Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 107
Filtrar
1.
EBioMedicine ; 82: 104161, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35841873

RESUMO

BACKGROUND: Ocular diseases may exhibit common clinical symptoms and epidemiological comorbidity. However, the extent of pleiotropic mechanisms across ocular diseases remains unclear. We aim to examine shared genetic etiology in age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma, retinal detachment (RD), and myopia. METHODS: We analyzed genome-wide association analyses for the five ocular diseases in 43,877 cases and 44,373 controls of European ancestry from UK Biobank, estimated their genetic relationships (LDSC, GNOVA, and Genomic SEM), and identified pleiotropic loci (ASSET and METASOFT). FINDINGS: The genetic correlation of common SNPs revealed a meaningful genetic structure within these diseases, identifying genetic correlations between AMD, DR, and glaucoma. Cross-trait meta-analysis identified 23 pleiotropic loci associated with at least two ocular diseases and 14 loci unique to individual disorders (non-pleiotropic). We found that the genes associated with these shared genetic loci are involved in neuron differentiation (P = 8.80 × 10-6) and eye development systems (P = 3.86 × 10-5), and single cell RNA sequencing data reveals their heightened gene expression from multipotent progenitors to other differentiated retinal cells during retina developmental process. INTERPRETATION: These results highlighted the potential common genetic architectures among these ocular diseases and can deepen the understanding of the molecular mechanisms underlying the related diseases. FUNDING: The National Natural Science Foundation of China (61871294), Zhejiang Provincial Natural Science Foundation of China (LR19C060001), and the Scientific Research Foundation for Talents of Wenzhou Medical University (QTJ18023).


Assuntos
Retinopatia Diabética , Glaucoma , Degeneração Macular , Bancos de Espécimes Biológicos , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Glaucoma/epidemiologia , Glaucoma/genética , Humanos , Degeneração Macular/epidemiologia , Degeneração Macular/genética , Miopia , Polimorfismo de Nucleotídeo Único , Descolamento Retiniano , Reino Unido/epidemiologia
2.
Comput Struct Biotechnol J ; 20: 2648-2656, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35685368

RESUMO

Adenosine-to-inosine (A-to-I) RNA editing leads to functional change of neurotransmitter receptor which is essential for neurotransmission and normal neuronal development. As a highly accessible part of central nervous system, retina has been extensively studied, however, it remains largely unknown how RNA editing regulates its development. Here, a genome-wide screening of high-confidence RNA editing events were performed to decipher the dynamic transcriptome regulation by RNA editing during mouse retinal development. 2000 high-confidence editing sites across eight developmental stages of retina were called. Three unique patterns (RNA-editinghigh pattern, RNA-editingmedium pattern and RNA-editinglow pattern) were identified by clustering these editing sites based on their editing level during retinal development. Editing events from RNA-editinghigh pattern were significantly associated with glutamate receptors and regulated synaptic transmission. Interestingly, most non-synonymous high-editing sites were mapped to ion channel genes of glutamatergic synapse which were associated with neurotransmission by controlling ion channel permeability and affecting exocytosis. Meanwhile, these non-synonymous editing sites were evolutionarily conserved and exhibited a consistently increasing editing levels between mouse and human retinal development. Single-cell RNA-seq data analysis revealed that RNA editing events prefer to occur in two main cell types including bipolar and amacrine cells. Genes with non-synonymous high-editing sites were enriched in both bipolar cells and retina ganglion cells, which may mediate retina ganglion cell differentiation by altering channel ion permeability. Together, our results provide novel insights into mechanism of post-transcriptional regulation during retinal development and help to develop novel RNA editing-guided therapeutic strategies for retinal disorders.

3.
Sci Total Environ ; 833: 155013, 2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-35381251

RESUMO

Dissolved inorganic carbon (DIC) and its stable isotope (δ13C-DIC) are important parameters for studying carbon cycling in aquatic environments. Traditional methods based on isotope-ratio mass spectrometers are labor-intensive and not easily deployable at field sites. Here we report the performance of a method that simultaneously measures DIC concentration and its stable isotope by using a CO2 extraction device and a Cavity Ring-Down Spectroscopy (CRDS) detector. A multi-port valve is used to increase sample throughput and improve precision. The instrument achieves average precisions of better than ±1.95 µmol kg-1 and ±0.06‰, respectively, for DIC and δ13C-DIC in seawater based on three injections for each sample. We also provide recommendations on how to precisely determine δ13C-DIC samples with a wide range of DIC content in different types of waters by examining injection volume and concentration effects. This technique was applied to study carbon cycling in the Delaware Estuary. It demonstrates that a simultaneous and precise determination of both DIC and δ13C-DIC is a powerful and effective approach for constraining the processes controlling aquatic carbon cycling and CO2 fluxes. Both laboratory tests and field applications confirmed that this system can be used with high precision to study carbon cycling in various aquatic environments.


