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1.
J Cell Physiol ; 2021 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-33393109

RESUMO

Our understanding of signaling pathways regulating the cell fate of human embryonic stem cells (hESCs) is limited. Calcineurin-NFAT signaling is associated with a wide range of biological processes and diseases. However, its role in controlling hESC fate remains unclear. Here, we report that calcineurin A gamma and the NFATc3/SRPX2 axis control the expression of lineage and epithelial-mesenchymal transition (EMT) markers in hESCs. Knockdown of PPP3CC, the gene encoding calcineurin A gamma, or NFATC3, downregulates certain markers both at the self-renewal state and during differentiation of hESCs. Furthermore, NFATc3 interacts with c-JUN and regulates the expression of SRPX2, the gene encoding a secreted glycoprotein known as a ligand of uPAR. We show that SRPX2 is a downstream target of NFATc3. Both SRPX2 and uPAR participate in controlling expression of lineage and EMT markers. Importantly, SRPX2 knockdown diminishes the upregulation of multiple lineage and EMT markers induced by co-overexpression of NFATc3 and c-JUN in hESCs. Together, this study uncovers a previously unknown role of calcineurin A gamma and the NFATc3/SRPX2 axis in modulating the fate determination of hESCs.

2.
Cancer Biomark ; 2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33337349

RESUMO

BACKGROUND: Metastasis regularly is a marker of the disease development of cancers. Some metastatic sites significantly showed more serious clinical outcomes in non-small cell lung cancer (NSCLC). Whether they are caused by tissue-specific (TS) or non-tissue-specific (NTS) mechanisms is still unclear. OBJECTIVE: Explore co-expression gene modules of non-small cell lung cancer metastases. METHODS: Weighted Correlation Network Analysis (WGCNA) was used to identify the gene modules among the metastases of NSCLC. The clinical significance of those gene modules was evaluated with the Cox hazard proportional model with another independent dataset. Functions of each gene module were analyzed with gene ontology. Typical genes were further studied. RESULTS: There were two TS gene modules and two NTS gene modules identified. One TS gene module (green module) and one NTS gene module (purple module) significantly correlated with survival. This NTS gene module (purple module) was significantly enriched in the epithelial-to-mesenchymal transition (EMT) process. Higher expression of the typical genes (CA14, SOX10, TWIST1, and ALX1) from EMT process was significantly associated with a worse survival. CONCLUSION: The lethality of NSCLC metastases was caused by TS gene modules and NTS gene modules, among which the EMT-related gene module was critical for a worse clinical outcome.

4.
Cancer Med ; 8(18): 7669-7678, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31692284

RESUMO

BACKGROUND: Immune-therapy with anti-PD1 inhibitors, such as pembrolizumab, is revolutionizing the treatment of non-small cell lung cancers (NSCLC). However, identifying patients for the potential therapeutic response and predicting therapy resistance and early relapse remains a challenge. METHODS: Between 2016 and 2018, 60 patients were treated with pembrolizumab, among who 12 NSCLC patients had both baseline (before treatment) and serial (on treatment) periodical circulating tumor DNA (ctDNA) samples. Those samples were sequenced on a 329 pan cancer-related gene panel. Analyses of tumor burden, blood tumor mutational burden (bTMB), maximum somatic allele frequency (MSAF), and tumor clonal structure were performed in association with clinical response. Candidate resistance mutations involved in relapse and metastases were further investigated. RESULTS: ctDNA was detected and mutational profiling was performed for each patient. Those with a high baseline bTMB level showed significantly improved progression-free survival (PFS) after pembrolizumab treatment. Tumor burden and therapeutic response significantly correlated with the MSAF instead of the bTMB. Clone analysis detected tumor progression about 2-4 months ahead of computed tomography (CT) scan. One mutation in gene PTCH1 (Protein patched homolog 1) and two acquired anti-PD1 candidate resistance mutations of gene B2M (ß2 microglobulin) were identified in association with distant metastasis. The evolutionary tree of a representative patient was also described. CONCLUSION: This pilot study showed that MSAF could be another good indicator of therapeutic response, and clonal analysis could be clinically useful in monitoring clonal dynamics and detecting remote metastasis and early relapse.


