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1.
Int J Mol Sci ; 22(14)2021 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-34299284

RESUMO

Forkhead box E1 (FOXE1) is a lineage-restricted transcription factor involved in thyroid cancer susceptibility. Cancer-associated polymorphisms map in regulatory regions, thus affecting the extent of gene expression. We have recently shown that genetic reduction of FOXE1 dosage modifies multiple thyroid cancer phenotypes. To identify relevant effectors playing roles in thyroid cancer development, here we analyse FOXE1-induced transcriptional alterations in thyroid cells that do not express endogenous FOXE1. Expression of FOXE1 elicits cell migration, while transcriptome analysis reveals that several immune cells-related categories are highly enriched in differentially expressed genes, including several upregulated chemokines involved in macrophage recruitment. Accordingly, FOXE1-expressing cells induce chemotaxis of co-cultured monocytes. We then asked if FOXE1 was able to regulate macrophage infiltration in thyroid cancers in vivo by using a mouse model of cancer, either wild type or with only one functional FOXE1 allele. Expression of the same set of chemokines directly correlates with FOXE1 dosage, and pro-tumourigenic M2 macrophage infiltration is decreased in tumours with reduced FOXE1. These data establish a novel link between FOXE1 and macrophages recruitment in the thyroid cancer microenvironment, highlighting an unsuspected function of this gene in the crosstalk between neoplastic and immune cells that shape tumour development and progression.


Assuntos
Quimiotaxia/fisiologia , Fatores de Transcrição Forkhead/genética , Macrófagos/patologia , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/biossíntese , Fatores de Transcrição Forkhead/metabolismo , Humanos , Técnicas In Vitro , Macrófagos/citologia , Camundongos , Camundongos Knockout , Ratos , Ratos Endogâmicos F344 , Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo
2.
Trends Genet ; 36(9): 650-663, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32736810

RESUMO

High-throughput sequencing and genome-wide association studies have revealed a sex bias in human diseases. The underlying molecular mechanisms remain, however, unknown. Here, we cover recent advances in cancer and autoimmunity focusing on intrinsic genetic and epigenetic differences underlying sex biases in human disease. These studies reveal a central role of genome regulatory mechanisms including genome repair, chromosome folding, and epigenetic regulation in dictating the sex bias. These highlight the importance of considering sex as a variable in both basic science and clinical investigations. Understanding the molecular mechanisms underlying sex bias in human diseases will be instrumental in making a first step forwards into the era of personalized medicine.


Assuntos
Autoimunidade/genética , Epigênese Genética , Estudo de Associação Genômica Ampla , Neoplasias/genética , Medicina de Precisão , Humanos , Fatores Sexuais
3.
Nat Commun ; 11(1): 310, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964862

RESUMO

Regulations currently in force enable to claim that the lead content in perovskite solar cells is low enough to be safe, or no more dangerous, than other electronics also containing lead. However, the actual environmental impact of lead from perovskite is unknown. Here we show that the lead from perovskite leaking into the ground can enter plants, and consequently the food cycle, ten times more effectively than other lead contaminants already present as the result of the human activities. We further demonstrate that replacing lead with tin represents an environmentally-safer option. Our data suggest that we need to treat the lead from perovskite with exceptional care. In particular, we point out that the safety level for lead content in perovskite-based needs to be lower than other lead-containing electronics. We encourage replacing lead completely with more inert metals to deliver safe perovskite technologies.