Assuntos
Dióxido de Carbono , Carbono , Isótopos de Carbono/análise , Dacarbazina , Água do Mar/química
4.
Genome Med ; 14(1): 21, 2022 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-35209950

RESUMO

BACKGROUND: Identifying breast cancer patients with DNA repair pathway-related germline pathogenic variants (GPVs) is important for effectively employing systemic treatment strategies and risk-reducing interventions. However, current criteria and risk prediction models for prioritizing genetic testing among breast cancer patients do not meet the demands of clinical practice due to insufficient accuracy. METHODS: The study population comprised 3041 breast cancer patients enrolled from seven hospitals between October 2017 and 11 August 2019, who underwent germline genetic testing of 50 cancer predisposition genes (CPGs). Associations among GPVs in different CPGs and endophenotypes were evaluated using a case-control analysis. A phenotype-based GPV risk prediction model named DNA-repair Associated Breast Cancer (DrABC) was developed based on hierarchical neural network architecture and validated in an independent multicenter cohort. The predictive performance of DrABC was compared with currently used models including BRCAPRO, BOADICEA, Myriad, PENN II, and the NCCN criteria. RESULTS: In total, 332 (11.3%) patients harbored GPVs in CPGs, including 134 (4.6%) in BRCA2, 131 (4.5%) in BRCA1, 33 (1.1%) in PALB2, and 37 (1.3%) in other CPGs. GPVs in CPGs were associated with distinct endophenotypes including the age at diagnosis, cancer history, family cancer history, and pathological characteristics. We developed a DrABC model to predict the risk of GPV carrier status in BRCA1/2 and other important CPGs. In predicting GPVs in BRCA1/2, the performance of DrABC (AUC = 0.79 [95% CI, 0.74-0.85], sensitivity = 82.1%, specificity = 63.1% in the independent validation cohort) was better than that of previous models (AUC range = 0.57-0.70). In predicting GPVs in any CPG, DrABC (AUC = 0.74 [95% CI, 0.69-0.79], sensitivity = 83.8%, specificity = 51.3% in the independent validation cohort) was also superior to previous models in their current versions (AUC range = 0.55-0.65). After training these previous models with the Chinese-specific dataset, DrABC still outperformed all other methods except for BOADICEA, which was the only previous model with the inclusion of pathological features. The DrABC model also showed higher sensitivity and specificity than the NCCN criteria in the multi-center validation cohort (83.8% and 51.3% vs. 78.8% and 31.2%, respectively, in predicting GPVs in any CPG). The DrABC model implementation is available online at http://gifts.bio-data.cn/ . CONCLUSIONS: By considering the distinct endophenotypes associated with different CPGs in breast cancer patients, a phenotype-driven prediction model based on hierarchical neural network architecture was created for identification of hereditary breast cancer. The model achieved superior performance in identifying GPV carriers among Chinese breast cancer patients.


Assuntos
Neoplasias da Mama , Aprendizado Profundo , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Reparo do DNA , Feminino , Predisposição Genética para Doença , Células Germinativas , Mutação em Linhagem Germinativa , Humanos , Mutação , Fenótipo
5.
RNA Biol ; 19(1): 290-304, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35130112

RESUMO

Simultaneous measurement of multiple modalities in single-cell analysis, represented by CITE-seq, is a promising approach to link transcriptional changes to cellular phenotype and function, requiring new computational methods to define cellular subtypes and states based on multiple data types. Here, we design a flexible single-cell multimodal analysis framework, called CITEMO, to integrate the transcriptome and antibody-derived tags (ADT) data to capture cell heterogeneity from the multi omics perspective. CITEMO uses Principal Component Analysis (PCA) to obtain a low-dimensional representation of the transcriptome and ADT, respectively, and then employs PCA again to integrate these low-dimensional multimodal data for downstream analysis. To investigate the effectiveness of the CITEMO framework, we apply CITEMO to analyse the cell subtypes of Cord Blood Mononuclear Cells (CBMC) samples. Results show that the CITEMO framework can comprehensively analyse single-cell multimodal samples and accurately identify cell subtypes. Besides, we find some specific immune cells that co-express multiple ADT markers. To better describe the co-expression phenomenon, we introduce the co-expression entropy to measure the heterogeneous distribution of the ADT combinations. To further validate the robustness of the CITEMO framework, we analyse Human Bone Marrow Cell (HBMC) samples and identify different states of the same cell type. CITEMO has an excellent performance in identifying cell subtypes and states for multimodal omics data. We suggest that the flexible design idea of CITEMO can be an inspiration for other single-cell multimodal tasks. The complete source code and dataset of the CITEMO framework can be obtained from https://github.com/studentiz/CITEMO.


