Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 131
Filtrar
Más filtros

Banco de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
Cell ; 146(6): 1016-28, 2011 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-21925322

RESUMEN

We report the identification of 67 previously undescribed histone modifications, increasing the current number of known histone marks by about 70%. We further investigated one of the marks, lysine crotonylation (Kcr), confirming that it represents an evolutionarily-conserved histone posttranslational modification. The unique structure and genomic localization of histone Kcr suggest that it is mechanistically and functionally different from histone lysine acetylation (Kac). Specifically, in both human somatic and mouse male germ cell genomes, histone Kcr marks either active promoters or potential enhancers. In male germinal cells immediately following meiosis, Kcr is enriched on sex chromosomes and specifically marks testis-specific genes, including a significant proportion of X-linked genes that escape sex chromosome inactivation in haploid cells. These results therefore dramatically extend the repertoire of histone PTM sites and designate Kcr as a specific mark of active sex chromosome-linked genes in postmeiotic male germ cells.


Asunto(s)
Regulación de la Expresión Génica , Código de Histonas , Animales , Células HeLa , Histonas/química , Histonas/metabolismo , Humanos , Lisina/metabolismo , Masculino , Meiosis , Ratones , Procesamiento Proteico-Postraduccional , Testículo/citología , Testículo/metabolismo
2.
Mol Cell ; 66(1): 89-101.e8, 2017 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-28366643

RESUMEN

Histone replacement by transition proteins (TPs) and protamines (Prms) constitutes an essential step for the successful production of functional male gametes, yet nothing is known on the underlying functional interplay between histones, TPs, and Prms. Here, by studying spermatogenesis in the absence of a spermatid-specific histone variant, H2A.L.2, we discover a fundamental mechanism involved in the transformation of nucleosomes into nucleoprotamines. H2A.L.2 is synthesized at the same time as TPs and enables their loading onto the nucleosomes. TPs do not displace histones but rather drive the recruitment and processing of Prms, which are themselves responsible for histone eviction. Altogether, the incorporation of H2A.L.2 initiates and orchestrates a series of successive transitional states that ultimately shift to the fully compacted genome of the mature spermatozoa. Hence, the current view of histone-to-nucleoprotamine transition should be revisited and include an additional step with H2A.L.2 assembly prior to the action of TPs and Prms.


Asunto(s)
Ensamble y Desensamble de Cromatina , Cromatina/metabolismo , Histonas/metabolismo , Nucleosomas/metabolismo , Protaminas/metabolismo , Espermatogénesis , Espermatozoides/metabolismo , Animales , Células COS , Chlorocebus aethiops , Cromatina/genética , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Biología Computacional , Bases de Datos Genéticas , Fertilidad , Regulación del Desarrollo de la Expresión Génica , Predisposición Genética a la Enfermedad , Genoma , Histonas/deficiencia , Histonas/genética , Infertilidad Masculina/genética , Infertilidad Masculina/metabolismo , Infertilidad Masculina/patología , Infertilidad Masculina/fisiopatología , Masculino , Ratones de la Cepa 129 , Ratones Noqueados , Nucleosomas/genética , Fenotipo , Espermatogénesis/genética , Espermatozoides/patología , Transfección
3.
Acc Chem Res ; 56(24): 3581-3594, 2023 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-38047525

