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1.
Nat Rev Endocrinol ; 16(9): 519-533, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32620937

RESUMO

Reproductive function adjusts in response to environmental conditions in order to optimize success. In humans, this plasticity includes age of pubertal onset, hormone levels and age at menopause. These reproductive characteristics vary across populations with distinct lifestyles and following specific childhood events, and point to a role for the early-life environment in shaping adult reproductive trajectories. Epigenetic mechanisms respond to external signals, exert long-term effects on gene expression and have been shown in animal and cellular studies to regulate normal reproductive function, strongly implicating their role in these adaptations. Moreover, human cohort data have revealed differential DNA methylation signatures in proxy tissues that are associated with reproductive phenotypic variation, although the cause-effect relationships are difficult to discern, calling for additional complementary approaches to establish functionality. In this Review, we summarize how adult reproductive function can be shaped by childhood events. We discuss why the influence of the childhood environment on adult reproductive function is an important consideration in understanding how reproduction is regulated and necessitates consideration by clinicians treating women with diverse life histories. The resolution of the molecular mechanisms responsible for human reproductive plasticity could also lead to new approaches for intervention by targeting these epigenetic modifications.


Assuntos
Adaptação Fisiológica/genética , Meio Ambiente , Epigênese Genética/fisiologia , Reprodução/genética , Envelhecimento , Animais , Metilação de DNA , Feminino , Fertilidade , Desenvolvimento Fetal , Humanos , Estilo de Vida , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Fenótipo , Gravidez , Progesterona/sangue , Puberdade/genética , Reprodução/fisiologia , Testosterona/sangue , Migrantes
2.
Proc Natl Acad Sci U S A ; 117(25): 14322-14330, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32518115

RESUMO

Phosphorothioate (PT) DNA modifications-in which a nonbonding phosphate oxygen is replaced with sulfur-represent a widespread, horizontally transferred epigenetic system in prokaryotes and have a highly unusual property of occupying only a small fraction of available consensus sequences in a genome. Using Salmonella enterica as a model, we asked a question of fundamental importance: How do the PT-modifying DndA-E proteins select their GPSAAC/GPSTTC targets? Here, we applied innovative analytical, sequencing, and computational tools to discover a novel behavior for DNA-binding proteins: The Dnd proteins are "parked" at the G6mATC Dam methyltransferase consensus sequence instead of the expected GAAC/GTTC motif, with removal of the 6mA permitting extensive PT modification of GATC sites. This shift in modification sites further revealed a surprising constancy in the density of PT modifications across the genome. Computational analysis showed that GAAC, GTTC, and GATC share common features of DNA shape, which suggests that PT epigenetics are regulated in a density-dependent manner partly by DNA shape-driven target selection in the genome.


Assuntos
Bactérias/genética , Bactérias/metabolismo , DNA Bacteriano/metabolismo , Epigênese Genética/fisiologia , Epigenômica , Fosfatos/metabolismo , 2-Aminopurina , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Sequência de Bases , Sítios de Ligação , Sequência Consenso , DNA Bacteriano/química , DNA Bacteriano/genética , Proteínas de Ligação a DNA/metabolismo , Escherichia coli/metabolismo , Genoma Bacteriano , Salmonella enterica/genética
3.
Aging (Albany NY) ; 12(10): 9959-9981, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: covidwho-430864

RESUMO

The severity and outcome of coronavirus disease 2019 (COVID-19) largely depends on a patient's age. Adults over 65 years of age represent 80% of hospitalizations and have a 23-fold greater risk of death than those under 65. In the clinic, COVID-19 patients most commonly present with fever, cough and dyspnea, and from there the disease can progress to acute respiratory distress syndrome, lung consolidation, cytokine release syndrome, endotheliitis, coagulopathy, multiple organ failure and death. Comorbidities such as cardiovascular disease, diabetes and obesity increase the chances of fatal disease, but they alone do not explain why age is an independent risk factor. Here, we present the molecular differences between young, middle-aged and older people that may explain why COVID-19 is a mild illness in some but life-threatening in others. We also discuss several biological age clocks that could be used in conjunction with genetic tests to identify both the mechanisms of the disease and individuals most at risk. Finally, based on these mechanisms, we discuss treatments that could increase the survival of older people, not simply by inhibiting the virus, but by restoring patients' ability to clear the infection and effectively regulate immune responses.


