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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(4): 1295-1300, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34362519

RESUMO

OBJECTIVE: To investigate the clinical characteristic of coagulation, possible causes and countermeasures of patients with severe corona virus disease 2019 (COVID-19). METHODS: The clinical data of the 142 patients diagnosed as COVID-19 at Wuhan Third Hospital in Wuhan, China, from February 10 to February 16, 2020 were collected and analyzed retrospective. Among the patients, 17 cases of dead patients were divided into observe group, and 125 cases of cured patients were divided into control group. The clinical characteristics, laboratory tests, influencing factors, anticoagulant therapy, embolization and bleeding events of the two groups were observed. RESULTS: The average hospital stay time in 142 patients was 22 d. For the 17 dead patients in the observe group, the average hospital stay time was 9.9 d, and the D-dimer, prothrombin time, WBC count and Padua score of the patients in the observe group were significantly higher as compared with the patients in the control group. PT(OR=1.064, 95%CI 1.012-1.119) and D-D(OR=1.045, 95%CI 1.027-1.064) were the independent risk factors that causing the death of COVID-19 patients. Among the patients, 36(25.4%) patients received low-molecular-weight heparin for anticoagulant therapy, with the average course of 9.6 d. The cumulative incidence of the embolism of the patients in the observe group was 7(41.2%), while 2(11.8%) patients developed to deep vein thrombosis (DVT) and pulmonary embolism (PE), 3 (17.6%) patients occurred acute cerebral infarction and 2 (11.8%) patients occurred acute myocardial infarction. 3 (17.6%) dead patients revealed dominant disseminated intravascular coagulation (DIC). CONCLUSION: Most patients with severe COVID-19 shows a variety of risk factors for thrombus, and those with coagulation dysfunction shows a high dead rate and rapid disease progression. Therefore, coagulation indicators should be dynamically monitored, and mechanical and drug prevention should be actively carried out.


Assuntos
COVID-19 , Coagulação Intravascular Disseminada , Anticoagulantes , Humanos , Estudos Retrospectivos , SARS-CoV-2
2.
Nat Commun ; 12(1): 4897, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385432

RESUMO

Precise control of mammalian gene expression is facilitated through epigenetic mechanisms and nuclear organization. In particular, insulated chromosome structures are important for regulatory control, but the phenotypic consequences of their boundary disruption on developmental processes are complex and remain insufficiently understood. Here, we generated deeply sequenced Hi-C data for human pluripotent stem cells (hPSCs) that allowed us to identify CTCF loop domains that have highly conserved boundary CTCF sites and show a notable enrichment of individual developmental regulators. Importantly, perturbation of such a boundary in hPSCs interfered with proper differentiation through deregulated distal enhancer-promoter activity. Finally, we found that germline variations affecting such boundaries are subject to purifying selection and are underrepresented in the human population. Taken together, our findings highlight the importance of developmental gene isolation through chromosomal folding structures as a mechanism to ensure their proper expression.


Assuntos
Diferenciação Celular/genética , Perfilação da Expressão Gênica/métodos , Genoma Humano/genética , Células-Tronco Embrionárias Humanas/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Elementos Reguladores de Transcrição/genética , Sítios de Ligação/genética , Western Blotting , Fator de Ligação a CCCTC/genética , Fator de Ligação a CCCTC/metabolismo , Linhagem Celular , Elementos Facilitadores Genéticos/genética , Células-Tronco Embrionárias Humanas/citologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Regiões Promotoras Genéticas/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA/métodos
3.
PLoS Comput Biol ; 16(11): e1008452, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33253170

RESUMO

Deconvolution of heterogeneous bulk tumor samples into distinct cellular populations is an important yet challenging problem, particularly when only partial references are available. A common approach to dealing with this problem is to deconvolve the mixed signals using available references and leverage the remaining signal as a new cell component. However, as indicated in our simulation, such an approach tends to over-estimate the proportions of known cell types and fails to detect novel cell types. Here, we propose PREDE, a partial reference-based deconvolution method using an iterative non-negative matrix factorization algorithm. Our method is verified to be effective in estimating cell proportions and expression profiles of unknown cell types based on simulated datasets at a variety of parameter settings. Applying our method to TCGA tumor samples, we found that proportions of pure cancer cells better indicate different subtypes of tumor samples. We also detected several cell types for each cancer type whose proportions successfully predicted patient survival. Our method makes a significant contribution to deconvolution of heterogeneous tumor samples and could be widely applied to varieties of high throughput bulk data. PREDE is implemented in R and is freely available from GitHub (https://xiaoqizheng.github.io/PREDE).


