencing (ChIP-seq) as a readout for ChIP assays. In addition to the numerous other ways in which it is superior to arrays, by eliminating the need to design and manufacture them, sequencing also opened the door to carrying out comparative analyses of genome-wide transcription factor occupancy across species and studying chromatin biology in previously less accessible model and nonmodel organisms, thus allowing us to understand the evolution and diversity of regulatory mechanisms in unprecedented detail. Here, we review the biological insights obtained from such studies in recent years and discuss anticipated future developments in the field.
  • 机译 从单细胞组学数据映射基因调控网络
    摘要:Single-cell techniques are advancing rapidly and are yielding unprecedented insight into cellular heterogeneity. Mapping the gene regulatory networks (GRNs) underlying cell states provides attractive opportunities to mechanistically understand this heterogeneity. In this review, we discuss recently emerging methods to map GRNs from single-cell transcriptomics data, tackling the challenge of increased noise levels and data sparsity compared with bulk data, alongside increasing data volumes. Next, we discuss how new techniques for single-cell epigenomics, such as single-cell ATAC-seq and single-cell DNA methylation profiling, can be used to decipher gene regulatory programmes. We finally look forward to the application of single-cell multi-omics and perturbation techniques that will likely play important roles for GRN inference in the future.

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