Assuntos
Biologia Computacional/métodos , Heterogeneidade Genética , Sistema Imunitário/citologia , Sistema Imunitário/metabolismo , Análise de Célula Única/métodos , Software , Linhagem da Célula/genética , Regulação da Expressão Gênica , Genômica/métodos , Humanos , Sistema Imunitário/imunologia
6.
Genome Med ; 14(1): 16, 2022 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-35172892

RESUMO

BACKGROUND: Understanding the host genetic architecture and viral immunity contributes to the development of effective vaccines and therapeutics for controlling the COVID-19 pandemic. Alterations of immune responses in peripheral blood mononuclear cells play a crucial role in the detrimental progression of COVID-19. However, the effects of host genetic factors on immune responses for severe COVID-19 remain largely unknown. METHODS: We constructed a computational framework to characterize the host genetics that influence immune cell subpopulations for severe COVID-19 by integrating GWAS summary statistics (N = 969,689 samples) with four independent scRNA-seq datasets containing healthy controls and patients with mild, moderate, and severe symptom (N = 606,534 cells). We collected 10 predefined gene sets including inflammatory and cytokine genes to calculate cell state score for evaluating the immunological features of individual immune cells. RESULTS: We found that 34 risk genes were significantly associated with severe COVID-19, and the number of highly expressed genes increased with the severity of COVID-19. Three cell subtypes that are CD16+monocytes, megakaryocytes, and memory CD8+T cells were significantly enriched by COVID-19-related genetic association signals. Notably, three causal risk genes of CCR1, CXCR6, and ABO were highly expressed in these three cell types, respectively. CCR1+CD16+monocytes and ABO+ megakaryocytes with significantly up-regulated genes, including S100A12, S100A8, S100A9, and IFITM1, confer higher risk to the dysregulated immune response among severe patients. CXCR6+ memory CD8+ T cells exhibit a notable polyfunctionality including elevation of proliferation, migration, and chemotaxis. Moreover, we observed an increase in cell-cell interactions of both CCR1+ CD16+monocytes and CXCR6+ memory CD8+T cells in severe patients compared to normal controls among both PBMCs and lung tissues. The enhanced interactions of CXCR6+ memory CD8+T cells with epithelial cells facilitate the recruitment of this specific population of T cells to airways, promoting CD8+T cell-mediated immunity against COVID-19 infection. CONCLUSIONS: We uncover a major genetics-modulated immunological shift between mild and severe infection, including an elevated expression of genetics-risk genes, increase in inflammatory cytokines, and of functional immune cell subsets aggravating disease severity, which provides novel insights into parsing the host genetic determinants that influence peripheral immune cells in severe COVID-19.


Assuntos
Linfócitos T CD8-Positivos/virologia , COVID-19/genética , COVID-19/patologia , Monócitos/virologia , Análise de Célula Única/métodos , COVID-19/imunologia , Biologia Computacional/métodos , Proteínas Ligadas por GPI/metabolismo , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Células Progenitoras de Megacariócitos/imunologia , Células Progenitoras de Megacariócitos/virologia , Monócitos/metabolismo , Locos de Características Quantitativas , Receptores CCR1/imunologia , Receptores CCR1/metabolismo , Receptores CXCR6/imunologia , Receptores CXCR6/metabolismo , Receptores de IgG/metabolismo , Análise de Sequência de RNA , Índice de Gravidade de Doença
7.
Am J Hum Genet ; 109(2): 270-281, 2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-35063063