Assuntos
Neoplasias/patologia , Algoritmos , Animais , Linhagem Celular Tumoral , Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Humanos , Neoplasias/classificação , Neoplasias/genética , Ratos , Reprodutibilidade dos Testes
4.
Cancer Rep (Hoboken) ; 3(5): e1269, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32721120

RESUMO

BACKGROUND: CRISPR-Cas9-based technologies have revolutionized experimental manipulation of mammalian genomes. None-the-less, limitations of the delivery and efficacy of these technologies restrict their application in primary cells. AIMS: To create an optimized protocol for penetrant, reproducible, and fast targeted genome editing in cell cultures derived from primary cells, using patient-derived glioblastoma stem-like cells (GSCs) and human neural stem/progenitor cells (NSCs) for proof-of-concept experiments. METHODS AND RESULTS: We employed transient nucleofection of Cas9:sgRNA ribonucleoprotein complexes composed of chemically synthesized 2'-O-methyl 3'phosphorothioate-modified sgRNAs and purified Cas9 protein. Insertion-deletion mutation (indel) frequency and size distribution were measured via computational deconvolution of Sanger sequencing trace data. We found that this optimized technique routinely allows for >90% indel formation in only 3 days, without the need to create clonal lines for simple loss-of-function experiments. Using Western blotting, we observed near-total protein loss of target genes in cell pools. Additionally, we found that this approach allows for the creation of targeted genomic deletions. Furthermore, by using RNA-seq in edited NSCs to assess gene expression changes resulting from knockout of tumor suppressors commonly altered in glioblastoma, we also demonstrated the utility of this method for quickly creating a series of gene knockouts that allow for the study of oncogenic activities. CONCLUSION: Our data suggest that this relatively simple method can be used for highly efficient and fast gene knockout, as well as for targeted genomic deletions, even in hyperdiploid cells (such as GSCs). This represents an extremely useful tool for the cancer research community when wishing to inactivate not only coding genes, but also non-coding RNAs, UTRs, enhancers, and promoters. This method can be readily applied to diverse cell types by varying the nucleofection conditions.

5.
Mol Cell ; 78(6): 1096-1113.e8, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32416067

RESUMO

BET bromodomain inhibitors (BBDIs) are candidate therapeutic agents for triple-negative breast cancer (TNBC) and other cancer types, but inherent and acquired resistance to BBDIs limits their potential clinical use. Using CRISPR and small-molecule inhibitor screens combined with comprehensive molecular profiling of BBDI response and resistance, we identified synthetic lethal interactions with BBDIs and genes that, when deleted, confer resistance. We observed synergy with regulators of cell cycle progression, YAP, AXL, and SRC signaling, and chemotherapeutic agents. We also uncovered functional similarities and differences among BRD2, BRD4, and BRD7. Although deletion of BRD2 enhances sensitivity to BBDIs, BRD7 loss leads to gain of TEAD-YAP chromatin binding and luminal features associated with BBDI resistance. Single-cell RNA-seq, ATAC-seq, and cellular barcoding analysis of BBDI responses in sensitive and resistant cell lines highlight significant heterogeneity among samples and demonstrate that BBDI resistance can be pre-existing or acquired.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Proteínas/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Azepinas/farmacologia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proteínas Cromossômicas não Histona/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Proteínas Nucleares/metabolismo , Proteínas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Triazóis/farmacologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
6.
Bioinformatics ; 36(7): 2017-2024, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31769783