Assuntos
Envelhecimento/fisiologia , Infecções por Coronavirus , Epigênese Genética/fisiologia , Imunidade/fisiologia , Pandemias , Administração dos Cuidados ao Paciente/métodos , Pneumonia Viral , Idoso , Betacoronavirus/isolamento & purificação , Betacoronavirus/fisiologia , Comorbidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Humanos , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Síndrome do Desconforto Respiratório do Adulto/etiologia , Síndrome do Desconforto Respiratório do Adulto/imunologia , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença
4.
J Headache Pain ; 21(1): 42, 2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32349653

RESUMO

Chronic migraine is a neurological disorder characterized by 15 or more headache days per month of which at least 8 days show typical migraine features. The process that describes the development from episodic migraine into chronic migraine is commonly referred to as migraine transformation or chronification. Ample studies have attempted to identify factors associated with migraine transformation from different perspectives. Understanding CM as a pathological brain state with trigeminovascular participation where biological changes occur, we have completed a comprehensive review on the clinical, epidemiological, genetic, molecular, structural, functional, physiological and preclinical evidence available.


Assuntos
Progressão da Doença , Transtornos de Enxaqueca/diagnóstico por imagem , Transtornos de Enxaqueca/fisiopatologia , Doença Crônica , Epigênese Genética/fisiologia , Humanos , Transtornos de Enxaqueca/genética , Neuroimagem/tendências
5.
PLoS Genet ; 16(5): e1008749, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32453742

RESUMO

Indonesia is the world's fourth most populous country, host to striking levels of human diversity, regional patterns of admixture, and varying degrees of introgression from both Neanderthals and Denisovans. However, it has been largely excluded from the human genomics sequencing boom of the last decade. To serve as a benchmark dataset of molecular phenotypes across the region, we generated genome-wide CpG methylation and gene expression measurements in over 100 individuals from three locations that capture the major genomic and geographical axes of diversity across the Indonesian archipelago. Investigating between- and within-island differences, we find up to 10.55% of tested genes are differentially expressed between the islands of Sumba and New Guinea. Variation in gene expression is closely associated with DNA methylation, with expression levels of 9.80% of genes correlating with nearby promoter CpG methylation, and many of these genes being differentially expressed between islands. Genes identified in our differential expression and methylation analyses are enriched in pathways involved in immunity, highlighting Indonesia's tropical role as a source of infectious disease diversity and the strong selective pressures these diseases have exerted on humans. Finally, we identify robust within-island variation in DNA methylation and gene expression, likely driven by fine-scale environmental differences across sampling sites. Together, these results strongly suggest complex relationships between DNA methylation, transcription, archaic hominin introgression and immunity, all jointly shaped by the environment. This has implications for the application of genomic medicine, both in critically understudied Indonesia and globally, and will allow a better understanding of the interacting roles of genomic and environmental factors shaping molecular and complex phenotypes.