Assuntos
Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/genética , Transformação Celular Neoplásica/genética , DNA Tumoral Circulante , Evolução Clonal/genética , Neoplasias Pulmonares/genética , Idoso , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Mutação , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Carga Tumoral
5.
Stem Cell Reports ; 11(4): 973-987, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30269953

RESUMO

The protein level of OCT4, a core pluripotency transcription factor, is vital for embryonic stem cell (ESC) maintenance, differentiation, and somatic cell reprogramming. However, how OCT4 protein levels are controlled during reprogramming remains largely unknown. Here, we identify ubiquitin conjugation sites of OCT4 and report that disruption of WWP2-catalyzed OCT4 ubiquitination or ablation of Wwp2 significantly promotes the efficiency of pluripotency induction from mouse embryonic fibroblasts. Mechanistically, disruption of WWP2-mediated OCT4 ubiquitination elevates OCT4 protein stability and H3K4 methylation level during the reprogramming process. Furthermore, we reveal that OCT4 directly activates expression of Ash2l-b, and that ASH2L-B is a major isoform of ASH2L highly expressed in ESCs and required for somatic cell reprogramming. Together, this study emphasizes the importance of ubiquitination manipulation of the reprogramming factor and its interplay with the epigenetic regulator for successful reprogramming, opening a new avenue to improve the efficiency of pluripotency induction.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Histonas/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Lisina/metabolismo , Proteínas Nucleares/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , Fatores de Transcrição/metabolismo , Ubiquitinação , Sequência de Aminoácidos , Animais , Reprogramação Celular , Embrião de Mamíferos/citologia , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Fatores de Transcrição Kruppel-Like/metabolismo , Metilação , Camundongos , Mutação/genética , Fator 3 de Transcrição de Octâmero/química , Ligação Proteica , Estabilidade Proteica , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases
6.
Cell Death Dis ; 9(9): 924, 2018 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-30206204

RESUMO

Trophoblast lineages, precursors of the placenta, are essential for post-implantation embryo survival. However, the regulatory network of trophoblast development remains incompletely understood. Here, we report that Cited1, a transcription coactivator, is a robust inducer for trophoblast-like state from mouse embryonic stem cells (ESCs). Depletion of Cited1 in ESCs compromises the trophoblast lineage specification induced by BMP signaling. In contrast, overexpression of Cited1 in ESCs induces a trophoblast-like state with elevated expression of trophoblast marker genes in vitro and generation of trophoblastic tumors in vivo. Furthermore, global transcriptome profile analysis indicates that ectopic Cited1 activates a trophoblast-like transcriptional program in ESCs. Mechanistically, Cited1 interacts with Bmpr2 and Smad4 to activate the Cited1-Bmpr2-Smad1/5/8 axis in the cytoplasm and Cited1-Smad4-p300 complexes in the nucleus, respectively. Collectively, our results show that Cited1 plays an important role in regulating trophoblast lineage specification through activating the BMP signaling pathway.


Assuntos
Proteína Morfogenética Óssea 1/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Células-Tronco Embrionárias Murinas/citologia , Proteínas Nucleares/metabolismo , Transativadores/metabolismo , Trofoblastos/citologia , Animais , Proteínas Reguladoras de Apoptose , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Linhagem Celular , Proteína p300 Associada a E1A/metabolismo , Feminino , Camundongos , Proteínas Nucleares/genética , Placenta/embriologia , Gravidez , Transdução de Sinais , Proteína Smad4/metabolismo , Transativadores/genética , Transcrição Genética/genética
7.
Int J STD AIDS ; 29(7): 632-640, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-28799825

RESUMO

Interrupting vertical transmission of HIV from mothers to infants provides opportunity to transform the HIV/AIDS epidemic by eliminating new infections among children. We estimate mother-to-child transmission rates of infants born to known HIV-positive mothers offered prevention of mother-to-child transmission interventions and provide an indication of Kenya's progress toward elimination of perinatal transmission. We obtained from the Kenya National Early Infant Diagnosis (EID) database, all 131,451 DNA polymerase chain reaction test results of HIV-exposed infants aged 0-18 months who had dried blood spot samples taken between January 2008 and October 2013. The majority of samples were from infants aged 0-6 months (81.0%). Infants aged 6-12 months comprised 15.5%, while those aged 12-18 months were 3.5%. Overall, 11,439 (8.7%) were HIV-positive. Positivity rates were higher among older age groups: 6.8, 14.6, and 27.5% in age groups 0-6 months, 6-12 months, and 12-18 months old, respectively. In Kenya, scale-up and decentralization to primary health centers of EID services has been remarkable. Both increasing HIV-positivity trends in age groups 12-18 months and differences between provinces require further interrogation. Although significant, declining HIV-positivity trends in age groups 0-6 months and 6-12 months old observed between 2008 and 2013 is insufficient to achieve the elimination agenda.