RESUMO

In recent years, exome sequencing (ES) has shown great utility in the diagnoses of Mendelian disorders. However, after rigorous filtering, a typical ES analysis still involves the interpretation of hundreds of variants, which greatly hinders the rapid identification of causative genes. Since the interpretations of ES data require comprehensive clinical analyses, taking clinical expertise into consideration can speed the molecular diagnoses of Mendelian disorders. To leverage clinical expertise to prioritize candidate genes, we developed PhenoApt, a phenotype-driven gene prioritization tool that allows users to assign a customized weight to each phenotype, via a machine-learning algorithm. Using the ability to rank causative genes in top-10 lists as an evaluation metric, baseline analysis demonstrated that PhenoApt outperformed previous phenotype-driven gene prioritization tools by a relative increase of 22.7%-140.0% in three independent, real-world, multi-center cohorts (cohort 1, n = 185; cohort 2, n = 784; and cohort 3, n = 208). Additional trials showed that, by adding weights to clinical indications, which should be explained by the causative gene, PhenoApt performance was improved by a relative increase of 37.3% in cohort 2 (n = 471) and 21.4% in cohort 3 (n = 208). Moreover, PhenoApt could assign an intrinsic weight to each phenotype based on the likelihood of its being a Mendelian trait using term frequency-inverse document frequency techniques. When clinical indications were assigned with intrinsic weights, PhenoApt performance was improved by a relative increase of 23.7% in cohort 2 and 15.5% in cohort 3. For the integration of PhenoApt into clinical practice, we developed a user-friendly website and a command-line tool.


Assuntos
Doenças Genéticas Inatas/genética , Perda Auditiva Neurossensorial/genética , Deficiência Intelectual/genética , Aprendizado de Máquina , Microcefalia/genética , Nistagmo Congênito/genética , Escoliose/genética , Estudos de Coortes , Biologia Computacional , Bases de Dados Genéticas , Exoma , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/patologia , Testes Genéticos , Genótipo , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/patologia , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Microcefalia/diagnóstico , Microcefalia/patologia , Nistagmo Congênito/diagnóstico , Nistagmo Congênito/patologia , Fenótipo , Escoliose/diagnóstico , Escoliose/patologia , Software , Sequenciamento Completo do Exoma
8.
Nucleic Acids Res ; 50(D1): D848-D857, 2022 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-34551435

RESUMO

From industry to food to health, bacteria play an important role in all facets of life. Some of the most important bacteria have been purposely engineered to produce commercial quantities of antibiotics and therapeutics, and non-classical secretion systems are at the forefront of these technologies. Unlike the classical Sec or Tat pathways, non-classically secreted proteins share few common characteristics and use much more diverse secretion pathways for protein transport. Systematically categorizing and investigating the non-classically secreted proteins will enable a deeper understanding of their associated secretion mechanisms and provide a landscape of the Gram-positive secretion pathway distribution. We therefore developed PncsHub (https://pncshub.erc.monash.edu/), the first universal platform for comprehensively annotating and analyzing Gram-positive bacterial non-classically secreted proteins. PncsHub catalogs 4,914 non-classically secreted proteins, which are delicately categorized into 8 subtypes (including the 'unknown' subtype) and annotated with data compiled from up to 26 resources and visualisation tools. It incorporates state-of-the-art predictors to identify new and homologous non-classically secreted proteins and includes three analytical modules to visualise the relationships between known and putative non-classically secreted proteins. As such, PncsHub aims to provide integrated services for investigating, predicting and identifying non-classically secreted proteins to promote hypothesis-driven laboratory-based experiments.


Assuntos
Proteínas de Bactérias/genética , Bases de Dados de Proteínas , Bactérias Gram-Positivas/genética , Interface Usuário-Computador , Proteínas de Bactérias/classificação , Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica , Bactérias Gram-Positivas/classificação , Bactérias Gram-Positivas/metabolismo , Internet , Anotação de Sequência Molecular , Filogenia , Transporte Proteico
9.
Signal Transduct Target Ther ; 7(1): 53, 2022 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-35210398

RESUMO

This study investigates aberrant DNA methylations as potential diagnosis and prognosis markers for esophageal squamous-cell carcinoma (ESCC), which if diagnosed at advanced stages has <30% five-year survival rate. Comparing genome-wide methylation sites of 91 ESCC and matched adjacent normal tissues, we identified 35,577 differentially methylated CpG sites (DMCs) and characterized their distribution patterns. Integrating whole-genome DNA and RNA-sequencing data of the same samples, we found multiple dysregulated transcription factors and ESCC-specific genomic correlates of identified DMCs. Using featured DMCs, we developed a 12-marker diagnostic panel with high accuracy in our dataset and the TCGA ESCC dataset, and a 4-marker prognostic panel distinguishing high-risk patients. In-vitro experiments validated the functions of 4 marker host genes. Together these results provide additional evidence for the important roles of aberrant DNA methylations in ESCC development and progression. Our DMC-based diagnostic and prognostic panels have potential values for clinical care of ESCC, laying foundations for developing targeted methylation assays for future non-invasive cancer detection methods.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Ilhas de CpG/genética , DNA , Metilação de DNA/genética , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Humanos , Prognóstico
10.
Front Microbiol ; 12: 770191, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34867904