RESUMEN

ConspectusThe Barton-McCombie deoxygenation reaction first established the use of O-alkyl thiocarbonyl derivatives as powerful redox-active agents for C(sp3)-O reduction. In recent years, first-row transition metals capable of engaging with alkyl radical intermediates generated from O-alkyl thiocarbonyl derivatives using alternative stoichiometric radical precursors have been developed. Given the ability of select Ni catalysts to both participate in single-electron oxidative addition pathways and intercept alkyl radical intermediates, our group has investigated the use of O-alkyl thiocarbonyl derivatives as electrophiles in novel cross-coupling reactions. After describing related work in this area, this Account will first summarize our entry point into this field. Here, we used the cyclopropane ring as a reporter of leaving group reactivity to aid in the design and optimization of a novel redox-active O-thiocarbamate leaving group for C(sp3)-O arylation. Motivation for this pursuit was driven by the propensity of the cyclopropane ring to undergo ring opening under polar (2e) oxidative addition pathways or to be maintained under single-electron (1e) conditions. Using these guiding principles, we developed a method for the deoxygenative arylation of cyclopropanol derivatives using a Ni catalyst without the need for a stoichiometric external reductant or photocatalyst. We next summarize our evaluation of an alternative redox-active O-thiocarbonyl imidazole auxiliary in a related deoxygenative cross-coupling. This work demonstrated an extension of our initial approach to the deoxygenative arylation of primary and secondary aliphatic alcohol derivatives. A brief mechanistic investigation revealed that this reaction likely proceeds via a distinct mechanism involving direct homolytic C(sp3)-O bond cleavage. We conclude this Account with a summary of work aimed toward a unique approach for thiocarboxylic acid derivative synthesis. This project was inspired by the efficiency of thionoester generation under most of the reaction conditions evaluated in our prior investigations. Using alcohol, amine, or thiol starting materials, which were activated with convenient thiocarbonyl sources in a single step, we optimized for a Ni-catalyzed cross-coupling capable of providing access to a range of thionoester, thioamide, or dithioester products. In summary, our work has revealed the potential of redox-active thiocarbonyl auxiliaries in Ni-catalyzed cross-couplings with C(sp3)-O electrophiles. We anticipate that the continued investigation of aliphatic thiocarbonyl derivatives as radical precursors with alternative single-electron inputs will be an area of continued growth in the years to come.

4.
J Org Chem ; 2024 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-38197128

RESUMEN

A nickel-catalyzed reductive cross-coupling of redox active N-hydroxyphthalimide (NHP) esters and iodoarenes for the synthesis of α-aryl nitriles is described. The NHP ester substrate is derived from cyanoacetic acid, which allows for a modular synthesis of substituted α-aryl nitriles, an important scaffold in the pharmaceutical sciences. The reaction exhibits a broad scope, and many functional groups are compatible under the reaction conditions, including complex highly functionalized medicinal agents. Mechanistic studies reveal that reduction and decarboxylation of the NHP ester to the reactive radical intermediate are accomplished by a combination of a chlorosilane additive and Zn dust. We demonstrate that stoichiometric chlorosilane is essential for product formation and that chlorosilane plays a role beyond activation of the metal reductant.

5.
Mol Cell ; 62(2): 169-180, 2016 04 21.
Artículo en Inglés | MEDLINE | ID: mdl-27105113

RESUMEN

Recently discovered histone lysine acylation marks increase the functional diversity of nucleosomes well beyond acetylation. Here, we focus on histone butyrylation in the context of sperm cell differentiation. Specifically, we investigate the butyrylation of histone H4 lysine 5 and 8 at gene promoters where acetylation guides the binding of Brdt, a bromodomain-containing protein, thereby mediating stage-specific gene expression programs and post-meiotic chromatin reorganization. Genome-wide mapping data show that highly active Brdt-bound gene promoters systematically harbor competing histone acetylation and butyrylation marks at H4 K5 and H4 K8. Despite acting as a direct stimulator of transcription, histone butyrylation competes with acetylation, especially at H4 K5, to prevent Brdt binding. Additionally, H4 K5K8 butyrylation also marks retarded histone removal during late spermatogenesis. Hence, alternating H4 acetylation and butyrylation, while sustaining direct gene activation and dynamic bromodomain binding, could impact the final male epigenome features.


Asunto(s)
Butiratos/metabolismo , Epigénesis Genética , Regulación del Desarrollo de la Expresión Génica , Histonas/metabolismo , Proteínas Nucleares/genética , Regiones Promotoras Genéticas , Procesamiento Proteico-Postraduccional , Espermatocitos/metabolismo , Acetilación , Animales , Sitios de Unión , Diferenciación Celular , Ensamble y Desensamble de Cromatina , Estudio de Asociación del Genoma Completo , Histonas/química , Histonas/genética , Lisina , Masculino , Ratones , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Conformación Proteica , Relación Estructura-Actividad , Transcripción Genética , Activación Transcripcional
6.
Angew Chem Int Ed Engl ; 63(17): e202402912, 2024 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-38418404

RESUMEN

Despite the importance of heteroatom-substituted cyclopropane derivatives in drug design and organic synthesis, cyclopropanethiols remain critically underexplored. Inspired by the wide use of the Newman-Kwart rearrangement to access valuable thiophenols from phenol feedstocks, we report the development of a photocatalytic approach for efficient ambient temperature aliphatic O- to S-rearrangement on tertiary cyclopropanol derivatives. After demonstrating that a range of cyclopropanethiols-that are difficult to access by other methods-can be obtained with this strategy, we show that these rearranged products can be easily hydrolyzed and further derivatized. We conclude this study with mechanistic findings that enabled an initial extension of this approach toward other classes of aliphatic alcohols.