Assuntos
Metilação de DNA , Grupos Étnicos/genética , Interação Gene-Ambiente , Transcriptoma , Ilhas de CpG , Meio Ambiente , Epigênese Genética/fisiologia , Grupos Étnicos/estatística & dados numéricos , Perfilação da Expressão Gênica/estatística & dados numéricos , Genética Populacional , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Genômica/métodos , Humanos , Indonésia/epidemiologia , Ilhas/epidemiologia , Ilhas do Pacífico/epidemiologia , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , RNA-Seq
6.
Aging (Albany NY) ; 12(10): 9959-9981, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32470948

RESUMO

The severity and outcome of coronavirus disease 2019 (COVID-19) largely depends on a patient's age. Adults over 65 years of age represent 80% of hospitalizations and have a 23-fold greater risk of death than those under 65. In the clinic, COVID-19 patients most commonly present with fever, cough and dyspnea, and from there the disease can progress to acute respiratory distress syndrome, lung consolidation, cytokine release syndrome, endotheliitis, coagulopathy, multiple organ failure and death. Comorbidities such as cardiovascular disease, diabetes and obesity increase the chances of fatal disease, but they alone do not explain why age is an independent risk factor. Here, we present the molecular differences between young, middle-aged and older people that may explain why COVID-19 is a mild illness in some but life-threatening in others. We also discuss several biological age clocks that could be used in conjunction with genetic tests to identify both the mechanisms of the disease and individuals most at risk. Finally, based on these mechanisms, we discuss treatments that could increase the survival of older people, not simply by inhibiting the virus, but by restoring patients' ability to clear the infection and effectively regulate immune responses.


Assuntos
Envelhecimento/fisiologia , Infecções por Coronavirus , Epigênese Genética/fisiologia , Imunidade/fisiologia , Pandemias , Administração dos Cuidados ao Paciente/métodos , Pneumonia Viral , Idoso , Betacoronavirus/isolamento & purificação , Betacoronavirus/fisiologia , Comorbidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Humanos , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Síndrome do Desconforto Respiratório do Adulto/etiologia , Síndrome do Desconforto Respiratório do Adulto/imunologia , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença
7.
Mol Cell ; 78(6): 1086-1095, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32407673

RESUMO

Transcription is epigenetically regulated by the orchestrated function of chromatin-binding proteins that tightly control the expression of master transcription factors, effectors, and supportive housekeeping genes required for establishing and propagating the normal and malignant cell state. Rapid advances in chemical biology and functional genomics have facilitated exploration of targeting epigenetic proteins, yielding effective strategies to target transcription while reducing toxicities to untransformed cells. Here, we review recent developments in conventional active site and allosteric inhibitors, peptidomimetics, and novel proteolysis-targeted chimera (PROTAC) technology that have deepened our understanding of transcriptional processes and led to promising preclinical compounds for therapeutic translation, particularly in cancer.


Assuntos
Epigênese Genética/efeitos dos fármacos , Epigênese Genética/genética , Neoplasias/genética , Animais , Antineoplásicos/farmacologia , Cromatina/genética , Cromatina/metabolismo , Epigênese Genética/fisiologia , Epigenômica/métodos , Humanos , Neoplasias/terapia , Proteólise/efeitos dos fármacos , Fatores de Transcrição/metabolismo
8.
PLoS Comput Biol ; 16(4): e1007195, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32275652

RESUMO

DNA methylation is a heritable epigenetic modification that plays an essential role in mammalian development. Genomic methylation patterns are dynamically maintained, with DNA methyltransferases mediating inheritance of methyl marks onto nascent DNA over cycles of replication. A recently developed experimental technique employing immunoprecipitation of bromodeoxyuridine labeled nascent DNA followed by bisulfite sequencing (Repli-BS) measures post-replication temporal evolution of cytosine methylation, thus enabling genome-wide monitoring of methylation maintenance. In this work, we combine statistical analysis and stochastic mathematical modeling to analyze Repli-BS data from human embryonic stem cells. We estimate site-specific kinetic rate constants for the restoration of methyl marks on >10 million uniquely mapped cytosines within the CpG (cytosine-phosphate-guanine) dinucleotide context across the genome using Maximum Likelihood Estimation. We find that post-replication remethylation rate constants span approximately two orders of magnitude, with half-lives of per-site recovery of steady-state methylation levels ranging from shorter than ten minutes to five hours and longer. Furthermore, we find that kinetic constants of maintenance methylation are correlated among neighboring CpG sites. Stochastic mathematical modeling provides insight to the biological mechanisms underlying the inference results, suggesting that enzyme processivity and/or collaboration can produce the observed kinetic correlations. Our combined statistical/mathematical modeling approach expands the utility of genomic datasets and disentangles heterogeneity in methylation patterns arising from replication-associated temporal dynamics versus stable cell-to-cell differences.