RESUMO

Coagulase-negative Staphylococcus (CoNS) is the most common pathogen causing traumatic endophthalmitis. Among which, Staphylococcus epidermidis is the most common species that colonizes human skin, eye surfaces, and nasal cavity. It is also the main cause of nosocomial infection, specially foreign body-related bloodstream infections (FBR-BSIs). Although some studies have reported the genome characteristics of S. epidermidis, the genome of ocular trauma-sourced S. epidermidis strain and a comprehensive understanding of its pathogenicity are still lacking. Our study sequenced, analyzed, and reported the whole genomes of 11 ocular trauma-sourced samples of S. epidermidis that caused traumatic endophthalmitis. By integrating publicly available genomes, we obtained a total of 187 S. epidermidis samples from healthy and diseased eyes, skin, respiratory tract, and blood. Combined with pan-genome, phylogenetic, and comparative genomic analyses, our study showed that S. epidermidis, regardless of niche source, exhibits two founder lineages with different pathogenicity. Moreover, we identified several potential biomarkers associated with the virulence of S. epidermidis, including essD, uhpt, sdrF, sdrG, fbe, and icaABCDR. EssD and uhpt have high homology with esaD and hpt in Staphylococcus aureus, showing that the genomes of S. epidermidis and S. aureus may have communicated during evolution. SdrF, sdrG, fbe, and icaABCDR are related to biofilm formation. Compared to S. epidermidis from blood sources, ocular-sourced strains causing intraocular infection had no direct relationship with biofilm formation. In conclusion, this study provided additional data resources for studies on S. epidermidis and improved our understanding of the evolution and pathogenicity among strains of different sources.

11.
J Nanobiotechnology ; 19(1): 406, 2021 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-34872583

RESUMO

BACKGROUND: Primary biliary cholangitis (PBC) is a classical autoimmune disease, which is highly influenced by genetic determinants. Many genome-wide association studies (GWAS) have reported that numerous genetic loci were significantly associated with PBC susceptibility. However, the effects of genetic determinants on liver cells and its immune microenvironment for PBC remain unclear. RESULTS: We constructed a powerful computational framework to integrate GWAS summary statistics with scRNA-seq data to uncover genetics-modulated liver cell subpopulations for PBC. Based on our multi-omics integrative analysis, 29 risk genes including ORMDL3, GSNK2B, and DDAH2 were significantly associated with PBC susceptibility. By combining GWAS summary statistics with scRNA-seq data, we found that cholangiocytes exhibited a notable enrichment by PBC-related genetic association signals (Permuted P < 0.05). The risk gene of ORMDL3 showed the highest expression proportion in cholangiocytes than other liver cells (22.38%). The ORMDL3+ cholangiocytes have prominently higher metabolism activity score than ORMDL3- cholangiocytes (P = 1.38 × 10-15). Compared with ORMDL3- cholangiocytes, there were 77 significantly differentially expressed genes among ORMDL3+ cholangiocytes (FDR < 0.05), and these significant genes were associated with autoimmune diseases-related functional terms or pathways. The ORMDL3+ cholangiocytes exhibited relatively high communications with macrophage and monocyte. Compared with ORMDL3- cholangiocytes, the VEGF signaling pathway is specific for ORMDL3+ cholangiocytes to interact with other cell populations. CONCLUSIONS: To the best of our knowledge, this is the first study to integrate genetic information with single cell sequencing data for parsing genetics-influenced liver cells for PBC risk. We identified that ORMDL3+ cholangiocytes with higher metabolism activity play important immune-modulatory roles in the etiology of PBC.