7.
BMC Genomics ; 24(1): 463, 2023 Aug 17.
Artículo en Inglés | MEDLINE | ID: mdl-37592220

RESUMEN

BACKGROUND: In breast cancer, as in all cancers, genetic and epigenetic deregulations can result in out-of-context expressions of a set of normally silent tissue-specific genes. The activation of some of these genes in various cancers empowers tumours cells with new properties and drives enhanced proliferation and metastatic activity, leading to a poor survival prognosis. RESULTS: In this work, we undertook an unprecedented systematic and unbiased analysis of out-of-context activations of a specific set of tissue-specific genes from testis, placenta and embryonic stem cells, not expressed in normal breast tissue as a source of novel prognostic biomarkers. To this end, we combined a strict machine learning framework of transcriptomic data analysis, and successfully created a new robust tool, validated in several independent datasets, which is able to identify patients with a high risk of relapse. This unbiased approach allowed us to identify a panel of five biomarkers, DNMT3B, EXO1, MCM10, CENPF and CENPE, that are robustly and significantly associated with disease-free survival prognosis in breast cancer. Based on these findings, we created a new Gene Expression Classifier (GEC) that stratifies patients. Additionally, thanks to the identified GEC, we were able to paint the specific molecular portraits of the particularly aggressive tumours, which show characteristics of male germ cells, with a particular metabolic gene signature, associated with an enrichment in pro-metastatic and pro-proliferation gene expression. CONCLUSIONS: The GEC classifier is able to reliably identify patients with a high risk of relapse at early stages of the disease. We especially recommend to use the GEC tool for patients with the luminal-A molecular subtype of breast cancer, generally considered of a favourable disease-free survival prognosis, to detect the fraction of patients undergoing a high risk of relapse.


Asunto(s)
Neoplasias de la Mama , Femenino , Embarazo , Humanos , Masculino , Neoplasias de la Mama/genética , Recurrencia Local de Neoplasia/genética , Genes cdc , Mama , Enfermedad Crónica , Células Madre Embrionarias
8.
J Am Chem Soc ; 2023 Nov 04.
Artículo en Inglés | MEDLINE | ID: mdl-37924301

RESUMEN

The development of a nickel-catalyzed reductive alkyne hydrocyanation is described using 2-methyl-2-phenylmalononitrile (MPMN), a C-bound electrophilic transnitrilation reagent. Reproducibility issues led to the detection of oxidized hemiaminal impurities within N,N-dimethylacetamide. These impurities release formaldehyde in situ, which was ultimately identified as a critical reaction additive. A range of diaryl and aryl-alkyl alkynes underwent hydrocyanation. Mechanistic experiments revealed that formaldehyde and MPMN undergo a Ni-catalyzed reductive coupling of two π-components, leading to the controlled release of glycolonitrile as the active cyanating agent.

9.
Chem Rev ; 121(1): 3-79, 2021 01 13.
Artículo en Inglés | MEDLINE | ID: mdl-33085458

RESUMEN

The carbon-carbon (C-C) bond cleavage of cyclopropanols is a wide area of research with much current activity. This review highlights new developments in this area over the past two decades. A summary is made of the three main reactivity modes, namely, homoenolate chemistry, ß-keto radical chemistry, and acid-catalyzed ring-opening, as well as all other methods for the C-C bond cleavage and functionalization of cyclopropanols, including base-mediated ring-opening, metal-catalyzed C-C insertions and eliminations, oxidative fragmentation using hypervalent iodine reagents, reactions of donor-acceptor cyclopropanols, and pericylic reactions. Emphasis is placed on the synthetic utility of cyclopropanols and related derivatives, which have emerged as unique three-carbon synthons.

10.
BMC Genomics ; 23(1): 467, 2022 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-35751016

RESUMEN

BACKGROUND: T cell acute lymphoblastic leukemia (T-ALL) defines a group of hematological malignancies with heterogeneous aggressiveness and highly variable outcome, making therapeutic decisions a challenging task. We tried to discover new predictive model for T-ALL before treatment by using a specific pipeline designed to discover aberrantly active gene. RESULTS: The expression of 18 genes was significantly associated with shorter survival, including ACTRT2, GOT1L1, SPATA45, TOPAZ1 and ZPBP (5-GEC), which were used as a basis to design a prognostic classifier for T-ALL patients. The molecular characterization of the 5-GEC positive T-ALL unveiled specific characteristics inherent to the most aggressive T leukemic cells, including a drastic shut-down of genes located on the mitochondrial genome and an upregulation of histone genes, the latter characterizing high risk forms in adult patients. These cases fail to respond to the induction treatment, since 5-GEC either predicted positive minimal residual disease (MRD) or a short-term relapse in MRD negative patients. CONCLUSION: Overall, our investigations led to the discovery of a homogenous group of leukemic cells with profound alterations of their biology. It also resulted in an accurate predictive tool that could significantly improve the management of T-ALL patients.


Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Adulto , Expresión Génica Ectópica , Humanos , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Pronóstico , Linfocitos T/patología , Resultado del Tratamiento
11.
Mol Hum Reprod ; 28(2)2022 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-35150275

RESUMEN

Histone-to-protamine transition is an essential step in the generation of fully functional spermatozoa in various mammalian species. In human and mouse, one of the two protamine-encoding genes produces a precursor pre-protamine 2 (pre-PRM2) protein, which is then processed and assembled. Here, we design an original approach based on the generation of pre-PRM2-specific antibodies to visualize the unprocessed pre-PRM2 by microscopy, flow cytometry and immunoblotting. Using mouse models with characterized failures in histone-to-protamine replacement, we show that pre-PRM2 retention is tightly linked to impaired nucleosome disassembly. Additionally, in elongating/condensing spermatids, we observe that pre-PRM2 and transition protein are co-expressed spatiotemporally, and their physical interaction suggests that these proteins act simultaneously rather than successively during histone replacement. By using our anti-human pre-PRM2 antibody, we also measured pre-PRM2 retention rates in the spermatozoa from 49 men of a series of infertile couples undergoing ICSI, which shed new light on the debated relation between pre-PRM2 retention and sperm parameters. Finally, by monitoring 2-pronuclei embryo formation following ICSI, we evaluated the fertilization ability of the sperm in these 49 patients. Our results suggest that the extent of pre-PRM2 retention in sperm, rather than pre-PRM2 accumulation per se, is associated with fertilization failure. Hence, anti-pre-PRM2 antibodies are valuable tools that could be used in routine monitoring of sperm parameters in fertility clinics, as well as in experimental research programmes to better understand the obscure process of histone-to-protamine transition.


Asunto(s)
Histonas , Inyecciones de Esperma Intracitoplasmáticas , Animales , Femenino , Histonas/metabolismo , Humanos , Masculino , Mamíferos , Ratones , Protaminas/metabolismo , Espermatozoides/metabolismo
12.
Ann Hematol ; 101(12): 2633-2643, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36195681

RESUMEN

In low-risk myelodysplastic syndrome (LR-MDS), erythropoietin (EPO) is widely used for the treatment of chronic anemia. However, initial response to EPO has time-limited effects. Luspatercept reduces red blood cell transfusion dependence in LR-MDS patients. Here, we investigated the molecular action of luspatercept (RAP-536) in an in vitro model of erythroid differentiation of MDS, and also in a in vivo PDX murine model with primary samples of MDS patients carrying or not SF3B1 mutation. In our in vitro model, RAP-536 promotes erythroid proliferation by increasing the number of cycling cells without any impact on apoptosis rates. RAP-536 promoted late erythroid precursor maturation while decreasing intracellular reactive oxygen species level. RNA sequencing of erythroid progenitors obtained under RAP-536 treatment showed an enrichment of genes implicated in positive regulation of response to oxidative stress and erythroid differentiation. In our PDX model, RAP-536 induces a higher hemoglobin level. RAP-536 did not modify variant allele frequencies in vitro and did not have any effect against leukemic burden in our PDX model. These results suggest that RAP-536 promotes in vivo and in vitro erythroid cell differentiation by decreasing ROS level without any remarkable impact on iron homeostasis and on mutated allele burden.


Asunto(s)
Síndromes Mielodisplásicos , Humanos , Ratones , Animales , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/genética , Mutación , Estrés Oxidativo
13.
Org Biomol Chem ; 20(30): 5933-5937, 2022 08 03.
Artículo en Inglés | MEDLINE | ID: mdl-35315852

RESUMEN

Quaternary α-(hetero)arylnitriles are desirable biologically relevant products, however the existing methods for their synthesis can be unselective or require the use of undesirable reagents, such as cyanide salts. Herein we report a one-pot method for transnitrilation-mediated decyanation-metalation of disubstituted malononitriles, followed by treatment with (hetero)aryl electrophiles to access quaternary α-(hetero)arylnitrile products. A number of products were prepared using this method (34 examples, 27-99% yield). This method highlights the usefulness of malononitriles as precursors for alkylnitrile-containing compounds.


Asunto(s)
Sales (Química) , Catálisis , Indicadores y Reactivos , Nitrilos
14.
Int J Mol Sci ; 23(3)2022 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-35163833

RESUMEN

Preventing the cytokine storm observed in COVID-19 is a crucial goal for reducing the occurrence of severe acute respiratory failure and improving outcomes. Here, we identify Aldo-Keto Reductase 1B10 (AKR1B10) as a key enzyme involved in the expression of pro-inflammatory cytokines. The analysis of transcriptomic data from lung samples of patients who died from COVID-19 demonstrates an increased expression of the gene encoding AKR1B10. Measurements of the AKR1B10 protein in sera from hospitalised COVID-19 patients suggests a significant link between AKR1B10 levels and the severity of the disease. In macrophages and lung cells, the over-expression of AKR1B10 induces the expression of the pro-inflammatory cytokines Interleukin-6 (IL-6), Interleukin-1ß (IL-1ß) and Tumor Necrosis Factor a (TNFα), supporting the biological plausibility of an AKR1B10 involvement in the COVID-19-related cytokine storm. When macrophages were stressed by lipopolysaccharides (LPS) exposure and treated by Zopolrestat, an AKR1B10 inhibitor, the LPS-induced production of IL-6, IL-1ß, and TNFα is significantly reduced, reinforcing the hypothesis that the pro-inflammatory expression of cytokines is AKR1B10-dependant. Finally, we also show that AKR1B10 can be secreted and transferred via extracellular vesicles between different cell types, suggesting that this protein may also contribute to the multi-organ systemic impact of COVID-19. These experiments highlight a relationship between AKR1B10 production and severe forms of COVID-19. Our data indicate that AKR1B10 participates in the activation of cytokines production and suggest that modulation of AKR1B10 activity might be an actionable pharmacological target in COVID-19 management.


Asunto(s)
Aldo-Ceto Reductasas/fisiología , COVID-19/genética , Síndrome de Liberación de Citoquinas/genética , Síndrome de Dificultad Respiratoria/genética , Aldo-Ceto Reductasas/antagonistas & inhibidores , Aldo-Ceto Reductasas/genética , Animales , COVID-19/complicaciones , COVID-19/metabolismo , COVID-19/patología , Estudios de Casos y Controles , Células Cultivadas , Síndrome de Liberación de Citoquinas/metabolismo , Síndrome de Liberación de Citoquinas/patología , Síndrome de Liberación de Citoquinas/virología , Citocinas/metabolismo , Inhibidores Enzimáticos/farmacología , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Gravedad del Paciente , Células RAW 264.7 , Síndrome de Dificultad Respiratoria/metabolismo , Síndrome de Dificultad Respiratoria/patología , Síndrome de Dificultad Respiratoria/virología , SARS-CoV-2/fisiología , Transcriptoma
15.
J Am Chem Soc ; 143(27): 10422-10428, 2021 07 14.
Artículo en Inglés | MEDLINE | ID: mdl-34197103

RESUMEN

The design of new ligands for cross-coupling is essential for developing new catalytic reactions that access valuable products such as pharmaceuticals. In this report, we exploit the reactivity of nitrile-containing additives in Ni catalysis to design a benzonitrile-containing ligand for cross-coupling involving tertiary nucleophiles. Kinetic and Hammett studies are used to elucidate the role of the optimized ligand, which demonstrate that the benzonitrile moiety acts as an electron-acceptor to promote reductive elimination over ß-hydride elimination and stabilize low-valent Ni. With these conditions, a protocol for decyanation-metalation and Ni-catalyzed arylation is conducted, enabling access to quaternary α-arylnitriles from disubstituted malononitriles.

16.
Br J Cancer ; 125(8): 1122-1134, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34290392

RESUMEN

BACKGROUND: Large-scale genetic and epigenetic deregulations enable cancer cells to ectopically activate tissue-specific expression programmes. A specifically designed strategy was applied to oral squamous cell carcinomas (OSCC) in order to detect ectopic gene activations and develop a prognostic stratification test. METHODS: A dedicated original prognosis biomarker discovery approach was implemented using genome-wide transcriptomic data of OSCC, including training and validation cohorts. Abnormal expressions of silent genes were systematically detected, correlated with survival probabilities and evaluated as predictive biomarkers. The resulting stratification test was confirmed in an independent cohort using immunohistochemistry. RESULTS: A specific gene expression signature, including a combination of three genes, AREG, CCNA1 and DDX20, was found associated with high-risk OSCC in univariate and multivariate analyses. It was translated into an immunohistochemistry-based test, which successfully stratified patients of our own independent cohort. DISCUSSION: The exploration of the whole gene expression profile characterising aggressive OSCC tumours highlights their enhanced proliferative and poorly differentiated intrinsic nature. Experimental targeting of CCNA1 in OSCC cells is associated with a shift of transcriptomic signature towards the less aggressive form of OSCC, suggesting that CCNA1 could be a good target for therapeutic approaches.


Asunto(s)
Anfirregulina/genética , Ciclina A1/genética , Proteína 20 DEAD-Box/genética , Perfilación de la Expresión Génica/métodos , Neoplasias de la Boca/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Anfirregulina/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Ciclina A1/metabolismo , Proteína 20 DEAD-Box/metabolismo , Minería de Datos , Femenino , Humanos , Masculino , Neoplasias de la Boca/genética , Neoplasias de la Boca/metabolismo , Invasividad Neoplásica , Estadificación de Neoplasias , Análisis de Secuencia por Matrices de Oligonucleótidos , Estudios Retrospectivos , Análisis de Secuencia de ARN , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo
17.
PLoS Comput Biol ; 16(5): e1007869, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32392248

RESUMEN

The hopes of precision medicine rely on our capacity to measure various high-throughput genomic information of a patient and to integrate them for personalized diagnosis and adapted treatment. Reaching these ambitious objectives will require the development of efficient tools for the detection of molecular defects at the individual level. Here, we propose a novel method, PenDA, to perform Personalized Differential Analysis at the scale of a single sample. PenDA is based on the local ordering of gene expressions within individual cases and infers the deregulation status of genes in a sample of interest compared to a reference dataset. Based on realistic simulations of RNA-seq data of tumors, we showed that PenDA outcompetes existing approaches with very high specificity and sensitivity and is robust to normalization effects. Applying the method to lung cancer cohorts, we observed that deregulated genes in tumors exhibit a cancer-type-specific commitment towards up- or down-regulation. Based on the individual information of deregulation given by PenDA, we were able to define two new molecular histologies for lung adenocarcinoma cancers strongly correlated to survival. In particular, we identified 37 biomarkers whose up-regulation lead to bad prognosis and that we validated on two independent cohorts. PenDA provides a robust, generic tool to extract personalized deregulation patterns that can then be used for the discovery of therapeutic targets and for personalized diagnosis. An open-access, user-friendly R package is available at https://github.com/bcm-uga/penda.


Asunto(s)
Adenocarcinoma del Pulmón/genética , Biología Computacional/métodos , Neoplasias Pulmonares/genética , Medicina de Precisión/métodos , Algoritmos , Conjuntos de Datos como Asunto , Humanos , Análisis de Secuencia de ARN
18.
Genes Dev ; 27(15): 1680-92, 2013 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-23884607

RESUMEN

The conversion of male germ cell chromatin to a nucleoprotamine structure is fundamental to the life cycle, yet the underlying molecular details remain obscure. Here we show that an essential step is the genome-wide incorporation of TH2B, a histone H2B variant of hitherto unknown function. Using mouse models in which TH2B is depleted or C-terminally modified, we show that TH2B directs the final transformation of dissociating nucleosomes into protamine-packed structures. Depletion of TH2B induces compensatory mechanisms that permit histone removal by up-regulating H2B and programming nucleosome instability through targeted histone modifications, including lysine crotonylation and arginine methylation. Furthermore, after fertilization, TH2B reassembles onto the male genome during protamine-to-histone exchange. Thus, TH2B is a unique histone variant that plays a key role in the histone-to-protamine packing of the male genome and guides genome-wide chromatin transitions that both precede and follow transmission of the male genome to the egg.