Assuntos
Biologia Computacional/métodos , Metilação de DNA/fisiologia , Animais , Bromodesoxiuridina/química , Ilhas de CpG , Citosina/metabolismo , DNA/metabolismo , Metilases de Modificação do DNA/genética , Células-Tronco Embrionárias/metabolismo , Epigênese Genética/genética , Epigênese Genética/fisiologia , Epigenômica/métodos , Genoma , Genômica , Humanos , Cinética , Modelos Estatísticos , Modelos Teóricos , Processos Estocásticos
9.
Med Sci (Paris) ; 36(3): 253-260, 2020 Mar.
Artigo em Francês | MEDLINE | ID: mdl-32228844

RESUMO

Upon priming by dendritic cells, naïve CD4 T lymphocytes are exposed to distinct molecular environments depending on the nature of the pathological stimulus. In response, they mobilize different gene networks that establish lineage-specific developmental programs, and coordinate the acquisition of specific phenotype and functions. Accordingly, CD4 T cells are capable of differentiation into a large variety of functionally-distinct T helper (Th) cell subsets. In this review, we describe the molecular events that control CD4 T cell differentiation at the level of the chromatin. We insist on recent works that have highlighted the key role of H3K9me3-dependent epigenetic mechanisms in the regulation of T cell identity. Interestingly, these pathways shape and control the developmental programs at least in part through the regulation of endogenous retroviruses-derived sequences that have been exapted into cis-regulatory modules of Th genes.


Assuntos
Retrovirus Endógenos/fisiologia , Fenômenos do Sistema Imunológico/fisiologia , Animais , Linfócitos T CD4-Positivos/fisiologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Células Dendríticas/imunologia , Células Dendríticas/fisiologia , Retrovirus Endógenos/genética , Retrovirus Endógenos/imunologia , Epigênese Genética/fisiologia , Humanos , Ativação Linfocitária/fisiologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/fisiologia
10.
Nat Commun ; 11(1): 1545, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32210226

RESUMO

Aging is characterized by a gradual loss of function occurring at the molecular, cellular, tissue and organismal levels. At the chromatin level, aging associates with progressive accumulation of epigenetic errors that eventually lead to aberrant gene regulation, stem cell exhaustion, senescence, and deregulated cell/tissue homeostasis. Nuclear reprogramming to pluripotency can revert both the age and the identity of any cell to that of an embryonic cell. Recent evidence shows that transient reprogramming can ameliorate age-associated hallmarks and extend lifespan in progeroid mice. However, it is unknown how this form of rejuvenation would apply to naturally aged human cells. Here we show that transient expression of nuclear reprogramming factors, mediated by expression of mRNAs, promotes a rapid and broad amelioration of cellular aging, including resetting of epigenetic clock, reduction of the inflammatory profile in chondrocytes, and restoration of youthful regenerative response to aged, human muscle stem cells, in each case without abolishing cellular identity.


Assuntos
Núcleo Celular/metabolismo , Reprogramação Celular/fisiologia , Senescência Celular/fisiologia , RNA Mensageiro/metabolismo , Rejuvenescimento/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Animais , Células Cultivadas , Condrócitos , Metilação de DNA/fisiologia , Células Endoteliais , Epigênese Genética/fisiologia , Feminino , Fibroblastos , Perfilação da Expressão Gênica , Humanos , Microscopia Intravital , Masculino , Camundongos , Pessoa de Meia-Idade , Células Musculares , Cultura Primária de Células , Células-Tronco , Adulto Jovem
11.
Curr Cardiol Rep ; 22(5): 26, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-32193645