Assuntos
Sistema Biliar , Cirrose Hepática Biliar , Proteínas de Membrana/genética , Análise de Célula Única/métodos , Sistema Biliar/citologia , Sistema Biliar/metabolismo , Células Cultivadas , Estudo de Associação Genômica Ampla , Humanos , Cirrose Hepática Biliar/genética , Cirrose Hepática Biliar/metabolismo , Proteínas de Membrana/metabolismo , RNA-Seq
12.
Proc Natl Acad Sci U S A ; 118(43)2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34663731

RESUMO

The genetic origins of nanoscale extracellular vesicles in our body fluids remains unclear. Here, we perform a tracking analysis of urinary exosomes via RNA sequencing, revealing that urine exosomes mostly express tissue-specific genes for the bladder and have close cell-genetic relationships to the endothelial cell, basal cell, monocyte, and dendritic cell. Tracking the differentially expressed genes of cancers and corresponding enrichment analysis show urine exosomes are intensively involved in immune activities, indicating that they may be harnessed as reliable biomarkers of noninvasive liquid biopsy in cancer genomic diagnostics and precision medicine.


Assuntos
Exossomos/metabolismo , Neoplasias/patologia , Urina , Humanos , Biópsia Líquida , Neoplasias/metabolismo
13.
Clin Epigenetics ; 13(1): 197, 2021 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-34689838

RESUMO

BACKGROUND: 5-Hydroxymethylcytosine (5hmC) is a significant DNA epigenetic modification. However, the 5hmC modification alterations in genomic regions encoding long non-coding RNA (lncRNA) and their clinical significance remain poorly characterized. RESULTS: A three-phase discovery-modeling-validation study was conducted to explore the potential of the plasma-derived 5hmC modification level in genomic regions encoding lncRNAs as a superior alternative biomarker for cancer diagnosis and surveillance. Genome-wide 5hmC profiles in the plasma circulating cell-free DNA of 1632 cancer and 1379 non-cancerous control samples from different cancer types and multiple centers were repurposed and characterized. A large number of altered 5hmC modifications were distributed at genomic regions encoding lncRNAs in cancerous compared with healthy subjects. Furthermore, most 5hmC-modified lncRNA genes were cancer-specific, with only a relatively small number of 5hmC-modified lncRNA genes shared by various cancer types. A 5hmC-LncRNA diagnostic score (5hLD-score) comprising 39 tissue-shared 5hmC-modified lncRNA gene markers was developed using elastic net regularization. The 5hLD-score was able to accurately distinguish tumors from healthy controls with an area under the curve (AUC) of 0.963 [95% confidence interval (CI) 0.940-0.985] and 0.912 (95% CI 0.837-0.987) in the training and internal validation cohorts, respectively. Results from three independent validations confirmed the robustness and stability of the 5hLD-score with an AUC of 0.851 (95% CI 0.786-0.916) in Zhang's non-small cell lung cancer cohort, AUC of 0.887 (95% CI 0.852-0.922) in Tian's esophageal cancer cohort, and AUC of 0.768 (95% CI 0.746-0.790) in Cai's hepatocellular carcinoma cohort. In addition, a significant association was identified between the 5hLD-score and the progression from hepatitis to liver cancer. Finally, lncRNA genes modified by tissue-specific 5hmC alteration were again found to be capable of identifying the origin and location of tumors. CONCLUSION: The present study will contribute to the ongoing effort to understand the transcriptional programs of lncRNA genes, as well as facilitate the development of novel invasive genomic tools for early cancer detection and surveillance.


Assuntos
5-Metilcitosina/análogos & derivados , Detecção Precoce de Câncer/métodos , Neoplasias/diagnóstico , 5-Metilcitosina/análise , Ácidos Nucleicos Livres/análise , Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/genética , Progressão da Doença , Detecção Precoce de Câncer/estatística & dados numéricos , Humanos , Neoplasias/genética , RNA Longo não Codificante/análise , RNA Longo não Codificante/sangue , RNA Longo não Codificante/genética
15.
NPJ Genom Med ; 6(1): 65, 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381055