Asunto(s)
Cromatina/metabolismo , Histonas/metabolismo , Protaminas/metabolismo , Animales , Epigénesis Genética , Femenino , Fertilización/fisiología , Regulación del Desarrollo de la Expresión Génica , Genoma , Histonas/genética , Masculino , Meiosis , Ratones , Nucleosomas , Espermatogénesis/genética , Testículo/metabolismo
19.
J Am Chem Soc ; 142(30): 13246-13254, 2020 07 29.
Artículo en Inglés | MEDLINE | ID: mdl-32609494

RESUMEN

The ability to understand and predict reactivity is essential for the development of new reactions. In the context of Ni-catalyzed C(sp3)-O functionalization, we have developed a unique strategy employing activated cyclopropanols to aid the design and optimization of a redox-active leaving group for C(sp3)-O arylation. In this chemistry, the cyclopropane ring acts as a reporter of leaving-group reactivity, since the ring-opened product is obtained under polar (2e) conditions, and the ring-closed product is obtained under radical (1e) conditions. Mechanistic studies demonstrate that the optimal leaving group is redox-active and are consistent with a Ni(I)/Ni(III) catalytic cycle. The optimized reaction conditions are also used to synthesize a number of arylcyclopropanes, which are valuable pharmaceutical motifs.

20.
BMC Med ; 18(1): 306, 2020 10 07.
Artículo en Inglés | MEDLINE | ID: mdl-33023569

RESUMEN

BACKGROUND: Although exposure to cigarette smoking during pregnancy has been associated with alterations of DNA methylation in the cord blood or placental cells, whether such exposure before pregnancy could induce epigenetic alterations in the placenta of former smokers has never been investigated. METHODS: Our approach combined the analysis of placenta epigenomic (ENCODE) data with newly generated DNA methylation data obtained from 568 pregnant women, the largest cohort to date, either actively smoking during their pregnancy or formerly exposed to tobacco smoking. RESULTS: This strategy resulted in several major findings. First, among the 203 differentially methylated regions (DMRs) identified by the epigenome-wide association study, 152 showed "reversible" alterations of DNA methylation, only present in the placenta of current smokers, whereas 26 were also found altered in former smokers, whose placenta had not been exposed directly to cigarette smoking. Although the absolute methylation changes were smaller than those observed in other contexts, such as in some congenital diseases, the observed alterations were consistent within each DMR. This observation was further supported by a demethylation of LINE-1 sequences in the placentas of both current (beta-coefficient (ß) (95% confidence interval (CI)), - 0.004 (- 0.008; 0.001)) and former smokers (ß (95% CI), - 0.006 (- 0.011; - 0.001)) compared to nonsmokers. Second, the 203 DMRs were enriched in epigenetic marks corresponding to enhancer regions, including monomethylation of lysine 4 and acetylation of lysine 27 of histone H3 (respectively H3K4me1 and H3K27ac). Third, smoking-associated DMRs were also found near and/or overlapping 10 imprinted genes containing regions (corresponding to 16 genes), notably including the NNAT, SGCE/PEG10, and H19/MIR675 loci. CONCLUSIONS: Our results pointing towards genomic regions containing the imprinted genes as well as enhancers as preferential targets suggest mechanisms by which tobacco could directly impact the fetus and future child. The persistence of significant DNA methylation changes in the placenta of former smokers supports the hypothesis of an "epigenetic memory" of exposure to cigarette smoking before pregnancy. This observation not only is conceptually revolutionary, but these results also bring crucial information in terms of public health concerning potential long-term detrimental effects of smoking in women.


Asunto(s)
Metilación de ADN/genética , Placenta/fisiopatología , Fumar/efectos adversos , Estudios de Cohortes , Femenino , Humanos , Embarazo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA