Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 28.210
Filtrar
1.
Gene ; 718: 144049, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31430520

RESUMO

The role of epigenetics in development has garnered attention in recent years due to their ability to modulate the embryonic developmental gene expression in response to the environmental cues. The epigenetic mechanisms - DNA methylation, histone modification, and non-coding RNAs have a unique impact on vertebrate development. Zebrafish, a model vertebrate organism is being used widely in developmental studies due to their high fecundability and rapid organogenesis. With increased studies on various aspects of epigenetics in development, this review gives a glimpse of the major epigenetic modifications and their role in zebrafish development. In this review, the basic mechanism behind each modification followed by their status in zebrafish has been reviewed. Further, recent advancements in the epigenetic aspect of zebrafish development have been discussed.


Assuntos
Metilação de DNA/fisiologia , Embrião não Mamífero/embriologia , Desenvolvimento Embrionário/fisiologia , Epigênese Genética/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Peixe-Zebra/embriologia , Animais , Histonas/genética , Histonas/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Peixe-Zebra/genética
2.
Results Probl Cell Differ ; 67: 17-25, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31435790

RESUMO

Acetylation is among the most prevalent posttranslational modifications in cells and regulates a number of physiological processes such as gene transcription, cell metabolism, and cell signaling. Although initially discovered on nuclear histones, many non-nuclear proteins have subsequently been found to be acetylated as well. The centrosome is the major microtubule-organizing center in most metazoans. Recent proteomic data indicate that a number of proteins in this subcellular compartment are acetylated. This review gives an overview of our current knowledge on protein acetylation at the centrosome and its functional relevance in organelle biology.


Assuntos
Centrossomo/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas/metabolismo , Acetilação , Animais , Histonas/metabolismo , Humanos , Proteômica
3.
Anticancer Res ; 39(8): 4179-4184, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366503

RESUMO

BACKGROUND/AIM: Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of polycomb repressive complex 2 (PRC2), possesses histone N-methyltransferase (HMT) activity and plays an essential role in cancer initiation and development. The aim of the present study was to investigate the potential of Wedelolactone (WL) to inhibit the methylation activity of EZH2. MATERIALS AND METHODS: The mantle cell lymphoma (MCL) cell line, Mino, was treated with WL, while untreated cells were used as control. HMT activity and EZH2 amount were measured in nuclear extracts from WL-treated and control Mino cells. RESULTS: WL was found to target EZH2-mediated histone H3K27 methylation. Along with the inhibition of H3K27 methylation in vitro (IC50=0.3 µM), WL suppressed HMT activity in Mino cells with an IC50 value of 3.2 µM. We detected a reduced amount of EZH2 in Mino cells treated with WL, compared to untreated control cells. CONCLUSION: This is the first study to show that WL induces inhibition of H3K27 methylation via EZH2 modulation and decreases cell proliferation in MCL, in vitro. WL is proposed as a promising agent and a novel epigenetic approach in MCL investigation and treatment.


Assuntos
Cumarínicos/farmacologia , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Código das Histonas/genética , Linfoma de Célula do Manto/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Código das Histonas/efeitos dos fármacos , Histona Metiltransferases/genética , Histona Metiltransferases/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Metilação/efeitos dos fármacos , Complexo Repressor Polycomb 2/genética
4.
Life Sci ; 234: 116788, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31445935