Assuntos
Infecções por HIV/transmissão , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Complicações Infecciosas na Gravidez/prevenção & controle , Fármacos Anti-HIV/uso terapêutico , Criança , Estudos Transversais , Diagnóstico Precoce , Feminino , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Humanos , Lactente , Recém-Nascido , Quênia , Masculino , Mães , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico
8.
J Biol Chem ; 292(23): 9840-9854, 2017 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-28298438

RESUMO

The mammalian post-implantation embryo has been extensively investigated at the tissue level. However, to unravel the molecular basis for the cell-fate plasticity and determination, it is essential to study the characteristics of individual cells. In particular, the individual definitive endoderm (DE) cells have not been characterized in vivo Here, we report gene expression patterns in single cells freshly isolated from mouse embryos on days 5.5 and 6.5. Initial transcriptome data from 124 single cells yielded signature genes for the epiblast, visceral endoderm, and extra-embryonic ectoderm and revealed a unique distribution pattern of fibroblast growth factor (FGF) ligands and receptors. Further analysis indicated that early-stage epiblast cells do not segregate into lineages of the major germ layers. Instead, some cells began to diverge from epiblast cells, displaying molecular features of the premesendoderm by expressing higher levels of mesendoderm markers and lower levels of Sox3 transcripts. Analysis of single-cell high-throughput quantitative RT-PCR data from 441 cells identified a late stage of the day 6.5 embryo in which mesoderm and DE cells emerge, with many of them coexpressing Oct4 and Gata6 Analysis of single-cell RNA-sequence data from 112 cells of the late-stage day 6.5 embryos revealed differentially expressed signaling genes and networks of transcription factors that might underlie the segregation of the mesoderm and DE lineages. Moreover, we discovered a subpopulation of mesoderm cells that possess molecular features of the extraembryonic mesoderm. This study provides fundamental insight into the molecular basis for lineage segregation in post-implantation mouse embryos.


Assuntos
Antígenos de Diferenciação/biossíntese , Linhagem da Célula/fisiologia , Embrião de Mamíferos , Desenvolvimento Embrionário/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Transcriptoma/fisiologia , Animais , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Fator de Transcrição GATA6/biossíntese , Camundongos , Fator 3 de Transcrição de Octâmero/biossíntese , Fatores de Transcrição SOXB1/biossíntese
9.
Cell Stem Cell ; 20(2): 274-289.e7, 2017 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-27939217

RESUMO

The chromatin landscape and cellular metabolism both contribute to cell fate determination, but their interplay remains poorly understood. Using genome-wide siRNA screening, we have identified prohibitin (PHB) as an essential factor in self-renewal of human embryonic stem cells (hESCs). Mechanistically, PHB forms protein complexes with HIRA, a histone H3.3 chaperone, and stabilizes the protein levels of HIRA complex components. Like PHB, HIRA is required for hESC self-renewal. PHB and HIRA act together to control global deposition of histone H3.3 and gene expression in hESCs. Of particular note, PHB and HIRA regulate the chromatin architecture at the promoters of isocitrate dehydrogenase genes to promote transcription and, thus, production of α-ketoglutarate, a key metabolite in the regulation of ESC fate. Our study shows that PHB has an unexpected nuclear role in hESCs that is required for self-renewal and that it acts with HIRA in chromatin organization to link epigenetic organization to a metabolic circuit.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Epigênese Genética , Chaperonas de Histonas/metabolismo , Células-Tronco Embrionárias Humanas/metabolismo , Proteínas Repressoras/metabolismo , Fatores de Transcrição/metabolismo , Autorrenovação Celular/genética , Cromatina/metabolismo , Imunoprecipitação da Cromatina , Genes Controladores do Desenvolvimento , Genoma Humano , Células HEK293 , Histonas/metabolismo , Células-Tronco Embrionárias Humanas/citologia , Humanos , Isocitrato Desidrogenase/metabolismo , Ácidos Cetoglutáricos/metabolismo , Masculino , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica/genética , RNA Interferente Pequeno/metabolismo
10.
PLoS One ; 11(9): e0163285, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27655530

RESUMO

The objective of this study was to identify and describe levels of household economic vulnerability in HIV-affected communities in Côte d'Ivoire, defined as those with a high prevalence of HIV and large numbers of orphans and vulnerable children. We conducted a cross-sectional survey of 3,749 households in five health regions of Côte d'Ivoire. Using principal component analysis, we attempted to identify sets of correlated vulnerabilities and derive a small number of composite scores to create an index for targeting interventions to vulnerable populations. The 65 vulnerability measures examined did not cluster in ways that would allow for the creation of a small number of composite measures. Instead, we found that households face numerous unique pathways to vulnerability.