RESUMO

PURPOSE OF REVIEW: Development, physiological growth and the response of the heart to injury are accompanied by changes of the transcriptome and epigenome of cardiac myocytes. Recently, cell sorting and next generation sequencing techniques have been applied to determine cardiac myocyte-specific transcriptional and epigenetic mechanisms. This review provides a comprehensive overview of studies analysing the transcriptome and epigenome of cardiac myocytes in mouse and human hearts during development, physiological growth and disease. RECENT FINDINGS: Adult cardiac myocytes express > 12,600 genes, and their expression levels correlate positively with active histone marks and inversely with gene body DNA methylation. DNA methylation accompanied the perinatal switch in sarcomere or metabolic isoform gene expression in cardiac myocytes, but remained rather stable in heart disease. DNA methylation and histone marks identified > 100,000 cis-regulatory regions in the cardiac myocyte epigenome with a dynamic spectrum of transcription factor binding sites. The ETS-related transcription factor ETV1 was identified as an atrial-specific element involved in the pathogenesis of atrial fibrillation. Thus, dynamic development of the atrial vs. ventricular cardiac myocyte epigenome provides a basis to identify location and time-dependent mechanisms of epigenetic control to shape pathological gene expression during heart disease. Identifying the four dimensions of the cardiac myocyte epigenome, atrial vs. ventricular location, time during development and growth, and disease-specific signals, may ultimately lead to new treatment strategies for heart disease.


Assuntos
Epigênese Genética/genética , Epigênese Genética/fisiologia , Epigenoma , Coração Fetal/fisiologia , Coração/crescimento & desenvolvimento , Miócitos Cardíacos/metabolismo , Adulto , Animais , Regulação da Expressão Gênica , Ventrículos do Coração , Humanos , Camundongos
12.
Am J Respir Cell Mol Biol ; 63(1): 36-45, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32150688

RESUMO

Global DNA hydroxymethylation mediated by the TET (ten-eleven translocation) enzyme was induced in allergen-induced airway hyperresponsiveness in mouse lung tissues and specifically in isolated airway smooth muscle (ASM) cells. TET is an α-ketoglutarate (α-KG)-dependent enzyme, and the production of α-KG is catalyzed by IDH (isocitrate dehydrogenase). However, the role of IDH in the regulation of DNA hydroxymethylation in ASM cells is unknown. In comparison with nonasthmatic cells, asthmatic ASM cells exhibited higher TET activity and IDH2 (but not IDH-1 or IDH-3) gene expression levels. We modified the expression of IDH2 in ASM cells from humans with asthma by siRNA and examined the α-KG levels, TET activity, global DNA hydroxymethylation, cell proliferation, and expression of ASM phenotypic genes. Inhibition of IDH2 in asthmatic ASM cells decreased the α-KG levels, TET activity, and global DNA hydroxymethylation, and reversed the aberrant ASM phenotypes (including decreased cell proliferation and ASM phenotypic gene expression). Specifically, asthmatic cells transfected with siRNA against IDH2 showed decreased 5hmC (5-hydroxymethylcytosine) levels at the TGFB2 (transforming growth factor-ß2) promoter determined by oxidative bisulfite sequencing. Taken together, our findings reveal that IDH2 plays an important role in the epigenetic regulation of ASM phenotypic changes in asthmatic ASM cells, suggesting that IDH2 is a potential therapeutic target for reversing the abnormal phenotypes seen in asthma.