RESUMO

Livin is an important member of the human inhibitor of apoptosis proteins (IAPs) family. IAPs are proteins with antiapoptotic abilities, and their functions are different from the Bcl-2 (B-cell lymphoma-2) family proteins. However, the precise role of Livin in colon cancer progression remains unclear. The purpose of this study is to assess the effect of overexpression Livin in colon cancer cells and to examine its molecular mechanism. We demonstrated that Livin induced a colon cancer phenotype, including proliferation and migration, by regulating H2A.XY39ph (histone family 2A variant (H2AX) phosphorylated on the 39th serine site). We elucidated that Livin degraded Jumonji-C domain-containing 6 protein (JMJD6), which was mediated by the proteasome murine double minute 2 (MDM2), thereby regulating H2A.XY39ph. Above all, the overexpression of JMJD6 recovered H2A.XY39ph in colon cancer cells with a high level of Livin, thus inhibiting colon cancer malignancy progression. These results reveal a previously unrecognized role for Livin in regulating the tumor-initiating capacity in colon cancer and provide a novel treatment strategy in cancer via the interruption of H2A.XY39ph function and the interaction between H2A.XY39ph and JMJD6.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias do Colo/patologia , Histonas/metabolismo , Proteínas Inibidoras de Apoptose/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Proteínas de Neoplasias/metabolismo , Mapas de Interação de Proteínas , Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Histonas/genética , Humanos , Proteínas Inibidoras de Apoptose/genética , Histona Desmetilases com o Domínio Jumonji/genética , Proteínas de Neoplasias/genética , Proteólise
5.
Nat Commun ; 10(1): 2894, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31263106

RESUMO

The Origin Recognition Complex (ORC) is essential for replication, heterochromatin formation, telomere maintenance and genome stability in eukaryotes. Here we present the structure of the yeast Orc1 BAH domain bound to the nucleosome core particle. Our data reveal that Orc1, unlike its close homolog Sir3 involved in gene silencing, does not appear to discriminate between acetylated and non-acetylated lysine 16, modification states of the histone H4 tail that specify open and closed chromatin respectively. We elucidate the mechanism for this unique feature of Orc1 and hypothesize that its ability to interact with nucleosomes regardless of K16 modification state enables it to perform critical functions in both hetero- and euchromatin. We also show that direct interactions with nucleosomes are essential for Orc1 to maintain the integrity of rDNA borders during meiosis, a process distinct and independent from its known roles in silencing and replication.


Assuntos
Nucleossomos/metabolismo , Complexo de Reconhecimento de Origem/química , Complexo de Reconhecimento de Origem/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Ciclo Celular , Montagem e Desmontagem da Cromatina , Eucromatina/genética , Eucromatina/metabolismo , Heterocromatina/genética , Heterocromatina/metabolismo , Histonas/genética , Histonas/metabolismo , Nucleossomos/genética , Complexo de Reconhecimento de Origem/genética , Ligação Proteica , Domínios Proteicos , Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas Reguladoras de Informação Silenciosa de Saccharomyces cerevisiae/genética , Proteínas Reguladoras de Informação Silenciosa de Saccharomyces cerevisiae/metabolismo
6.
Rinsho Ketsueki ; 60(6): 680-690, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31281161

RESUMO

Recent progress in whole genome sequencing has identified recurrent somatic mutations in the additional sex combs like 1 (ASXL1) gene in a variety of hematological disorders and even in premalignant conditions. However, the molecular mechanisms regarding the contribution of ASXL1 mutation to the pathogenesis of premalignant conditions remain largely unelucidated. Thus, we investigated the biological effects of mutant Asxl1 using newly-generated knock-in (KI) mice. Heterozygous mutant KI mice developed phenotypes resembling human low-risk myelodysplastic syndromes (MDS), and some of them developed an MDS/myeloproliferative neoplasm-like disease after a long latency. The H2AK119ub1 level around the promoter region of p16Ink4a was significantly decreased in KI hematopoietic stem cells (HSCs), suggesting perturbation of Bmi1-driven H2AK119ub1 histone modification by mutant Asxl1. The mutant Asxl1 failed to interact with Bmi1, although wild type ASXL1 protein did not. When p16Ink4a expression was depleted in Asxl1 KI mice, the HSC pool was restored, and apoptosis was ameliorated in HSCs. These findings demonstrate that the loss of protein interaction between mutant Asxl1 and Bmi1 affected the activity of Prc1. The subsequent derepression of p16Ink4a by aberrant histone ubiquitination could induce cellular senescence, resulting in low-risk MDS-like phenotypes in heterozygous Asxl1 KI mice.