11.
J Virus Erad ; 2(1): 36-42, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27482434

RESUMO

BACKGROUND: Limited data are available on factors associated with HIV-RNA viral load (VL) among antiretroviral treatment (ART)-naïve key populations in concentrated epidemics. METHODS: We conducted a cross-sectional survey of 1211 adult ART-naïve patients at 19 HIV clinics in Ho Chi Minh City (HCMC), Vietnam. Data collection included a standardised questionnaire, routine laboratory testing, hepatitis serology and HIV VL. Correlation between CD4 cell count and VL was assessed across all participants. In 904 participants not meeting Vietnam criteria for ART (CD4 cell count >350 cells/mm(3), WHO clinical stage 1 or 2 and not pregnant), multivariate analyses were conducted to assess factors associated with HIV VL. RESULTS: Pre-ART patients had a median age of 31 years and 54% were male. Median CD4 cell count was 533 cells/mm(3). Median HIV VL was 17,378 copies/mL; 60% had VL greater than 10,000 copies/mL and 16% had VL above 100,000 copies/mL. Although declining CD4 cell count was correlated with rising VL across all CD4 cell counts, correlation of VL with CD4 cell counts between 351 and 500 cell/mm(3) was not significant. On multivariate linear regression, higher HIV VL was independently associated with male sex, men who have sex with men (MSM), CD4 cell count 351-500, HIV diagnosis within the previous 6 months, and hepatitis B (HBV). Lower HIV VL was independently associated with hepatitis C (HCV). CONCLUSIONS: The majority of HIV patients who were not eligible for ART in HCMC in 2014 had HIV VL greater than 10,000 copies/mL. These data support expanded eligibility of ART to all HIV patients with the goal of treatment as prevention. This study is also among the first to demonstrate that MSM had a higher VL than women and heterosexual men and highlights the need for improved outreach and linkages to HIV care for this high-risk group.

12.
J Virus Erad ; 2(2): 94-101, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-27482442

RESUMO

BACKGROUND: Limited data are available on HIV viral suppression rates among men and women on antiretroviral therapy (ART) and factors associated with HIV RNA viral load (VL) suppression in Vietnam. METHODS: We conducted a cross-sectional survey of 1255 adult patients on ART for at least 1 year across four provinces in Vietnam. Data collection included a standardised questionnaire, routine laboratory testing, and an HIV VL assay. Bivariate and logistic multivariate analyses were conducted to assess viral suppression rates and factors associated with unsuppressed HIV VL. RESULTS: The median age was 34.5 years and the median time on ART was 46 months. Gender was 66% male (n=828) and 34% female (n=427). HIV viral suppression below 1000 copies/mL was 93%. Viral suppression among woman was not significantly different than among men (93.7% vs 92.9%; P=0.59). On multivariate analysis, unsuppressed HIV VL was independently associated with lower CD4 cell count, social isolation, high stigma, not receiving a single-tablet daily regimen, multiple late appointments in past year, and immunological failure. CONCLUSION: On-treatment viral load suppression rates in Vietnam are high and already exceed the UNAIDS 90% target for viral suppression on ART. Gender does not impact viral suppression rates of patients on ART in Vietnam. Access to routine viral load testing should be improved, adherence monitoring and counselling streamlined, and ART regimens simplified to maintain viral suppression rates, as more people start ART. Psychological and social factors are also associated with unsuppressed HIV VL, necessitating treatment support interventions to address social isolation and stigma among people living with HIV in Vietnam.