Assuntos
Metilação de DNA/fisiologia , DNA/metabolismo , Isocitrato Desidrogenase/metabolismo , Pulmão/metabolismo , Miócitos de Músculo Liso/metabolismo , Asma/metabolismo , Proliferação de Células/fisiologia , Células Cultivadas , Epigênese Genética/fisiologia , Expressão Gênica/fisiologia , Humanos , Ácidos Cetoglutáricos/metabolismo , Fenótipo
13.
Nat Protoc ; 15(3): 1188-1208, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32051613

RESUMO

During DNA replication, the genetic information of a cell is copied. Subsequently, identical genetic information is segregated reliably to the two daughter cells through cell division. Meanwhile, DNA replication is intrinsically linked to the process of chromatin duplication, which is required for regulating gene expression and establishing cell identities. Understanding how chromatin is established, maintained or changed during DNA replication represents a fundamental question in biology. Recently, we developed a method to directly visualize chromatin components at individual replication forks undergoing DNA replication. This method builds upon the existing chromatin fiber technique and combines it with cell type-specific chromatin labeling and superresolution microscopy. In this method, a short pulse of nucleoside analog labels replicative regions in the cells of interest. Chromatin fibers are subsequently isolated and attached to a glass slide, after which a laminar flow of lysis buffer extends the lysed chromatin fibers parallel with the direction of the flow. Fibers are then immunostained for different chromatin-associated proteins and mounted for visualization using superresolution microscopy. Replication foci, or 'bubbles,' are identified by the presence of the incorporated nucleoside analog. For researchers experienced in molecular biology and superresolution microscopy, this protocol typically takes 2-3 d from sample preparation to data acquisition, with an additional day for data processing and quantification.


Assuntos
Cromatina , Replicação do DNA/fisiologia , DNA/genética , Epigênese Genética/fisiologia , Animais , Linhagem Celular , Drosophila melanogaster , Microscopia de Fluorescência/métodos , Imagem Óptica/métodos , Imagem Individual de Molécula/métodos
14.
Cell Mol Life Sci ; 77(16): 3129-3159, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32072238

RESUMO

Protection of normal tissues against toxic effects of ionizing radiation is a critical issue in clinical and environmental radiobiology. Investigations in recent decades have suggested potential targets that are involved in the protection against radiation-induced damages to normal tissues and can be proposed for mitigation of radiation injury. Emerging evidences have been shown to be in contrast to an old dogma in radiation biology; a major amount of reactive oxygen species (ROS) production and cell toxicity occur during some hours to years after exposure to ionizing radiation. This can be attributed to upregulation of inflammatory and fibrosis mediators, epigenetic changes and disruption of the normal metabolism of oxygen. In the current review, we explain the cellular and molecular changes following exposure of normal tissues to ionizing radiation. Furthermore, we review potential targets that can be proposed for protection and mitigation of radiation toxicity.


Assuntos
Lesões por Radiação/metabolismo , Lesões por Radiação/prevenção & controle , Animais , Epigênese Genética/fisiologia , Humanos , Estresse Oxidativo/fisiologia , Radiação Ionizante , Espécies Reativas de Oxigênio/metabolismo
15.
Fertil Steril ; 113(3): 478-488, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32089255

RESUMO

The complexity of male reproductive impairment has hampered characterization of the underlying genetic causes of male infertility. However, in the last 20 years, more powerful and affordable tools to interrogate the genetic and epigenetic determinants of male infertility have accelerated the number of new discoveries in the characterization of male infertility. With this explosion of new data, integration in a systems-based approach-including complete phenotypic information-to male infertility is imperative. We briefly review the current understanding of genetic and epigenetic causes of male infertility and how findings may be translated into a practical component for the diagnosis and treatment of male infertility.


Assuntos
Big Data , Epigenômica/métodos , Infertilidade Masculina/genética , Técnicas de Reprodução Assistida/tendências , Análise Mutacional de DNA/métodos , Análise Mutacional de DNA/tendências , Epigênese Genética/fisiologia , Epigenômica/tendências , Sequenciamento de Nucleotídeos em Larga Escala/tendências , Humanos , Infertilidade Masculina/diagnóstico , Infertilidade Masculina/terapia , Masculino , Polimorfismo Genético , Análise de Sequência de DNA/tendências
16.
Nat Commun ; 11(1): 382, 2020 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959746