Assuntos
Mutação , Síndromes Mielodisplásicas/genética , Proteínas Repressoras/genética , Animais , Modelos Animais de Doenças , Técnicas de Introdução de Genes , Células-Tronco Hematopoéticas , Histonas/metabolismo , Camundongos , Fenótipo , Complexo Repressor Polycomb 1/genética , Proteínas Proto-Oncogênicas/genética , Ubiquitinação
7.
BMC Vet Res ; 15(1): 267, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31357995

RESUMO

BACKGROUND: In practical production, dairy cows are frequently exposed to bacterial endotoxin (lipopolysaccharide, LPS) when they are subjected to high-concentrate diets, poor hygienic environments, as well as mastitis and metritis. Histone acetylation is an important epigenetic control of DNA transcription and a higher histone acetylation is associated with facilitated transcription. LPS might reduce histone acetylation in the mammary epithelial cells, resulting in lower transcription and mRNA expression of lactation-related genes. This study was conducted to investigate the effect of LPS on histone acetylation in bovine mammary epithelial cells and the efficacy of sodium butyrate (SB) in suppressing the endotoxin-induced adverse effect. Firstly, the bovine mammary epithelial cell line MAC-T cells were treated for 48 h with LPS at different doses of 0, 1, 10, 100, and 1000 endotoxin units (EU)/mL (1 EU = 0.1 ng), and the acetylation levels of histones H3 and H4 as well as the histone deacetylase (HDAC) activity were measured. Secondly, the MAC-T cells were treated for 48 h as follows: control, LPS (100 EU/mL), and LPS (100 EU/mL) plus SB (10 mmol/L), and the acetylation levels of histones H3 and H4 as well as milk gene mRNA expressions were determined. RESULTS: The results showed that HDAC activity increased linearly with increasing LPS doses (P < 0.01). The histone H3 acetylation levels were significantly reduced by LPS, while the histone H4 acetylation levels were not affected by LPS (P > 0.05). Sodium butyrate, an inhibitor of HDAC, effectively suppressed the endotoxin-induced decline of histone H3 acetylation (P < 0.05). As a result, SB significantly enhanced the mRNA expression of lactation-related genes (P < 0.05). CONCLUSIONS: The results suggest one of the adverse effects of LPS on the lactation of bovine mammary gland epithelial cells was due to decreasing histone H3 acetylation through increasing HDAC activity, whereas the endotoxin-induced adverse effects were effectively suppressed by SB.


Assuntos
Ácido Butírico/farmacologia , Endotoxinas/toxicidade , Células Epiteliais/efeitos dos fármacos , Histonas/metabolismo , Glândulas Mamárias Animais/efeitos dos fármacos , Acetilação/efeitos dos fármacos , Animais , Bovinos , Feminino , Antagonistas dos Receptores Histamínicos/farmacologia , Glândulas Mamárias Animais/citologia
8.
BMC Bioinformatics ; 20(1): 401, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324140