RESUMO

Trimethylation of histone H3 lysine 27 trimethylation (H3K27me3) may be recruited by repressive Polycomb complexes to mediate gene silencing, which is critical for maintaining embryonic stem cell pluripotency and differentiation. However, the roles of aberrant H3K27me3 patterns in tumorigenesis are not fully understood. Here, we discovered that grand silencer domains (breadth > 50 kb) for H3K27me3 were significantly associated with epithelial cell differentiation and exhibited high gene essentiality and conservation in human esophageal epithelial cells. These grand H3K27me3 domains exhibited high modification signals involved in gene silencing, and preferentially occupied the entirety of topologically associating domains and interact with each other. We found that widespread loss of the grand H3K27me3 domains in of esophageal squamous cell carcinomas (ESCCs) were enriched in genes involved in epithelium and endothelium differentiation, which were significantly associated with overexpression with increase of active modifications of H3K4me3, H3K4me1, and H3K27ac marks, as well as DNA hypermethylation in the gene bodies. A total of 208 activated genes with loss of grand H3K27me3 domains in ESCC were identified, where the higher expression and mutation of T-box transcription factor 20 (TBX20) were associated with worse patients' outcomes. Our results showed that knockdown of TBX20 may have led to a striking defect in esophageal cancer cell growth and carcinogenesis-related pathway, including cell cycle and homologous recombination. Together, our results reveal that loss of grand H3K27me3 domains represent a catalog of remarkable activating regulators involved in carcinogenesis.

16.
Eye Vis (Lond) ; 8(1): 31, 2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34407890

RESUMO

BACKGROUND: Myopia is the most common visual impairment in children and adolescents worldwide. This study described an economical and effective population-based screening pipeline and performed the project of a million scale children and adolescents myopia survey (CAMS), which will shed light on the further study of myopia from the level of epidemiology and precision medicine. METHODS: We developed a novel population-based screening pattern, an intelligent screening process and internet-based information transmission and analysis system to carry out the survey consisting of school children in Wenzhou, China. The examination items include unaided distance visual acuity, presenting distance visual acuity, and non-cycloplegic autorefraction. Myopia and high myopia were defined as spherical equivalent (SE) ≤ - 1.00 diopters (D) and SE ≤ - 6.00 D, respectively. Next, the reports of the vision checking were automatically sent to parents and the related departments. The CAMS project will be done two to four times annually with the support of the government. An online eyesight status information management system (OESIMS) was developed to construct comprehensive and efficient electronic vision health records (EVHRs) for myopia information inquiry, risk pre-warning, and further study. RESULTS: The CAMS completed the first-round of screening within 30 days for 99.41% of Wenzhou students from districts and counties, in June 2019. A total of 1,060,925 participants were eligible for CAMS and 1,054,251 (99.37% participation rate) were selected through data quality control, which comprised 1305 schools, and 580,609, 251,050 and 170,967 elementary, middle, and high school students. The mean age of participants was 12.21 ± 3.32 years (6-20 years), the female-to-male ratio was 0.82. The prevalence of myopia in elementary, middle, and high school students was 38.16%, 77.52%, and 84.00%, respectively, and the high myopia incidence was 0.95%, 6.90%, and 12.98%. CONCLUSIONS: The CAMS standardized myopia screening model involves automating large-scale information collection, data transmission, data analysis and early warning, thereby supporting myopia prevention and control. The entire survey reduced 90% of staff, cost, and time consumption compared with previous surveys. This will provide new insights for decision support for public health intervention.

17.
Nat Commun ; 12(1): 4457, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294701

RESUMO

The role of cis-elements and their aberrations remains unclear in esophageal squamous cell carcinoma (ESCC, further abbreviated EC). Here we survey 28 H3K27ac-marked active enhancer profiles and 50 transcriptomes in primary EC, metastatic lymph node cancer (LNC), and adjacent normal (Nor) esophageal tissues. Thousands of gained or lost enhancers and hundreds of altered putative super-enhancers are identified in EC and LNC samples respectively relative to Nor, with a large number of common gained or lost enhancers. Moreover, these differential enhancers contribute to the transcriptomic aberrations in ECs and LNCs. We also reveal putative driver onco-transcription factors, depletion of which diminishes cell proliferation and migration. The administration of chemical inhibitors to suppress the predicted targets of gained super-enhances reveals HSP90AA1 and PDE4B as potential therapeutic targets for ESCC. Thus, our epigenomic profiling reveals a compendium of reprogrammed cis-regulatory elements during ESCC carcinogenesis and metastasis for uncovering promising targets for cancer treatment.


Assuntos
Elementos Facilitadores Genéticos , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Idoso , Carcinogênese/genética , Linhagem Celular Tumoral , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/secundário , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Código das Histonas/genética , Humanos , Metástase Linfática/genética , Masculino , Pessoa de Meia-Idade , Oncogenes , Fatores de Transcrição/genética
18.
Bioinformatics ; 2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34185079

RESUMO

MOTIVATION: The mathematically optimal solution in computational protein folding simulations does not always correspond to the native structure, due to the imperfection of the energy force fields. There is therefore a need to search for more diverse suboptimal solutions in order to identify the states close to the native. We propose a novel multimodal optimization protocol to improve the conformation sampling efficiency and modeling accuracy of de novo protein structure folding simulations. RESULTS: A distance-assisted multimodal optimization sampling algorithm, MMpred, is proposed for de novo protein structure prediction. The protocol consists of three stages. In the first modal exploration stage, a structural similarity evaluation model DMscore is designed to control the diversity of conformations, generating a population of diverse structures in different low-energy basins. In the second modal maintaining stage, an adaptive clustering algorithm MNDcluster is proposed to divide the populations and merge the modal by adjusting the annealing temperature to locate the promising basins. In the last stage of modal exploitation, a greedy search strategy is used to accelerate the convergence of the modal. Distance constraint information is used to construct the conformation scoring model to guide sampling. MMpred is tested on 320 non-redundant proteins, where MMpred obtains models with TM-score ≥ 0.5 on 268 cases, which is 20.3% higher than that of Rosetta guided with the same distance constraints. In addition, on 320 benchmark proteins, the average TM-score of the enhanced version of MMpred (E-MMpred) is 0.732 on the best model, which is comparable to trRosetta (0.730). AVAILABILITY: The source code and executable are freely available at https://github.com/iobio-zjut/MMpred. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

19.
NAR Genom Bioinform ; 3(2): lqab050, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34085038

RESUMO

Eye diseases are remarkably common and encompass a large and diverse range of morbidities that affect different components of the visual system and visual function. With advances in omics technology of eye disorders, genome-scale datasets have been rapidly accumulated in genetics and epigenetics field. However, the efficient collection and comprehensive analysis of different kinds of omics data are lacking. Herein, we developed EyeDiseases (https://eyediseases.bio-data.cn/), the first database for multi-omics data integration and interpretation of human eyes diseases. It contains 1344 disease-associated genes with genetic variation, 1774 transcription files of bulk cell expression and single-cell RNA-seq, 105 epigenomics data across 185 kinds of human eye diseases. Using EyeDiseases, we investigated SARS-CoV-2 potential tropism in eye infection and found that the SARS-CoV-2 entry factors, ACE2 and TMPRSS2 are highly correlated with cornea and keratoconus, suggest that ocular surface cells are susceptible to infection by SARS-CoV-2. Additionally, integrating analysis of Age-related macular degeneration (AMD) GWAS loci and co-expression data revealed 9 associated genes involved in HIF-1 signaling pathway and voltage-gate potassium channel complex. The EyeDiseases provides a valuable resource for accelerating the discovery and validation of candidate loci and genes contributed to the molecular diagnosis and therapeutic vulnerabilities with various eyes diseases.

20.
Hum Mol Genet ; 30(13): 1247-1258, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-33949668

RESUMO

The systematic identification of host genetic risk factors is essential for the understanding and treatment of coronavirus disease 2019 (COVID-19). By performing a meta-analysis of two independent genome-wide association summary datasets (N = 680 128), a novel locus at 21q22.11 was identified to be associated with COVID-19 infection (rs9976829 in IFNAR2-IL10RB, odds ratio = 1.16, 95% confidence interval = 1.09-1.23, P = 2.57 × 10-6). The rs9976829 represents a strong splicing quantitative trait locus for both IFNAR2 and IL10RB genes, especially in lung tissue (P = 1.8 × 10-24). Integrative genomics analysis of combining genome-wide association study with expression quantitative trait locus data showed the expression variations of IFNAR2 and IL10RB have prominent effects on COVID-19 in various types of tissues, especially in lung tissue. The majority of IFNAR2-expressing cells were dendritic cells (40%) and plasmacytoid dendritic cells (38.5%), and IL10RB-expressing cells were mainly nonclassical monocytes (29.6%). IFNAR2 and IL10RB are targeted by several interferons-related drugs. Together, our results uncover 21q22.11 as a novel susceptibility locus for COVID-19, in which individuals with G alleles of rs9976829 have a higher probability of COVID-19 susceptibility than those with non-G alleles.


Assuntos
COVID-19/genética , Cromossomos Humanos Par 21 , Subunidade beta de Receptor de Interleucina-10/genética , Receptor de Interferon alfa e beta/genética , Alelos , Antivirais/farmacologia , COVID-19/tratamento farmacológico , COVID-19/imunologia , Citocinas/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica/métodos , Humanos , Terapia de Alvo Molecular , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...