Assuntos
Compostos de Cálcio/normas , Chumbo/normas , Mentha spicata/efeitos dos fármacos , Óxidos/normas , Poluentes do Solo/normas , Níveis Máximos Permitidos , Titânio/normas , Compostos de Cálcio/química , Compostos de Cálcio/toxicidade , Eletrônica/normas , Chumbo/toxicidade , Óxidos/química , Óxidos/toxicidade , Solo/química , Poluentes do Solo/toxicidade , Energia Solar/normas , Titânio/química , Titânio/toxicidade
4.
Front Cell Dev Biol ; 7: 385, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32010697

RESUMO

Embryonic stem cells (ESCs) are derived from inner cell mass (ICM) of the blastocyst. In serum/LIF culture condition, they show variable expression of pluripotency genes that mark cell fluctuation between pluripotency and differentiation metastate. The ESCs subpopulation marked by zygotic genome activation gene (ZGA) signature, including Zscan4, retains a wider differentiation potency than epiblast-derived ESCs. We have recently shown that retinoic acid (RA) significantly enhances Zscan4 cell population. However, it remains unexplored how RA initiates the ESCs to 2-cell like reprogramming. Here we found that RA is decisive for ESCs to 2C-like cell transition, and reconstructed the gene network surrounding Zscan4. We revealed that RA regulates 2C-like population co-activating Dux and Duxbl1. We provided novel evidence that RA dependent ESCs to 2C-like cell transition is regulated by Dux, and antagonized by Duxbl1. Our suggested mechanism could shed light on the role of RA on ESC reprogramming.

5.
Philos Trans R Soc Lond B Biol Sci ; 372(1733)2017 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-28947657

RESUMO

X-chromosome inactivation (XCI) is an exemplar of epigenetic regulation that is set up as pluripotent cells differentiate. Once established, XCI is stably propagated, but can be reversed in vivo or by pluripotent reprogramming in vitro Although reprogramming provides a useful model for inactive X (Xi) reactivation in mouse, the relative instability and heterogeneity of human embryonic stem (ES) cells and induced pluripotent stem cells hampers comparable progress in human. Here we review studies aimed at reactivating the human Xi using different reprogramming strategies. We outline our recent results using mouse ES cells to reprogramme female human fibroblasts by cell-cell fusion. We show that pluripotent reprogramming induces widespread and rapid chromatin remodelling in which the human Xi loses XIST and H3K27m3 enrichment and selected Xi genes become reactivated, ahead of mitotic division. Using RNA sequencing to map the extent of human Xi reactivation, and chromatin-modifying drugs to potentiate reactivation, we outline how this approach could be used to better design strategies to re-express human X-linked loci. As cell fusion induces the expression of human pluripotency genes that represent both the 'primed' and 'naive' states, this approach may also offer a fresh opportunity to segregate human pluripotent states with distinct Xi expression profiles, using single-cell-based approaches.This article is part of the themed issue 'X-chromosome inactivation: a tribute to Mary Lyon'.


Assuntos
Reprogramação Celular , Cromossomos Humanos X/genética , Predisposição Genética para Doença/genética , Inativação do Cromossomo X/genética , Animais , Linhagem Celular , Células-Tronco Embrionárias/fisiologia , Feminino , Fibroblastos , Humanos , Camundongos , RNA Longo não Codificante
6.
Genome Biol ; 18(1): 2, 2017 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-28118853

RESUMO

BACKGROUND: Inactivation of one X chromosome is established early in female mammalian development and can be reversed in vivo and in vitro when pluripotency factors are re-expressed. The extent of reactivation along the inactive X chromosome (Xi) and the determinants of locus susceptibility are, however, poorly understood. Here we use cell fusion-mediated pluripotent reprograming to study human Xi reactivation and allele-specific single nucleotide polymorphisms (SNPs) to identify reactivated loci. RESULTS: We show that a subset of human Xi genes is rapidly reactivated upon re-expression of the pluripotency network. These genes lie within the most evolutionary recent segments of the human X chromosome that are depleted of LINE1 and enriched for SINE elements, predicted to impair XIST spreading. Interestingly, this cadre of genes displays stochastic Xi expression in human fibroblasts ahead of reprograming. This stochastic variability is evident between clones, by RNA-sequencing, and at the single-cell level, by RNA-FISH, and is not attributable to differences in repressive histone H3K9me3 or H3K27me3 levels. Treatment with the DNA demethylating agent 5-deoxy-azacytidine does not increase Xi expression ahead of reprograming, but instead reveals a second cadre of genes that only become susceptible to reactivation upon induction of pluripotency. CONCLUSIONS: Collectively, these data not only underscore the multiple pathways that contribute to maintaining silencing along the human Xi chromosome but also suggest that transcriptional stochasticity among human cells could be useful for predicting and engineering epigenetic strategies to achieve locus-specific or domain-specific human Xi gene reactivation.


Assuntos
Alelos , Fusão Celular , Reprogramação Celular , Genes Ligados ao Cromossomo X , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Ativação Transcricional , Cromatina/genética , Cromatina/metabolismo , Análise por Conglomerados , Metilação de DNA , Células-Tronco Embrionárias/metabolismo , Feminino , Fibroblastos , Expressão Gênica , Perfilação da Expressão Gênica , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Polimorfismo de Nucleotídeo Único , Inativação do Cromossomo X/genética
7.
Nat Commun ; 7: 12354, 2016 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-27507283

RESUMO

Erasure of epigenetic memory is required to convert somatic cells towards pluripotency. Reactivation of the inactive X chromosome (Xi) has been used to model epigenetic reprogramming in mouse, but human studies are hampered by Xi epigenetic instability and difficulties in tracking partially reprogrammed iPSCs. Here we use cell fusion to examine the earliest events in the reprogramming-induced Xi reactivation of human female fibroblasts. We show that a rapid and widespread loss of Xi-associated H3K27me3 and XIST occurs in fused cells and precedes the bi-allelic expression of selected Xi-genes by many heterokaryons (30-50%). After cell division, RNA-FISH and RNA-seq analyses confirm that Xi reactivation remains partial and that induction of human pluripotency-specific XACT transcripts is rare (1%). These data effectively separate pre- and post-mitotic events in reprogramming-induced Xi reactivation and reveal a complex hierarchy of epigenetic changes that are required to reactivate the genes on the human Xi chromosome.


Assuntos
Reprogramação Celular/genética , Cromatina/genética , Cromossomos Humanos X/genética , Histonas/genética , RNA Longo não Codificante/genética , Inativação do Cromossomo X/genética , Animais , Fusão Celular/métodos , Linhagem Celular , Núcleo Celular/genética , Núcleo Celular/metabolismo , Epigênese Genética , Feminino , Fibroblastos , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Camundongos , Mitose , Células-Tronco Embrionárias Murinas/metabolismo
8.
Cell Rep ; 12(4): 573-86, 2015 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-26190104

RESUMO

Jarid2 is part of the Polycomb Repressor complex 2 (PRC2) responsible for genome-wide H3K27me3 deposition. Unlike other PRC2-deficient embryonic stem cells (ESCs), however, Jarid2-deficient ESCs show a severe differentiation block, altered colony morphology, and distinctive patterns of deregulated gene expression. Here, we show that Jarid2(-/-) ESCs express constitutively high levels of Nanog but reduced PCP signaling components Wnt9a, Prickle1, and Fzd2 and lowered ß-catenin activity. Depletion of Wnt9a/Prickle1/Fzd2 from wild-type ESCs or overexpression of Nanog largely phenocopies these cellular defects. Co-culture of Jarid2(-/-) with wild-type ESCs restores variable Nanog expression and ß-catenin activity and can partially rescue the differentiation block of mutant cells. In addition, we show that ESCs lacking Jarid2 or Wnt9a/Prickle1/Fzd2 or overexpressing Nanog induce multiple ICM formation when injected into normal E3.5 blastocysts. These data describe a previously unrecognized role for Jarid2 in regulating a core pluripotency and Wnt/PCP signaling circuit that is important for ESC differentiation and for pre-implantation development.


Assuntos
Blastocisto/metabolismo , Diferenciação Celular , Células-Tronco Embrionárias/metabolismo , Proteínas de Homeodomínio/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Via de Sinalização Wnt , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Células Cultivadas , Células-Tronco Embrionárias/citologia , Receptores Frizzled/genética , Receptores Frizzled/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo , Camundongos , Proteína Homeobox Nanog , Complexo Repressor Polycomb 2/genética , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
9.
Nat Struct Mol Biol ; 20(3): 282-9, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23463313

RESUMO

Cell identity is determined by specific gene expression patterns that are conveyed by interactions between transcription factors and DNA in the context of chromatin. In development, epigenetic modifiers are thought to stabilize gene expression and ensure that patterns of DNA methylation and histone modification are reinstated in cells as they divide. Global erasure of epigenetic marks occurs naturally at two stages in the mammalian life cycle, but it can also be artificially engineered using a variety of reprogramming strategies. Here we review some of the recent advances in understanding how epigenetic remodeling contributes to conversion of cell fate in vivo and in vitro. We summarize current models of epigenetic erasure and discuss the various enzymes and mechanisms that may operate in cellular reprogramming.


Assuntos
Diferenciação Celular/genética , Metilação de DNA , Epigênese Genética , Regulação da Expressão Gênica no Desenvolvimento , Animais , Blastocisto/fisiologia , Cromatina/genética , Cromatina/metabolismo , Células Germinativas , Histonas/genética , Histonas/metabolismo , Humanos , Mamíferos/embriologia , Mamíferos/genética , Mamíferos/crescimento & desenvolvimento , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
10.
Cell ; 152(4): 873-83, 2013 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-23415233

RESUMO

Embryonic stem cells (ESCs) can instruct the conversion of differentiated cells toward pluripotency following cell-to-cell fusion by a mechanism that is rapid but poorly understood. Here, we used centrifugal elutriation to enrich for mouse ESCs at sequential stages of the cell cycle and showed that ESCs in S/G2 phases have an enhanced capacity to dominantly reprogram lymphocytes and fibroblasts in heterokaryon and hybrid assays. Reprogramming success was associated with an ability to induce precocious nucleotide incorporation within the somatic partner nuclei in heterokaryons. BrdU pulse-labeling experiments revealed that virtually all successfully reprogrammed somatic nuclei, identified on the basis of Oct4 re-expression, had undergone DNA synthesis within 24 hr of fusion with ESCs. This was essential for successful reprogramming because drugs that inhibited DNA polymerase activity effectively blocked pluripotent conversion. These data indicate that nucleotide incorporation is an early and critical event in the epigenetic reprogramming of somatic cells in experimental ESC-heterokaryons.


Assuntos
Replicação do DNA , Células-Tronco Embrionárias/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Animais , Linfócitos B/citologia , Fusão Celular , Núcleo Celular/metabolismo , Reprogramação Celular , Células-Tronco Embrionárias/citologia , Fibroblastos/citologia , Humanos , Camundongos , Nucleotídeos/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo
11.
Philos Trans R Soc Lond B Biol Sci ; 366(1575): 2260-5, 2011 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-21727131

RESUMO

Reprogramming differentiated cells towards pluripotency can be achieved by different experimental strategies including the forced expression of specific 'inducers' and nuclear transfer. While these offer unparalleled opportunities to generate stem cells and advance disease modelling, the relatively low levels of successful reprogramming achieved (1-2%) makes a direct analysis of the molecular events associated with productive reprogramming very challenging. The generation of transient heterokaryons between human differentiated cells (such as lymphocytes or fibroblasts) and mouse pluripotent stem cell lines results in a much higher frequency of successful conversion (15% SSEA4 expressing cells) and provides an alternative approach to study early events during reprogramming. Under these conditions, differentiated nuclei undergo a series of remodelling events before initiating human pluripotent gene expression and silencing differentiation-associated genes. When combined with genetic or RNAi-based approaches and high-throughput screens, heterokaryon studies can provide important new insights into the factors and mechanisms required to reprogramme unipotent cells towards pluripotency.