RESUMO

MOTIVATION: Inference of differentially methylated (DM) CpG sites between two groups of tumor samples with different geno- or pheno-types is a critical step to uncover the epigenetic mechanism of tumorigenesis, and identify biomarkers for cancer subtyping. However, as a major source of confounding factor, uneven distributions of tumor purity between two groups of tumor samples will lead to biased discovery of DM sites if not properly accounted for. RESULTS: We here propose InfiniumDM, a generalized least square model to adjust tumor purity effect for differential methylation analysis. Our method is applicable to a variety of experimental designs including with or without normal controls, different sources of normal tissue contaminations. We compared our method with conventional methods including minfi, limma and limma corrected by tumor purity using simulated datasets. Our method shows significantly better performance at different levels of differential methylation thresholds, sample sizes, mean purity deviations and so on. We also applied the proposed method to breast cancer samples from TCGA database to further evaluate its performance. Overall, both simulation and real data analyses demonstrate favorable performance over existing methods serving similar purpose. AVAILABILITY AND IMPLEMENTATION: InfiniumDM is a part of R package InfiniumPurify, which is freely available from GitHub (https://github.com/Xiaoqizheng/InfiniumPurify). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Metilação de DNA , Neoplasias/genética , Sequência de Bases , Bases de Dados Factuais , Humanos , Projetos de Pesquisa
7.
Exp Ther Med ; 18(3): 2199-2206, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31410172

RESUMO

In the present study, a hypoxia/reoxygenation (H/R) model of cardiomyocytes was established to investigate the effects of long non-coding RNA (LncRNA) Nuclear Enriched Abundant Transcript 1 (NEAT1) and microRNA (miR)-520a on H/R-induced cardiomyocyte apoptosis. Flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling staining were used to evaluate cell apoptosis. Luciferase activity assay was used to investigate whether miR-520a targets NEAT1. Results revealed that NEAT1 was significantly upregulated and miR-520a was downregulated in the ischemia/reperfusion myocardium and the cardiomyocytes that received H/R treatment. Further study demonstrated that knockdown of NEAT1 and overexpression of miR-520a serves a protective role against H/R-induced cardiomyocyte apoptosis. miR-520a directly targets NEAT1 and its expression level is negatively correlated with that of NEAT1. The findings suggested that NEAT1 and miR-520a may protect cardiomyocytes from apoptosis through regulating apoptotic proteins B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein, and altering cleaved caspase3 expression levels.

9.
J Cell Physiol ; 234(2): 1248-1256, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30191959

RESUMO

BACKGROUND: Numerous studies have evaluated the significance of the microRNA-10b (miR-10b) in the development and progression of many cancers. Their findings revealed that increased expression of miR-10b is associated with unfavorable prognosis in patients with cancer. RESULTS: A total of 1,834 patients from 19 studies were included in this study. A significantly shorter overall survival was observed in patients with increased expression of miR-10b (hazard ratio [HR] = 1.99, 95% confidence interval [CI]: 1.51-2.61). Statistical significance was also observed in subgroup meta-analysis stratified by the cancer type, cutoff value, analysis type, and sample size. Also, patients with a high expression level of miR-10b had a poorer disease-free survival rate (HR = 1.18, 95% CI: 1.05-1.33). In addition, the pooled odds ratios (ORs) showed that increased miR-10b was also associated with positive lymph node metastasis (OR = 2.09, 95% CI: 1.45-3.03), distant metastasis (OR = 2.40, 95% CI: 1.57-3.67), tumor size (OR = 3.86, 95% CI: 2.25-6.64), and poor clinical stage (OR = 5.02, 95% CI: 3.37-7.47). MATERIALS AND METHODS: A systematic literature search was conducted on a number of electronic databases, including PubMed, Embase, Web of Science, China National Knowledge Infrastructure, Springer, Google Scholar, and Gene expression omnibus. We retrieved the relevant articles to examine the association between the miR-10b expression levels and patients' prognosis. The meta-analysis was conducted using the RevMan 5.2 software and Stata SE12.0 software. CONCLUSIONS: High miR-10b expression was correlated with poor clinical outcome, which indicated the potential clinical use of miR-10b as a molecular biomarker for cancer, particularly in assessing prognosis for patients with cancers. Further studies should be performed to verify the clinical utility of miR-10b in human solid tumors.