RESUMO

BACKGROUND: Visualization tools for deep learning models typically focus on discovering key input features without considering how such low level features are combined in intermediate layers to make decisions. Moreover, many of these methods examine a network's response to specific input examples that may be insufficient to reveal the complexity of model decision making. RESULTS: We present DeepResolve, an analysis framework for deep convolutional models of genome function that visualizes how input features contribute individually and combinatorially to network decisions. Unlike other methods, DeepResolve does not depend upon the analysis of a predefined set of inputs. Rather, it uses gradient ascent to stochastically explore intermediate feature maps to 1) discover important features, 2) visualize their contribution and interaction patterns, and 3) analyze feature sharing across tasks that suggests shared biological mechanism. We demonstrate the visualization of decision making using our proposed method on deep neural networks trained on both experimental and synthetic data. DeepResolve is competitive with existing visualization tools in discovering key sequence features, and identifies certain negative features and non-additive feature interactions that are not easily observed with existing tools. It also recovers similarities between poorly correlated classes which are not observed by traditional methods. DeepResolve reveals that DeepSEA's learned decision structure is shared across genome annotations including histone marks, DNase hypersensitivity, and transcription factor binding. We identify groups of TFs that suggest known shared biological mechanism, and recover correlation between DNA hypersensitivities and TF/Chromatin marks. CONCLUSIONS: DeepResolve is capable of visualizing complex feature contribution patterns and feature interactions that contribute to decision making in genomic deep convolutional networks. It also recovers feature sharing and class similarities which suggest interesting biological mechanisms. DeepResolve is compatible with existing visualization tools and provides complementary insights.


Assuntos
Algoritmos , Aprendizado Profundo , Genômica , Redes Neurais (Computação) , Sequência de Bases , Bases de Dados Genéticas , Código das Histonas , Histonas/metabolismo , Fatores de Transcrição/metabolismo
9.
Nat Commun ; 10(1): 2950, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31270318

RESUMO

X-chromosome inactivation triggers fusion of A/B compartments to inactive X (Xi)-specific structures known as S1 and S2 compartments. SMCHD1 then merges S1/S2s to form the Xi super-structure. Here, we ask how S1/S2 compartments form and reveal that Xist RNA drives their formation via recruitment of Polycomb repressive complex 1 (PRC1). Ablating Smchd1 in post-XCI cells unveils S1/S2 structures. Loss of SMCHD1 leads to trapping Xist in the S1 compartment, impairing RNA spreading into S2. On the other hand, depleting Xist, PRC1, or HNRNPK precludes re-emergence of S1/S2 structures, and loss of S1/S2 compartments paradoxically strengthens the partition between Xi megadomains. Finally, Xi-reactivation in post-XCI cells can be enhanced by depleting both SMCHD1 and DNA methylation. We conclude that Xist, PRC1, and SMCHD1 collaborate in an obligatory, sequential manner to partition, fuse, and direct self-association of Xi compartments required for proper spreading of Xist RNA.


Assuntos
Proteínas Cromossômicas não Histona/metabolismo , Cromossomos de Mamíferos/genética , Complexo Repressor Polycomb 1/metabolismo , RNA Longo não Codificante/metabolismo , Cromossomo X/química , Cromossomo X/genética , Animais , Metilação de DNA/genética , Histonas/metabolismo , Lisina/metabolismo , Camundongos , Modelos Genéticos , Inativação do Cromossomo X/genética
10.
Nat Commun ; 10(1): 2955, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31273203

RESUMO

Dendritic cells (DCs), a vital component of the innate immune system, are considered to lack antigen specificity and be devoid of immunological memory. Strategies that can induce memory-like responses from innate cells can be utilized to elicit protective immunity in immune deficient persons. Here we utilize an experimental immunization strategy to modulate DC inflammatory and memory-like responses against an opportunistic fungal pathogen that causes significant disease in immunocompromised individuals. Our results show that DCs isolated from protectively immunized mice exhibit enhanced transcriptional activation of interferon and immune signaling pathways. We also show long-term memory-like cytokine responses upon subsequent challenge with the fungal pathogen that are abrogated with inhibitors of specific histone modifications. Altogether, our study demonstrates that immunization strategies can be designed to elicit memory-like DC responses against infectious disease.