RESUMO

Neurogenesis, a highly orchestrated process, entails the transition from a pluripotent to neural state and involves neural progenitor cells (NPCs) and neuronal/glial subtypes. However, the precise epigenetic mechanisms underlying fate decision remain poorly understood. Here, we delete KDM6s (JMJD3 and/or UTX), the H3K27me3 demethylases, in human embryonic stem cells (hESCs) and show that their deletion does not impede NPC generation from hESCs. However, KDM6-deficient NPCs exhibit poor proliferation and a failure to differentiate into neurons and glia. Mechanistically, both JMJD3 and UTX are found to be enriched in gene loci essential for neural development in hNPCs, and KDM6 impairment leads to H3K27me3 accumulation and blockade of DNA accessibility at these genes. Interestingly, forced expression of neuron-specific chromatin remodelling BAF (nBAF) rescues the neuron/glia defect in KDM6-deficient NPCs despite H3K27me3 accumulation. Our findings uncover the differential requirement of KDM6s in specifying NPCs and neurons/glia and highlight the contribution of individual epigenetic regulators in fate decisions in a human development model.


Assuntos
Diferenciação Celular/genética , Regulação da Expressão Gênica no Desenvolvimento , Histona Desmetilases/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Células-Tronco Neurais/fisiologia , Linhagem Celular , Proliferação de Células/genética , Metilação de DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Células-Tronco Embrionárias/fisiologia , Epigênese Genética/fisiologia , Técnicas de Introdução de Genes , Técnicas de Inativação de Genes , Histona Desmetilases/genética , Histonas/genética , Histonas/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Neurogênese/genética , RNA-Seq
17.
Annu Rev Pathol ; 15: 149-177, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31977296

RESUMO

Chronic lymphocytic leukemia is a common disease in Western countries and has heterogeneous clinical behavior. The relevance of the genetic basis of the disease has come to the forefront recently, with genome-wide studies that have provided a comprehensive view of structural variants, somatic mutations, and different layers of epigenetic changes. The mutational landscape is characterized by relatively common copy number alterations, a few mutated genes occurring in 10-15% of cases, and a large number of genes mutated in a small number of cases. The epigenomic profile has revealed a marked reprogramming of regulatory regions in tumor cells compared with normal B cells. All of these alterations are differentially distributed in clinical and biological subsets of the disease, indicating that they may underlie the heterogeneous evolution of the disease. These global studies are revealing the molecular complexity of chronic lymphocytic leukemia and provide new perspectives that have helped to understand its pathogenic mechanisms and improve the clinical management of patients.


Assuntos
Epigênese Genética/fisiologia , Leucemia Linfocítica Crônica de Células B/genética , Mutação/fisiologia , Variações do Número de Cópias de DNA , Epigenômica , Genoma Humano/fisiologia , Genômica/métodos , Humanos , Leucemia Linfocítica Crônica de Células B/patologia
18.
Proc Natl Acad Sci U S A ; 117(6): 3326-3336, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-31974313

RESUMO

Preclinical and clinical studies suggest that inflammation and vascular dysfunction contribute to the pathogenesis of major depressive disorder (MDD). Chronic social stress alters blood-brain barrier (BBB) integrity through loss of tight junction protein claudin-5 (cldn5) in male mice, promoting passage of circulating proinflammatory cytokines and depression-like behaviors. This effect is prominent within the nucleus accumbens, a brain region associated with mood regulation; however, the mechanisms involved are unclear. Moreover, compensatory responses leading to proper behavioral strategies and active resilience are unknown. Here we identify active molecular changes within the BBB associated with stress resilience that might serve a protective role for the neurovasculature. We also confirm the relevance of such changes to human depression and antidepressant treatment. We show that permissive epigenetic regulation of cldn5 expression and low endothelium expression of repressive cldn5-related transcription factor foxo1 are associated with stress resilience. Region- and endothelial cell-specific whole transcriptomic analyses revealed molecular signatures associated with stress vulnerability vs. resilience. We identified proinflammatory TNFα/NFκB signaling and hdac1 as mediators of stress susceptibility. Pharmacological inhibition of stress-induced increase in hdac1 activity rescued cldn5 expression in the NAc and promoted resilience. Importantly, we confirmed changes in HDAC1 expression in the NAc of depressed patients without antidepressant treatment in line with CLDN5 loss. Conversely, many of these deleterious CLDN5-related molecular changes were reduced in postmortem NAc from antidepressant-treated subjects. These findings reinforce the importance of considering stress-induced neurovascular pathology in depression and provide therapeutic targets to treat this mood disorder and promote resilience.


Assuntos
Barreira Hematoencefálica/metabolismo , Transtorno Depressivo Maior/metabolismo , Estresse Psicológico/metabolismo , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Claudina-5/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Modelos Animais de Doenças , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/fisiologia , Histona Desacetilase 1/metabolismo , Humanos , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Núcleo Accumbens/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
19.
Gene ; 731: 144348, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-31927006

RESUMO

Mounting evidence demonstrates that N6-methyladenosine (m6A) play critical roles of m6A in the epigenetic regulation, especially for human cancer. The m6A modification is installed by methyltransferase and erased demethylases, leading to the significant modification for gene expression and cell fate. Here, we investigated the biological roles and mechanism of demethylase alkylation repair homolog protein 5 (ALKBH5) in the non-small cell lung cancer (NSCLC). Results revealed that ALKBH5 was ectopically up-regulated in the NSCLC tissue and cells, and closely correlated with the poor prognosis. Functionally, ALKBH5 promoted the proliferation and reduced apoptosis of NSCLC cells in vitro, and knockdown of ALKBH5 repressed the tumor growth in vivo. Mechanistically, RNA immunoprecipitation sequencing (RIP-Seq) revealed that ALKBH5 targeted the TIMP3. Moreover, ALKBH5 repressed TIMP3 mRNA stability and protein production. In conclusion, the present research confirmed the ALKBH5/TIMP3 pathway in the NSCLC oncogenesis progress, providing a novel insight for the epitranscriptome and potential therapeutic target for NSCLC.


Assuntos
Adenosina/análogos & derivados , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/fisiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Estabilidade de RNA/genética , Inibidor Tecidual de Metaloproteinase-3/genética , Células A549 , Adenosina/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/genética , Animais , Carcinogênese/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Progressão da Doença , Epigênese Genética/fisiologia , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , RNA Mensageiro/metabolismo
20.
Horm Behav ; 118: 104680, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31927018

RESUMO

Interactions between hormones and epigenetic factors are key regulators of behaviour, but the mechanisms that underlie their effects are complex. Epigenetic factors can modify sensitivity to hormones by altering hormone receptor expression, and hormones can regulate epigenetic factors by recruiting epigenetic regulators to DNA. The bidirectional nature of this relationship is becoming increasingly evident and suggests that the ability of hormones to regulate certain forms of behaviour may depend on their ability to induce changes in the epigenome. Moreover, sex differences have been reported for several epigenetic modifications, and epigenetic factors are thought to regulate sexual differentiation of behaviour, although specific mechanisms remain to be understood. Indeed, hormone-epigenome interactions are highly complex and involve both canonical and non-canonical regulatory pathways that may permit for highly specific gene regulation to promote variable forms of behavioural adaptation.


Assuntos
Adaptação Fisiológica , Comportamento/efeitos dos fármacos , Epigênese Genética/fisiologia , Epigenoma/efeitos dos fármacos , Epigenoma/fisiologia , Hormônios/farmacologia , Adaptação Fisiológica/efeitos dos fármacos , Adaptação Fisiológica/genética , Animais , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/fisiologia , Regulação Emocional/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Histonas/genética , Histonas/metabolismo , Hormônios/sangue , Humanos , Caracteres Sexuais
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