Assuntos
Diferenciação Celular/fisiologia , Reprogramação Celular/fisiologia , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/fisiologia , Animais , Técnicas Citológicas/métodos , Humanos
12.
Cell Stem Cell ; 8(2): 128-9, 2011 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-21295268

RESUMO

In recent publications in Nature and PNAS, Rada-Iglesias et al. (2010) and Creyghton et al. (2010) have uncovered unique chromatin signatures of developmental enhancers marking active, primed, or silent genes in human and mouse embryonic stem cells.

13.
Bioinformatics ; 26(18): i603-10, 2010 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-20823328

RESUMO

MOTIVATION: Investigating the relation between the structure and behavior of complex biological networks often involves posing the question if the hypothesized structure of a regulatory network is consistent with the observed behavior, or if a proposed structure can generate a desired behavior. RESULTS: The above questions can be cast into a parameter search problem for qualitative models of regulatory networks. We develop a method based on symbolic model checking that avoids enumerating all possible parametrizations, and show that this method performs well on real biological problems, using the IRMA synthetic network and benchmark datasets. We test the consistency between IRMA and time-series expression profiles, and search for parameter modifications that would make the external control of the system behavior more robust. AVAILABILITY: GNA and the IRMA model are available at http://ibis.inrialpes.fr/.


Assuntos
Simulação por Computador , Redes Reguladoras de Genes , Modelos Genéticos , Benchmarking , Processamento Eletrônico de Dados , Regulação Fúngica da Expressão Gênica , Software , Simbolismo , Biologia de Sistemas , Leveduras/genética
14.
PLoS One ; 4(12): e8083, 2009 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-19997611

RESUMO

Systems and Synthetic Biology use computational models of biological pathways in order to study in silico the behaviour of biological pathways. Mathematical models allow to verify biological hypotheses and to predict new possible dynamical behaviours. Here we use the tools of non-linear analysis to understand how to change the dynamics of the genes composing a novel synthetic network recently constructed in the yeast Saccharomyces cerevisiae for In-vivo Reverse-engineering and Modelling Assessment (IRMA). Guided by previous theoretical results that make the dynamics of a biological network depend on its topological properties, through the use of simulation and continuation techniques, we found that the network can be easily turned into a robust and tunable synthetic oscillator or a bistable switch. Our results provide guidelines to properly re-engineering in vivo the network in order to tune its dynamics.


Assuntos
Relógios Biológicos/genética , Genes de Troca/genética , Saccharomyces cerevisiae/genética , Simulação por Computador , Retroalimentação Fisiológica , Regulação Fúngica da Expressão Gênica , Genes Fúngicos/genética , Fatores de Tempo
15.
Cell ; 137(1): 172-81, 2009 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-19327819

RESUMO

Systems biology approaches are extensively used to model and reverse engineer gene regulatory networks from experimental data. Conversely, synthetic biology allows "de novo" construction of a regulatory network to seed new functions in the cell. At present, the usefulness and predictive ability of modeling and reverse engineering cannot be assessed and compared rigorously. We built in the yeast Saccharomyces cerevisiae a synthetic network, IRMA, for in vivo "benchmarking" of reverse-engineering and modeling approaches. The network is composed of five genes regulating each other through a variety of regulatory interactions; it is negligibly affected by endogenous genes, and it is responsive to small molecules. We measured time series and steady-state expression data after multiple perturbations. These data were used to assess state-of-the-art modeling and reverse-engineering techniques. A semiquantitative model was able to capture and predict the behavior of the network. Reverse engineering based on differential equations and Bayesian networks correctly inferred regulatory interactions from the experimental data.


Assuntos
Redes Reguladoras de Genes , Técnicas Genéticas , Modelos Genéticos , Saccharomyces cerevisiae/genética , Biologia de Sistemas/métodos , Biologia Computacional/métodos , Galactose/metabolismo , Perfilação da Expressão Gênica , Regulação Fúngica da Expressão Gênica , Glucose/metabolismo , Saccharomyces cerevisiae/metabolismo
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