Assuntos
Células Dendríticas/imunologia , Memória Imunológica , Animais , Criptococose/imunologia , Criptococose/microbiologia , Cryptococcus/fisiologia , Células Dendríticas/microbiologia , Feminino , Histonas/metabolismo , Imunidade Inata , Inflamação/genética , Inflamação/patologia , Interferon gama/metabolismo , Pulmão/imunologia , Pulmão/microbiologia , Camundongos Endogâmicos BALB C , Fenótipo , Processamento de Proteína Pós-Traducional , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Vacinação
11.
Toxicol Lett ; 314: 63-74, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31306741

RESUMO

This study aimed to verify the toxic effects of prenatal caffeine exposure (PCE) on the podocyte development in male offspring, and to explore the underlying intrauterine programming mechanisms. The pregnant rats were administered with caffeine (30 to 120 mg/kg⋅d) during gestational day (GD) 9 to 20. The male fetus on GD20 and the offspring at postnatal week (PW) 6 and PW28 were sacrificed. The results indicated that PCE caused ultrastructural abnormalities on podocyte, and inhibited the expression of podocyte marker genes such as Nephrin, Wilms tumor 1 (WT1), the histone 3 lysine 9 acetylation (H3K9ac) level in the Kruppel-like factor 4 (KLF4) promoter and its expression in the male offspring from GD20 to PW28. Meanwhile, the expression of glucocorticoid receptor (GR) and histone deacetylase 7 (HDAC7) in the fetus were increased by PCE. In vitro, corticosterone increased GR and HDAC7 whereas reduced the H3K9ac level of KLF4 and KLF4/Nephrin expression. KLF4 over-expression reversed the reduction of Nephrin expression, knockdown of HDAC7 and GR antagonist RU486 partially reversed the inhibitory effects of corticosterone on H3K9ac level and KLF4 expression. In conclusion, PCE caused podocyte developmental toxicity in male offspring, which was associated with corticosterone-induced low-functional programming of KLF4 through GR/HDAC7/H3K9ac pathway.


Assuntos
Cafeína/toxicidade , Estimulantes do Sistema Nervoso Central/toxicidade , Histonas/metabolismo , Nefropatias/induzido quimicamente , Fatores de Transcrição Kruppel-Like/metabolismo , Podócitos/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Acetilação , Animais , Células Cultivadas , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Idade Gestacional , Glucocorticoides/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Nefropatias/embriologia , Nefropatias/genética , Nefropatias/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Lisina , Masculino , Exposição Materna , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Fenótipo , Podócitos/metabolismo , Podócitos/ultraestrutura , Gravidez , Regiões Promotoras Genéticas , Ratos Wistar , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais/efeitos dos fármacos
12.
Adv Exp Med Biol ; 1166: 1-28, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31301043

RESUMO

Spermatozoa genome has unique features that make it a fascinating field of investigation: first, because, with oocyte genome, it can be transmitted generation after generation; second, because of genetic shuffling during meiosis, each spermatozoon is virtually unique in terms of genetic content, with consequences for species evolution; and finally, because its chromatin organization is very different from that of somatic cells or oocytes, as it is not based on nucleosomes but on nucleoprotamines which confer a higher order of packaging. Histone-to-protamine transition involves many actors, such as regulators of spermatid gene expression, components of the nuclear envelop, histone-modifying enzymes and readers, chaperones, histone variants, transition proteins, protamines, and certainly many more to be discovered.In this book chapter, we will present what is currently known about sperm chromatin structure and how it is established during spermiogenesis, with the aim to list the genetic factors that regulate its organization.


Assuntos
Cromatina/química , Cromatina/genética , Espermatozoides , Regulação da Expressão Gênica no Desenvolvimento , Histonas/metabolismo , Humanos , Masculino , Protaminas/metabolismo , Espermátides , Espermatogênese
13.
Nat Commun ; 10(1): 2669, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-31209209