Assuntos
Biomarcadores Tumorais/genética , MicroRNAs/genética , Neoplasias/genética , Sobreviventes de Câncer , Diferenciação Celular , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias/mortalidade , Neoplasias/patologia , Neoplasias/terapia , Fatores de Risco , Fatores de Tempo , Carga Tumoral
10.
Cancer Cell ; 34(6): 939-953.e9, 2018 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-30472020

RESUMO

Members of the KDM5 histone H3 lysine 4 demethylase family are associated with therapeutic resistance, including endocrine resistance in breast cancer, but the underlying mechanism is poorly defined. Here we show that genetic deletion of KDM5A/B or inhibition of KDM5 activity increases sensitivity to anti-estrogens by modulating estrogen receptor (ER) signaling and by decreasing cellular transcriptomic heterogeneity. Higher KDM5B expression levels are associated with higher transcriptomic heterogeneity and poor prognosis in ER+ breast tumors. Single-cell RNA sequencing, cellular barcoding, and mathematical modeling demonstrate that endocrine resistance is due to selection for pre-existing genetically distinct cells, while KDM5 inhibitor resistance is acquired. Our findings highlight the importance of cellular phenotypic heterogeneity in therapeutic resistance and identify KDM5A/B as key regulators of this process.


Assuntos
Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , Histona Desmetilases com o Domínio Jumonji/genética , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Proteína 2 de Ligação ao Retinoblastoma/genética , Transcriptoma/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Estradiol/farmacologia , Moduladores de Receptor Estrogênico/farmacologia , Feminino , Fulvestranto/farmacologia , Heterogeneidade Genética , Humanos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Células MCF-7 , Proteínas Nucleares/metabolismo , Proteínas Repressoras/metabolismo , Proteína 2 de Ligação ao Retinoblastoma/metabolismo , Transcriptoma/efeitos dos fármacos , Sequenciamento Completo do Exoma/métodos
11.
Nat Commun ; 9(1): 3116, 2018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-30082792

RESUMO

Glioblastoma multiforme (GBM) is an aggressive primary brain cancer that includes focal amplification of PDGFRα and for which there are no effective therapies. Herein, we report the development of a genetically engineered mouse model of GBM based on autocrine, chronic stimulation of overexpressed PDGFRα, and the analysis of GBM signaling pathways using proteomics. We discover the tubulin-binding protein Stathmin1 (STMN1) as a PDGFRα phospho-regulated target, and that this mis-regulation confers sensitivity to vinblastine (VB) cytotoxicity. Treatment of PDGFRα-positive mouse and a patient-derived xenograft (PDX) GBMs with VB in mice prolongs survival and is dependent on STMN1. Our work reveals a previously unconsidered link between PDGFRα activity and STMN1, and highlight an STMN1-dependent cytotoxic effect of VB in GBM.


Assuntos
Neoplasias da Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Estatmina/metabolismo , Vimblastina/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose , Ciclo Celular , Sobrevivência Celular , Células Cultivadas , Biologia Computacional , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imageamento por Ressonância Magnética , Masculino , Camundongos , Transplante de Neoplasias , Fosforilação , Proteômica , Transdução de Sinais
12.
Genes Dev ; 32(7-8): 512-523, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29632085

RESUMO

Glioblastoma is the most frequently occurring and invariably fatal primary brain tumor in adults. The vast majority of glioblastomas is characterized by chromosomal copy number alterations, including gain of whole chromosome 7 and loss of whole chromosome 10. Gain of whole chromosome 7 is an early event in gliomagenesis that occurs in proneural-like precursor cells, which give rise to all isocitrate dehydrogenase (IDH) wild-type glioblastoma transcriptional subtypes. Platelet-derived growth factor A (PDGFA) is one gene on chromosome 7 known to drive gliomagenesis, but, given its location near the end of 7p, there are likely several other genes located along chromosome 7 that select for its increased whole-chromosome copy number within glioblastoma cells. To identify other potential genes that could select for gain of whole chromosome 7, we developed an unbiased bioinformatics approach that identified homeobox A5 (HOXA5) as a gene whose expression correlated with gain of chromosome 7 and a more aggressive phenotype of the resulting glioma. High expression of HOXA5 in glioblastoma was associated with a proneural gene expression pattern and decreased overall survival in both human proneural and PDGF-driven mouse glioblastoma. Furthermore, HOXA5 overexpression promoted cellular proliferation and potentiated radioresistance. We also found enrichment of HOXA5 expression in recurrent human and mouse glioblastoma at first recurrence after radiotherapy. Overall, this study implicates HOXA5 as a chromosome 7-associated gene-level locus that promotes selection for gain of whole chromosome 7 and an aggressive phenotype in glioblastoma.


Assuntos
Neoplasias Encefálicas/genética , Cromossomos Humanos Par 7 , Glioblastoma/genética , Proteínas de Homeodomínio/metabolismo , Fosfoproteínas/metabolismo , Animais , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Proliferação de Células , Duplicação Cromossômica , Glioblastoma/mortalidade , Glioblastoma/patologia , Glioblastoma/radioterapia , Proteínas de Homeodomínio/genética , Humanos , Isocitrato Desidrogenase/genética , Camundongos , Recidiva Local de Neoplasia , Fosfoproteínas/genética , Tolerância a Radiação , Fatores de Transcrição
13.
Oncotarget ; 8(61): 104543-104551, 2017 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-29262659

RESUMO

Background: Reported studies on carcinoma have evaluated the significance of the microRNA miR-10b in the development and progression of many cancers. Increased expression of miR-10b is associated with the susceptibility to lymph node metastasis and distant metastasis in various tumors. Results: The results of the meta-analysis revealed that lymph node metastasis occurred more frequently in the patients group with high expression level of miR-10b than in the patients group with low expression level of miR-10b (OR=4.65, 95% CI: 3.40-6.37, P <0.00001, fixed-effects model). Additionally, a similar result was observed in the association between miR-10b expression and distant metastasis (OR=2.70, 95% CI: 1.79-4.08, P <0.00001, fixed-effects model). Materials and Methods: In this study, a meta-analysis, including the majority of the relevant articles, was conducted to investigate the association of the miR-10b expression level with metastasis in cancer patients. Systematic literature retrieval was performed by searching in a number of electronic databases. The meta-analysis was conducted using the RevMan 5.2 software and Stata SE12.0 software. A total of 962 patients with carcinoma from 9 studies were included in analysis. Conclusions: This meta-analysis demonstrated that the overexpression of miR-10b was significantly correlated with metastasis status, and indicated the potential clinical use of miR-10b as a molecular biomarker, particularly in assessing prognosis for patients with cancers.

14.
PLoS One ; 12(3): e0173589, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28333954

RESUMO

The degree of histologic cellular differentiation of a cancer has been associated with prognosis but is subjectively assessed. We hypothesized that information about tumor differentiation of individual cancers could be derived objectively from cancer gene expression data, and would allow creation of a cancer phylogenetic framework that would correlate with clinical, histologic and molecular characteristics of the cancers, as well as predict prognosis. Here we utilized mRNA expression data from 4,413 patient samples with 7 diverse cancer histologies to explore the utility of ordering samples by their distance in gene expression from that of stem cells. A differentiation baseline was obtained by including expression data of human embryonic stem cells (hESC) and human mesenchymal stem cells (hMSC) for solid tumors, and of hESC and CD34+ cells for liquid tumors. We found that the correlation distance (the degree of similarity) between the gene expression profile of a tumor sample and that of stem cells orients cancers in a clinically coherent fashion. For all histologies analyzed (including carcinomas, sarcomas, and hematologic malignancies), patients with cancers with gene expression patterns most similar to that of stem cells had poorer overall survival. We also found that the genes in all undifferentiated cancers of diverse histologies that were most differentially expressed were associated with up-regulation of specific oncogenes and down-regulation of specific tumor suppressor genes. Thus, a stem cell-oriented phylogeny of cancers allows for the derivation of a novel cancer gene expression signature found in all undifferentiated forms of diverse cancer histologies, that is competitive in predicting overall survival in cancer patients compared to previously published prediction models, and is coherent in that gene expression was associated with up-regulation of specific oncogenes and down-regulation of specific tumor suppressor genes associated with regulation of the multicellular state.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Neoplasias/genética , Oncogenes/genética , Células-Tronco/metabolismo , Transcriptoma/genética , Diferenciação Celular/genética , Regulação para Baixo/genética , Humanos , Regulação para Cima/genética
15.
FASEB J ; 31(2): 482-490, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28148777

RESUMO

Overexpression of the multiple myeloma set domain (MMSET) Wolf-Hirschhorn syndrome candidate 1 gene, which contains an orphan box H/ACA class small nucleolar RNA, ACA11, in an intron, is associated with several cancer types, including multiple myeloma (MM). ACA11 and MMSET are overexpressed cotranscriptionally as a result of the t(4;14) chromosomal translocation in a subset of patients with MM. RNA sequencing of CD138+ tumor cells from t(4;14)-positive and -negative MM patient bone marrow samples revealed an enhanced oxidative phosphorylation mRNA signature. Supporting these data, ACA11 overexpression in a t(4;14)-negative MM cell line, MM1.S, demonstrated enhanced reactive oxygen species (ROS) levels. In addition, an enhancement of cell proliferation, increased soft agar colony size, and elevated ERK1/2 phosphorylation were observed. This ACA11-driven hyperproliferative phenotype depended on increased ROS levels as exogenously added antioxidants attenuate the increased proliferation. A major transcriptional regulator of the cellular antioxidant response, nuclear factor (erythroid-derived 2)-like 2 (NRF2), shuttled to the nucleus, as expected, in response to ACA11-driven increases in ROS; however, transcriptional up-regulation of some of NRF2's antioxidant target genes was abrogated in the presence of ACA11 overexpression. These data show for the first time that ACA11 promotes proliferation through inhibition of NRF2 function resulting in sustained ROS levels driving cancer cell proliferation.-Mahajan, N., Wu, H.-J., Bennett, R. L., Troche, C., Licht, J. D., Weber, J. D., Maggi, L. B., Jr., Tomasson, M. H. Sabotaging of the oxidative stress response by an oncogenic noncoding RNA.


Assuntos
Fibroblastos/fisiologia , Regulação da Expressão Gênica/fisiologia , Oncogenes/fisiologia , RNA não Traduzido/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Células Cultivadas , Humanos , Camundongos , Mieloma Múltiplo/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , RNA não Traduzido/genética , Espécies Reativas de Oxigênio
16.
Genome Biol ; 18(1): 17, 2017 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-28122605

RESUMO

We present a set of statistical methods for the analysis of DNA methylation microarray data, which account for tumor purity. These methods are an extension of our previously developed method for purity estimation; our updated method is flexible, efficient, and does not require data from reference samples or matched normal controls. We also present a method for incorporating purity information for differential methylation analysis. In addition, we propose a control-free differential methylation calling method when normal controls are not available. Extensive analyses of TCGA data demonstrate that our methods provide accurate results. All methods are implemented in InfiniumPurify.


Assuntos
Metilação de DNA , Epigênese Genética , Epigenômica/métodos , Neoplasias/genética , Algoritmos , Análise por Conglomerados , Simulação por Computador , Ilhas de CpG , Humanos , Curva ROC
17.
Nucleic Acids Res ; 45(10): e77, 2017 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-28126923

RESUMO

Conventional DNA bisulfite sequencing has been extended to single cell level, but the coverage consistency is insufficient for parallel comparison. Here we report a novel method for genome-wide CpG island (CGI) methylation sequencing for single cells (scCGI-seq), combining methylation-sensitive restriction enzyme digestion and multiple displacement amplification for selective detection of methylated CGIs. We applied this method to analyzing single cells from two types of hematopoietic cells, K562 and GM12878 and small populations of fibroblasts and induced pluripotent stem cells. The method detected 21 798 CGIs (76% of all CGIs) per cell, and the number of CGIs consistently detected from all 16 profiled single cells was 20 864 (72.7%), with 12 961 promoters covered. This coverage represents a substantial improvement over results obtained using single cell reduced representation bisulfite sequencing, with a 66-fold increase in the fraction of consistently profiled CGIs across individual cells. Single cells of the same type were more similar to each other than to other types, but also displayed epigenetic heterogeneity. The method was further validated by comparing the CpG methylation pattern, methylation profile of CGIs/promoters and repeat regions and 41 classes of known regulatory markers to the ENCODE data. Although not every minor methylation differences between cells are detectable, scCGI-seq provides a solid tool for unsupervised stratification of a heterogeneous cell population.


Assuntos
Ilhas de CpG , Metilação de DNA , Epigênese Genética , Regiões Promotoras Genéticas , Análise de Célula Única/métodos , Linhagem Celular , Linhagem Celular Tumoral , Mapeamento Cromossômico , Enzimas de Restrição do DNA/química , Fibroblastos/citologia , Fibroblastos/metabolismo , Variação Genética , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Células K562 , Linfócitos/citologia , Linfócitos/metabolismo
18.
Bioinformatics ; 32(24): 3695-3701, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27531101

RESUMO

MOTIVATION: The Hi-C technology was designed to decode the three-dimensional conformation of the genome. Despite progress towards more and more accurate contact maps, several systematic biases have been demonstrated to affect the resulting data matrix. Here we report a new source of bias that can arise in tumor Hi-C data, which is related to the copy number of genomic DNA. To address this bias, we designed a chromosome-adjusted iterative correction method called caICB. Our caICB correction method leads to significant improvements when compared with the original iterative correction in terms of eliminating copy number bias. AVAILABILITY AND IMPLEMENTATION: The method is available at https://bitbucket.org/mthjwu/hicapp CONTACT: michor@jimmy.harvard.eduSupplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Biologia Computacional/métodos , Variações do Número de Cópias de DNA , Neoplasias/genética , Software , Humanos
19.
Bioinformatics ; 31(21): 3401-5, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26112293

RESUMO

MOTIVATION: In cancer genomics research, one important problem is that the solid tissue sample obtained from clinical settings is always a mixture of cancer and normal cells. The sample mixture brings complication in data analysis and results in biased findings if not correctly accounted for. Estimating tumor purity is of great interest, and a number of methods have been developed using gene expression, copy number variation or point mutation data. RESULTS: We discover that in cancer samples, the distributions of data from Illumina Infinium 450 k methylation microarray are highly correlated with tumor purities. We develop a simple but effective method to estimate purities from the microarray data. Analyses of the Cancer Genome Atlas lung cancer data demonstrate favorable performance of the proposed method. AVAILABILITY AND IMPLEMENTATION: The method is implemented in InfiniumPurify, which is freely available at https://bitbucket.org/zhengxiaoqi/infiniumpurify. CONTACT: xqzheng@shnu.edu.cn or hao.wu@emory.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Biologia Computacional/métodos , Variações do Número de Cópias de DNA , Metilação de DNA , Perfilação da Expressão Gênica , Genômica/métodos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Algoritmos , Genoma Humano , Humanos
20.
Genome Biol ; 15(8): 419, 2014 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-25103624

RESUMO

We propose a statistical algorithm MethylPurify that uses regions with bisulfite reads showing discordant methylation levels to infer tumor purity from tumor samples alone. MethylPurify can identify differentially methylated regions (DMRs) from individual tumor methylome samples, without genomic variation information or prior knowledge from other datasets. In simulations with mixed bisulfite reads from cancer and normal cell lines, MethylPurify correctly inferred tumor purity and identified over 96% of the DMRs. From patient data, MethylPurify gave satisfactory DMR calls from tumor methylome samples alone, and revealed potential missed DMRs by tumor to normal comparison due to tumor heterogeneity.


Assuntos
Adenocarcinoma/genética , Neoplasias da Mama/genética , Biologia Computacional/métodos , Metilação de DNA , Neoplasias Pulmonares/genética , Adenocarcinoma de Pulmão , Algoritmos , Mama/metabolismo , Mama/patologia , Linhagem Celular , Feminino , Heterogeneidade Genética , Humanos , Modelos Estatísticos , Análise de Sequência de DNA
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