13.
Cochrane Database Syst Rev ; (7): CD007373, 2015 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-26222246

RESUMO

BACKGROUND: Fear of pain during insertion of intrauterine contraception (IUC) is a barrier to use of this method. IUC includes copper-containing intrauterine devices and levonorgestrel-releasing intrauterine systems. Interventions for pain control during IUC insertion include non-steroidal anti-inflammatory drugs (NSAIDs), local cervical anesthetics, and cervical ripening agents such as misoprostol. OBJECTIVES: To review randomized controlled trials (RCTs) of interventions for reducing IUC insertion-related pain SEARCH METHODS: We searched for trials in CENTRAL, MEDLINE, EMBASE, POPLINE, ClinicalTrials.gov, and ICTRP. The most recent search was 22 June 2015. We examined reference lists of pertinent articles. For the initial review, we wrote to investigators to find other published or unpublished trials. SELECTION CRITERIA: We included RCTs that evaluated an intervention for preventing IUC insertion-related pain. The comparison could have been a placebo, no intervention, or another active intervention. The primary outcomes were self-reported pain at tenaculum placement, during IUC insertion, and after IUC insertion (up to six hours). DATA COLLECTION AND ANALYSIS: Two authors extracted data from eligible trials. For dichotomous variables, we calculated the Mantel-Haenszel odds ratio (OR) with 95% confidence interval (CI). For continuous variables, we computed the mean difference (MD) with 95% CI. In meta-analysis of trials with different measurement scales, we used the standardized mean difference (SMD). MAIN RESULTS: We included 33 trials with 5710 participants total; 29 were published from 2010 to 2015. Studies examined lidocaine, misoprostol, NSAIDs, and other interventions. Here we synthesize results from trials with sufficient outcome data and moderate- or high-quality evidence.For lidocaine, meta-analysis showed topical 2% gel had no effect on pain at tenaculum placement (two trials) or on pain during IUC insertion (three trials). Other formulations were effective compared with placebo in individual trials. Mean score for IUC-insertion pain was lower with lidocaine and prilocaine cream (MD -1.96, 95% CI -3.00 to -0.92). Among nulliparous women, topical 4% formulation showed lower scores for IUC-insertion pain assessed within 10 minutes (MD -15.90, 95% CI -22.77 to -9.03) and at 30 minutes later (MD -11.10, 95% CI -19.05 to -3.15). Among parous women, IUC-insertion pain was lower with 10% spray (median 1.00 versus 3.00). Compared with no intervention, pain at tenaculum placement was lower with 1% paracervical block (median 12 versus 28).For misoprostol, meta-analysis showed a higher mean score for IUC insertion compared with placebo (SMD 0.27, 95% CI 0.07 to 0.46; four studies). In meta-analysis, cramping was more likely with misoprostol (OR 2.64, 95% CI 1.46 to 4.76; four studies). A trial with nulliparous women found a higher score for IUC-insertion pain with misoprostol (median 46 versus 34). Pain before leaving the clinic was higher for misoprostol in two trials with nulliparous women (MD 7.60, 95% CI 6.48 to 8.72; medians 35.5 versus 20.5). In one trial with nulliparous women, moderate or severe pain at IUC insertion was less likely with misoprostol (OR 0.30, 95% CI 0.16 to 0.55). In the same trial, the misoprostol group was more likely to rate the experience favorably. Within two trials of misoprostol plus diclofenac, shivering, headache, or abdominal pain were more likely with misoprostol. Participants had no vaginal delivery. One trial showed the misoprostol group less likely to choose or recommend the treatment.Among multiparous women, mean score for IUC-insertion pain was lower for tramadol 50 mg versus naproxen 550 mg (MD -0.63, 95% CI -0.94 to -0.32) and for naproxen versus placebo (MD -1.94, 95% CI -2.35 to -1.53). The naproxen group was less likely than the placebo group to report the insertion experience as unpleasant and not want the medication in the future. An older trial showed repeated doses of naproxen 300 mg led to lower pain scores at one hour (MD -1.04, 95% CI -1.67 to -0.41) and two hours (MD -0.98, 95% CI -1.64 to -0.32) after insertion. Most women were nulliparous and also had lidocaine paracervical block. AUTHORS' CONCLUSIONS: Nearly all trials used modern IUC. Most effectiveness evidence was of moderate quality, having come from single trials. Lidocaine 2% gel, misoprostol, and most NSAIDs did not help reduce pain. Some lidocaine formulations, tramadol, and naproxen had some effect on reducing IUC insertion-related pain in specific groups. The ineffective interventions do not need further research.


Assuntos
Dispositivos Intrauterinos/efeitos adversos , Dor/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Feminino , Humanos , Ibuprofeno/uso terapêutico , Lidocaína/uso terapêutico , Misoprostol/uso terapêutico , Naproxeno/uso terapêutico , Ocitócicos/uso terapêutico , Dor/prevenção & controle , Prilocaína/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
14.
Biomed Res Int ; 2015: 269150, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25629041

RESUMO

Though pleiotropy, which refers to the phenomenon of a gene affecting multiple traits, has long played a central role in genetics, development, and evolution, estimation of the number of pleiotropy components remains a hard mission to accomplish. In this paper, we report a newly developed software package, Genepleio, to estimate the effective gene pleiotropy from phylogenetic analysis of protein sequences. Since this estimate can be interpreted as the minimum pleiotropy of a gene, it is used to play a role of reference for many empirical pleiotropy measures. This work would facilitate our understanding of how gene pleiotropy affects the pattern of genotype-phenotype map and the consequence of organismal evolution.


Assuntos
Pleiotropia Genética , Proteínas/química , Software , Sequência de Aminoácidos , Animais , Simulação por Computador , Bases de Dados Genéticas , Humanos
15.
Mol Genet Genomics ; 289(2): 137-47, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24322347

RESUMO

The age distribution of gene duplication events within the human genome exhibits two waves of duplications along with an ancient component. However, because of functional constraint differences, genes in different functional categories might show dissimilar retention patterns after duplication. It is known that genes in some functional categories are highly duplicated in the early stage of vertebrate evolution. However, the correlations of the age distribution pattern of gene duplication between the different functional categories are still unknown. To investigate this issue, we developed a robust pipeline to date the gene duplication events in the human genome. We successfully estimated about three-quarters of the duplication events within the human genome, along with the age distribution pattern in each Gene Ontology (GO) slim category. We found that some GO slim categories show different distribution patterns when compared to the whole genome. Further hierarchical clustering of the GO slim functional categories enabled grouping into two main clusters. We found that human genes located in the duplicated copy number variant regions, whose duplicate genes have not been fixed in the human population, were mainly enriched in the groups with a high proportion of recently duplicated genes. Moreover, we used a phylogenetic tree-based method to date the age of duplications in three signaling-related gene superfamilies: transcription factors, protein kinases and G-protein coupled receptors. These superfamilies were expressed in different subcellular localizations. They showed a similar age distribution as the signaling-related GO slim categories. We also compared the differences between the age distributions of gene duplications in multiple subcellular localizations. We found that the distribution patterns of the major subcellular localizations were similar to that of the whole genome. This study revealed the whole picture of the evolution patterns of gene functional categories in the human genome.


Assuntos
Evolução Molecular , Duplicação Gênica , Ontologia Genética , Genes , Família Multigênica , Distribuição por Idade , Genoma Humano , Humanos , Filogenia , Frações Subcelulares
16.
Mol Biol Evol ; 30(7): 1713-9, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23589455

RESUMO

DIVERGE is a software system for phylogeny-based analyses of protein family evolution and functional divergence. It provides a suite of statistical tools for selection and prioritization of the amino acid sites that are responsible for the functional divergence of a gene family. The synergistic efforts of DIVERGE and other methods have convincingly demonstrated that the pattern of rate change at a particular amino acid site may contain insightful information about the underlying functional divergence following gene duplication. These predicted sites may be used as candidates for further experiments. We are now releasing an updated version of DIVERGE with the following improvements: 1) a feasible approach to examining functional divergence in nearly complete sequences by including deletions and insertions (indels); 2) the calculation of the false discovery rate of functionally diverging sites; 3) estimation of the effective number of functional divergence-related sites that is reliable and insensitive to cutoffs; 4) a statistical test for asymmetric functional divergence; and 5) a new method to infer functional divergence specific to a given duplicate cluster. In addition, we have made efforts to improve software design and produce a well-written software manual for the general user.


Assuntos
Aminoácidos/genética , Duplicação Gênica , Filogenia , Proteínas/genética , Sequência de Aminoácidos , Animais , Evolução Molecular , Mutação INDEL , Modelos Genéticos , Família Multigênica , Proteínas/classificação , Software , Vertebrados/genética
17.
Biol Direct ; 5: 37, 2010 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-20497565

RESUMO

The debate of genomic correlations between sequence conservation, protein connectivity, gene essentiality and gene expression, has generated a number of new hypotheses that are challenging the classical framework of molecular evolution. For instance, the translational selection hypothesis claims that the determination of the rate of protein evolution is the protein stability to avoid the misfolding toxicity. In this short article, we propose that gene pleiotropy, the capacity for affecting multiple phenotypes, may play a vital role in molecular evolution. We discuss several approaches to testing this hypothesis.


Assuntos
Evolução Molecular , Proteínas/genética , Modelos Teóricos , Proteínas/classificação
18.
J Exp Zool B Mol Dev Evol ; 314(2): 115-22, 2010 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-19637279

RESUMO

Biologists have long recognized the importance of gene pleiotropy, that is, single genes affect multiple traits, which is one of the most commonly observed attributes of genes. Yet the extent of gene pleiotropy has been seriously under-explored. Theoretically, Fisher's model assumed a universal pleiotropy, that is, a mutation can potentially affect all phenotypic traits. On the other hand, experimental assays of a gene usually showed a few distinct phenotypes. Our recent work provides a new approach by estimating the degree of pleiotropy effectively from the phylogenetic sequence analysis. In this article, we estimated the effective gene pleiotropy for 321 vertebrate genes, and found that a gene typically affects 6-7 molecular phenotypes that correspond to the components of organismal fitness, respectively. The positive correlation of gene pleiotropy with the number of Gene Ontology biological processes, as well as the expression broadness provides a biological basis for the sequence-based estimation of gene pleiotropy. On the other hand, the degree of gene pleiotropy has been restricted to a digital number of molecular phenotypes, indicating that some cautions are needed for theoretical analysis of gene pleiotropy based on the assumption of universal pleiotropy.


Assuntos
Alelos , Variação Genética , Proteínas/genética , Vertebrados/genética , Sequência de Aminoácidos , Animais , Bovinos , Sequência Conservada , Cães , Evolução Molecular , Humanos , Camundongos , Modelos Genéticos , Fenótipo , Seleção Genética , Análise de Sequência de Proteína , Especificidade da Espécie
19.
J Exp Zool B Mol Dev Evol ; 312(7): 722-33, 2009 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-19373876

RESUMO

Genetical genomics, a novel approach combining microarray technology and quantitative genetic analysis, aims to identify the expression quantitative trait loci (eQTLs), which may regulate the genome-wide expression pattern. In this article, we have studied yeast genomic eQTL data to investigate how the genetic eQTL regulation of ancestral gene has diverged since gene duplication. Our findings are as follows: (i) Duplicate genes have higher heritability for gene expression than single-copy genes, but little difference in their epistasis and directional effect. (ii) The divergence of trans-acting eQTLs between duplicate pairs increases with the evolutionary time since gene duplication. (iii) Trans-acting eQTL divergence can explain about 21% of the variation in expression divergence between duplicate pairs with K(S)<2.0, which increases to 27% when the transcription factor (TF)-target interaction divergence is combined. Moreover, under the partial correlation analysis, trans-acting eQTL divergence seems make a bigger contribution to expression divergence than does TF divergence. (iv) Trans-acting eQTL divergence between duplicate pairs is correlated with gene ontology categories "Biological processes" and "Cellular components," but not with "Molecular functions," and is related to fitness defect under treatment conditions, but not with fitness under normal condition. We conclude that eQTL analysis provides a novel approach to explore the effect of gene duplications on the genetic regulatory network.


Assuntos
Regulação Fúngica da Expressão Gênica , Genes Duplicados , Genes Fúngicos , Variação Genética/genética , Genômica/métodos , Saccharomyces cerevisiae/genética , Locos de Características Quantitativas
20.
Sci China C Life Sci ; 49(1): 26-36, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16544573

RESUMO

A total of 28941 ESTs were sequenced from five 5'-directed non-normalized cDNA libraries, which were assembled into 2212 contigs and 5642 singlets using CAP3. These sequences were annotated and clustered into 6857 unique genes, 2072 of which having no functional annotations were considered as novel genes. These genes were further classified into Gene Ontology categories. By comparing the expression profiles, we identified some breed- and developmental-stage-specific gene groups. These genes may be relative to reproductive performance or play important roles in milk synthesis, secretion and mammary involution. The unknown EST sequences and expression profiles at different developmental stages and breeds are very important resources for further research.


Assuntos
Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Lactação/genética , Glândulas Mamárias Animais/metabolismo , Animais , Etiquetas de Sequências Expressas , Glândulas Mamárias Animais/fisiologia , Especificidade da Espécie , Suínos
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