RESUMO

The Mediator complex regulates transcription by connecting enhancers to promoters. High Mediator binding density defines super enhancers, which regulate cell-identity genes and oncogenes. Protein interactions of Mediator may explain its role in these processes but have not been identified comprehensively. Here, we purify Mediator from neural stem cells (NSCs) and identify 75 protein-protein interaction partners. We identify super enhancers in NSCs and show that Mediator-interacting chromatin modifiers colocalize with Mediator at enhancers and super enhancers. Transcription factor families with high affinity for Mediator dominate enhancers and super enhancers and can explain genome-wide Mediator localization. We identify E-box transcription factor Tcf4 as a key regulator of NSCs. Tcf4 interacts with Mediator, colocalizes with Mediator at super enhancers and regulates neurogenic transcription factor genes with super enhancers and broad H3K4me3 domains. Our data suggest that high binding-affinity for Mediator is an important organizing feature in the transcriptional network that determines NSC identity.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Redes Reguladoras de Genes/fisiologia , Complexo Mediador/metabolismo , Células-Tronco Neurais/fisiologia , Neurogênese/genética , Fator de Transcrição 4/metabolismo , Linhagem Celular , Elementos Facilitadores Genéticos/genética , Histonas/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Oxirredutases N-Desmetilantes/metabolismo , Regiões Promotoras Genéticas/genética , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Transcrição Genética/fisiologia
14.
Nat Commun ; 10(1): 2529, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175278

RESUMO

Substitution of lysine 27 with methionine in histone H3.3 is a recently discovered driver mutation of pediatric high-grade gliomas. Mutant cells show decreased levels and altered distribution of H3K27 trimethylation (H3K27me3). How these chromatin changes are established genome-wide and lead to tumorigenesis remains unclear. Here we show that H3.3K27M-mediated alterations in H3K27me3 distribution result in ectopic DNA replication and cell cycle progression of germ cells in Caenorhabditis elegans. By genetically inducing changes in the H3.3 distribution, we demonstrate that both H3.3K27M and pre-existing H3K27me3 act locally and antagonistically on Polycomb Repressive Complex 2 (PRC2) in a concentration-dependent manner. The heterochromatin changes result in extensive gene misregulation, and genetic screening identified upregulation of JNK as an underlying cause of the germcell aberrations. Moreover, JNK inhibition suppresses the replicative fate in human tumor-derived H3.3K27M cells, thus establishing C. elegans as a powerful model for the identification of potential drug targets for treatment of H3.3K27M tumors.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Ciclo Celular , Replicação do DNA , Regulação da Expressão Gênica , Histonas/metabolismo , Sistema de Sinalização das MAP Quinases , Animais , Neoplasias Encefálicas , Caenorhabditis elegans , Carcinogênese , Cromatina , Regulação Neoplásica da Expressão Gênica , Células Germinativas/metabolismo , Glioma , Heterocromatina , Código das Histonas , Metilação , Complexo Repressor Polycomb 2/metabolismo
15.
Nat Commun ; 10(1): 2427, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160593

RESUMO

Enhancer of zeste homolog 2 (EZH2)-mediated trimethylation of histone 3 lysine 27 (H3K27Me3) is critical for immune regulation. However, evidence is lacking to address the effect of EZH2 enzyme's activity on intestinal immune responses during inflammatory bowel disease (IBD). Here we report that suppressing EZH2 activity ameliorates experimental intestinal inflammation and delayed the onset of colitis-associated cancer. In addition, we identified an increased number of functional MDSCs in the colons, which are essential for EZH2 inhibitor activity. Moreover, inhibition of EZH2 activity promotes the generation of MDSCs from hematopoietic progenitor cells in vitro, demonstrating a previously unappreciated role for EZH2 in the development of MDSCs. Together, these findings suggest the feasibility of EZH2 inhibitor clinical trials for the control of IBD. In addition, this study identifies MDSC-promoting effects of EZH2 inhibitors that may be undesirable in other therapeutic contexts and should be addressed in a clinical trial setting.


Assuntos
Colite/imunologia , Colo/imunologia , Proteína Potenciadora do Homólogo 2 de Zeste/imunologia , Doenças Inflamatórias Intestinais/imunologia , Células Supressoras Mieloides/imunologia , Animais , Diferenciação Celular/efeitos dos fármacos , Colite/induzido quimicamente , Colite/complicações , Colite/patologia , Colo/efeitos dos fármacos , Colo/patologia , Neoplasias do Colo/etiologia , Sulfato de Dextrana/toxicidade , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Feminino , Células-Tronco Hematopoéticas/citologia , Código das Histonas , Histonas/metabolismo , Técnicas In Vitro , Indazóis/farmacologia , Indóis/farmacologia , Metilação , Camundongos , Células Supressoras Mieloides/citologia , Piridonas/farmacologia
16.
Cell Mol Life Sci ; 76(15): 2899-2916, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31147750

RESUMO

Methylation of histone H3 lysine 36 (H3K36) plays crucial roles in the partitioning of chromatin to distinctive domains and the regulation of a wide range of biological processes. Trimethylation of H3K36 (H3K36me3) demarcates body regions of the actively transcribed genes, providing signals for modulating transcription fidelity, mRNA splicing and DNA damage repair; and di-methylation of H3K36 (H3K36me2) spreads out within large intragenic regions, regulating distribution of histone H3 lysine 27 trimethylation (H3K27me3) and possibly DNA methylation. These H3K36 methylation-mediated events are biologically crucial and controlled by different classes of proteins responsible for either 'writing', 'reading' or 'erasing' of H3K36 methylation marks. Deregulation of H3K36 methylation and related regulatory factors leads to pathogenesis of disease such as developmental syndrome and cancer. Additionally, recurrent mutations of H3K36 and surrounding histone residues are detected in human tumors, further highlighting the importance of H3K36 in biology and medicine. This review will elaborate on current advances in understanding H3K36 methylation and related molecular players during various chromatin-templated cellular processes, their crosstalks with other chromatin factors, as well as their deregulations in the diseased contexts.


Assuntos
Histonas/metabolismo , Neoplasias/patologia , Transtornos do Neurodesenvolvimento/patologia , Metilases de Modificação do DNA/metabolismo , Reparo do DNA , Histona Desmetilases/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Metilação , Neoplasias/metabolismo , Transtornos do Neurodesenvolvimento/metabolismo , Processamento de RNA
17.
Cell Mol Life Sci ; 76(15): 2871-2872, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31177294

RESUMO

Protein post-translational modifications (PTMs) have long been a topic of intensive investigation. Covalent additions to the 20 genetically encoded amino acids can alter protein interactions and can even change enzymatic function. In eukarya, PTMs can amplify both the complexity and functional paradigms of the cellular environment. Therefore, PTMs have been of substantial research interest, both for understanding fundamental mechanisms and to provide insight into drug design. Indeed, targeting proteins involved in writing, reading, and erasing PTMs important for human pathologies are some of the most fruitful avenues of drug discovery. In this multi-author review, we explore exciting new work on lysine and arginine methylation, molecular and structural understanding of some of the lysine and arginine methyltransferases (KMTs and PRMTs, respectively), novel insights into nucleic acid methylation, and how the enzymes responsible for writing these PTMs and readers responsible for recognizing these PTMs could be drugged. Here, we introduce the background and the topics covered in this issue.


Assuntos
Processamento de Proteína Pós-Traducional , Arginina/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Humanos , Lisina/metabolismo , Metilação , Proteína-Arginina N-Metiltransferases/metabolismo
18.
Nat Immunol ; 20(7): 783-792, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31213714

RESUMO

Adaptation is the ability of cells, tissues and organisms to rapidly and reversibly modify their properties to maximize fitness in a changing environment. The activity of immune-system components unfolds in the remarkably heterogeneous milieus to which they are exposed in different tissues, during homeostasis or during various acute or chronic pathological states. Therefore, adaptation is essential for immune cells to tune their responses to a large variety of contexts and conditions. The adaptation of immune cells reflects the integration of multiple inputs acting simultaneously or in a temporal sequence, which eventually leads to transcriptional reprogramming and to various functional consequences, some of which extend beyond the duration of the stimulus. A range of adaptive responses have been observed in both adaptive immune cells and innate immune cells; these are referred to with terms such as 'plasticity', 'priming', 'training', 'exhaustion' and 'tolerance', among others, all of which can be useful for defining a certain immunological process or outcome but whose underlying molecular frameworks are often incompletely understood. Here we review and analyze mechanisms of adaptation and memory in immunity with the aim of providing basic concepts that rationalize the properties and molecular bases of these essential processes.


Assuntos
Adaptação Fisiológica , Imunidade , Memória Imunológica , Imunidade Adaptativa , Animais , Regulação da Expressão Gênica , Histonas/metabolismo , Humanos , Hipersensibilidade/imunologia , Sistema Imunitário/citologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Tolerância Imunológica , Imunidade Inata , Especificidade de Órgãos/imunologia , Fenótipo , Transdução de Sinais
19.
Nat Genet ; 51(6): 941-946, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31152160

RESUMO

The histone variant H3.3 is enriched at enhancers and active genes, as well as repeat regions such as telomeres and retroelements, in mouse embryonic stem cells (mESCs)1-3. Although recent studies demonstrate a role for H3.3 and its chaperones in establishing heterochromatin at repeat regions4-8, the function of H3.3 in transcription regulation has been less clear9-16. Here, we find that H3.3-specific phosphorylation17-19 stimulates activity of the acetyltransferase p300 in trans, suggesting that H3.3 acts as a nucleosomal cofactor for p300. Depletion of H3.3 from mESCs reduces acetylation on histone H3 at lysine 27 (H3K27ac) at enhancers. Compared with wild-type cells, those lacking H3.3 demonstrate reduced capacity to acetylate enhancers that are activated upon differentiation, along with reduced ability to reprogram cell fate. Our study demonstrates that a single amino acid in a histone variant can integrate signaling information and impact genome regulation globally, which may help to better understand how mutations in these proteins contribute to human cancers20,21.


Assuntos
Elementos Facilitadores Genéticos , Regulação da Expressão Gênica , Histonas/metabolismo , Serina/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo , Acetilação , Animais , Diferenciação Celular , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Camundongos , Fosforilação , Processamento de Proteína Pós-Traducional
20.
Nat Genet ; 51(6): 1060-1066, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31152164

RESUMO

Modulation of chromatin structure via histone modification is a major epigenetic mechanism and regulator of gene expression. However, the contribution of chromatin features to tumor heterogeneity and evolution remains unknown. Here we describe a high-throughput droplet microfluidics platform to profile chromatin landscapes of thousands of cells at single-cell resolution. Using patient-derived xenograft models of acquired resistance to chemotherapy and targeted therapy in breast cancer, we found that a subset of cells within untreated drug-sensitive tumors share a common chromatin signature with resistant cells, undetectable using bulk approaches. These cells, and cells from the resistant tumors, have lost chromatin marks-H3K27me3, which is associated with stable transcriptional repression-for genes known to promote resistance to treatment. This single-cell chromatin immunoprecipitation followed by sequencing approach paves the way to study the role of chromatin heterogeneity, not just in cancer but in other diseases and healthy systems, notably during cellular differentiation and development.


Assuntos
Neoplasias da Mama/genética , Imunoprecipitação da Cromatina , Cromatina/genética , Heterogeneidade Genética , Sequenciamento de Nucleotídeos em Larga Escala , Análise de Célula Única , Cromatina/metabolismo , Biologia Computacional/métodos , Epigênese Genética , Feminino , Histonas/metabolismo , Humanos , Técnicas Analíticas Microfluídicas , Análise de Célula Única/métodos , Células Estromais , Fluxo de Trabalho
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA