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1.
Nat Commun ; 11(1): 4873, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978376

RESUMO

Autism spectrum disorder (ASD) is a phenotypically and genetically heterogeneous neurodevelopmental disorder. Despite this heterogeneity, previous studies have shown patterns of molecular convergence in post-mortem brain tissue from autistic subjects. Here, we integrate genome-wide measures of mRNA expression, miRNA expression, DNA methylation, and histone acetylation from ASD and control brains to identify a convergent molecular subtype of ASD with shared dysregulation across both the epigenome and transcriptome. Focusing on this convergent subtype, we substantially expand the repertoire of differentially expressed genes in ASD and identify a component of upregulated immune processes that are associated with hypomethylation. We utilize eQTL and chromosome conformation datasets to link differentially acetylated regions with their cognate genes and identify an enrichment of ASD genetic risk variants in hyperacetylated noncoding regulatory regions linked to neuronal genes. These findings help elucidate how diverse genetic risk factors converge onto specific molecular processes in ASD.


Assuntos
Transtorno do Espectro Autista/genética , Epigenômica/métodos , RNA Mensageiro/metabolismo , Transcriptoma , Encéfalo/metabolismo , Metilação de DNA , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Genômica , Histonas/metabolismo , Humanos , MicroRNAs
2.
Nat Commun ; 11(1): 4779, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963246

RESUMO

Highly reproducible smoking-associated DNA methylation changes in whole blood have been reported by many Epigenome-Wide-Association Studies (EWAS). These epigenetic alterations could have important implications for understanding and predicting the risk of smoking-related diseases. To this end, it is important to establish if these DNA methylation changes happen in all blood cell subtypes or if they are cell-type specific. Here, we apply a cell-type deconvolution algorithm to identify cell-type specific DNA methylation signals in seven large EWAS. We find that most of the highly reproducible smoking-associated hypomethylation signatures are more prominent in the myeloid lineage. A meta-analysis further identifies a myeloid-specific smoking-associated hypermethylation signature enriched for DNase Hypersensitive Sites in acute myeloid leukemia. These results may guide the design of future smoking EWAS and have important implications for our understanding of how smoking affects immune-cell subtypes and how this may influence the risk of smoking related diseases.


Assuntos
Metilação de DNA/efeitos dos fármacos , Epigenoma , Fumar/efeitos adversos , Algoritmos , Grupo com Ancestrais do Continente Asiático , Sangue , Ilhas de CpG , Epigenômica/métodos , Grupos Étnicos , Feminino , Humanos , Linfócitos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Células Mieloides
3.
Clin Epigenetics ; 12(1): 118, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32758273

RESUMO

Coronaviruses (CoVs) are highly diverse single-stranded RNA viruses owing to their susceptibility to numerous genomic mutations and recombination. Such viruses involve human and animal pathogens including the etiologic agents of acute respiratory tract illnesses: severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and the highly morbific SARS-CoV-2. Coronavirus disease 2019 (COVID-19), an emerging disease with a quick rise in infected cases and deaths, was recently identified causing a worldwide pandemic. COVID-19 disease outcomes were found to increase in elderly and patients with a compromised immune system. Evidences indicated that the main culprit behind COVID-19 deaths is the cytokine storm, which is illustrated by an uncontrolled over-production of soluble markers of inflammation. The regulation process of coronavirus pathogenesis through molecular mechanism comprise virus-host interactions linked to viral entry, replication and transcription, escape, and immune system control. Recognizing coronavirus infections and COVID-19 through epigenetics lens will lead to potential alteration in gene expression thus limiting coronavirus infections. Focusing on epigenetic therapies reaching clinical trials, clinically approved epigenetic-targeted agents, and combination therapy of antivirals and epigenetic drugs is currently considered an effective and valuable approach for viral replication and inflammatory overdrive control.


Assuntos
Betacoronavirus , Infecções por Coronavirus , Epigenômica/métodos , Pandemias , Pneumonia Viral , Betacoronavirus/genética , Betacoronavirus/fisiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Descoberta de Drogas/métodos , Genoma Viral/efeitos dos fármacos , Humanos , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia
4.
BMC Bioinformatics ; 21(1): 268, 2020 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-32600298

RESUMO

BACKGROUND: High-throughput technologies enable the cost-effective collection and analysis of DNA methylation data throughout the human genome. This naturally entails missing values management that can complicate the analysis of the data. Several general and specific imputation methods are suitable for DNA methylation data. However, there are no detailed studies of their performances under different missing data mechanisms -(completely) at random or not- and different representations of DNA methylation levels (ß and M-value). RESULTS: We make an extensive analysis of the imputation performances of seven imputation methods on simulated missing completely at random (MCAR), missing at random (MAR) and missing not at random (MNAR) methylation data. We further consider imputation performances on the popular ß- and M-value representations of methylation levels. Overall, ß-values enable better imputation performances than M-values. Imputation accuracy is lower for mid-range ß-values, while it is generally more accurate for values at the extremes of the ß-value range. The MAR values distribution is on the average more dense in the mid-range in comparison to the expected ß-value distribution. As a consequence, MAR values are on average harder to impute. CONCLUSIONS: The results of the analysis provide guidelines for the most suitable imputation approaches for DNA methylation data under different representations of DNA methylation levels and different missing data mechanisms.


Assuntos
Metilação de DNA , Coleta de Dados , Epigenômica/métodos , Humanos
5.
Nat Commun ; 11(1): 2316, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385268

RESUMO

Our early-life environment has a profound influence on developing organs that impacts metabolic function and determines disease susceptibility across the life-course. Using a rat model for exposure to an endocrine disrupting chemical (EDC), we show that early-life chemical exposure causes metabolic dysfunction in adulthood and reprograms histone marks in the developing liver to accelerate acquisition of an adult epigenomic signature. This epigenomic reprogramming persists long after the initial exposure, but many reprogrammed genes remain transcriptionally silent with their impact on metabolism not revealed until a later life exposure to a Western-style diet. Diet-dependent metabolic disruption was largely driven by reprogramming of the Early Growth Response 1 (EGR1) transcriptome and production of metabolites in pathways linked to cholesterol, lipid and one-carbon metabolism. These findings demonstrate the importance of epigenome:environment interactions, which early in life accelerate epigenomic aging, and later in adulthood unlock metabolically restricted epigenetic reprogramming to drive metabolic dysfunction.


Assuntos
Epigenoma/genética , Animais , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Proteína 1 de Resposta de Crescimento Precoce/genética , Disruptores Endócrinos/toxicidade , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/genética , Epigenômica/métodos , Feminino , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Masculino , Ratos
6.
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
7.
Adv Exp Med Biol ; 1253: 95-104, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32445092

RESUMO

Genomic predisposition fails to fully explain the onset of complex diseases, which is well illustrated by the largely incomplete concordance among monozygotic twins. Epigenetic mechanisms, including DNA methylation, chromatin remodeling, and non-coding RNA, are the link between environmental stimuli and disease onset on a permissive genetic background in autoimmune and chronic inflammatory diseases. Autoimmune diseases now include almost 100 conditions and are estimated to cumulatively affect up to 5% of the world population with a healthcare expenditure superior to cancer worldwide. Many advances in medicine have been made to treat these conditions but there are still gaps, and an innovative and efficient therapy is needed. Systemic autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjogren syndrome, polymyositis, and dermatomyositis. Monozygotic twins discordant for any disease offer an ideal study design as they are matched for many factors, including genetic variation and this is a real advantage for epigenetics study. We will herein discuss the available data in the epigenetic differences leading to disease discordance in MZ twins for systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis.


Assuntos
Epigênese Genética , Epigenômica/métodos , Estudos em Gêmeos como Assunto , Gêmeos Monozigóticos/genética , Doenças Autoimunes/genética , Metilação de DNA , Humanos , Inflamação/genética
8.
Nat Rev Rheumatol ; 16(5): 268-281, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32273577

RESUMO

Research into the molecular genetics of osteoarthritis (OA) has been substantially bolstered in the past few years by the implementation of powerful genome-wide scans that have revealed a large number of novel risk loci associated with the disease. This refreshing wave of discovery has occurred concurrently with epigenetic studies of joint tissues that have examined DNA methylation, histone modifications and regulatory RNAs. These epigenetic analyses have involved investigations of joint development, homeostasis and disease and have used both human samples and animal models. What has become apparent from a comparison of these two complementary approaches is that many OA genetic risk signals interact with, map to or correlate with epigenetic mediators. This discovery implies that epigenetic mechanisms, and their effect on gene expression, are a major conduit through which OA genetic risk polymorphisms exert their functional effects. This observation is particularly exciting as it provides mechanistic insight into OA susceptibility. Furthermore, this knowledge reveals avenues for attenuating the negative effect of risk-conferring alleles by exposing the epigenome as an exploitable target for therapeutic intervention in OA.


Assuntos
Epigenômica/métodos , Estudo de Associação Genômica Ampla/métodos , Articulações/metabolismo , Osteoartrite/genética , Alelos , Animais , Condrócitos/metabolismo , Metilação de DNA/genética , Expressão Gênica , Código das Histonas/genética , Homeostase/genética , Homeostase/fisiologia , Humanos , Articulações/crescimento & desenvolvimento , Camundongos , Modelos Animais , Polimorfismo de Nucleotídeo Único/genética , Sequências Reguladoras de Ácido Ribonucleico/genética , Fatores de Risco
9.
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
10.
Mol Genet Genomics ; 295(4): 837-841, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32300860

RESUMO

This work presents a new method and tool to solve a common problem of molecular biologists and geneticists who use molecular markers in their scientific research and developments: curation of sequences. Omic studies conducted by molecular biologists and geneticists usually involve the use of molecular markers. AFLP, cDNA-AFLP, and MSAP are examples of markers that render information at the genomics, transcriptomics, and epigenomics levels, respectively. These three types of molecular markers use adaptors that are the template for PCR amplification. The sequences of the adaptors have to be eliminated for the analysis of the results. Since a large number of sequences are usually obtained in these studies, this clean-up of the data could demand long time and work. To automate this work, an R package, named CleanBSequences, was created that allows the sequences to be curated massively, quickly, without errors and can be used offline. The curating is performed by aligning the forward and/or reverse primers or ends of cloning vectors with the sequences to be removed. After the alignment, new subsequences are generated without biological fragments not desired by the user, i.e., sequences needed by the techniques. In conclusion, the CleanBSequences tool facilitates the work of researchers, reducing time, effort, and working errors. Therefore, the present tool would respond to the problems related to the curation of sequences obtained from the use of some types of molecular markers. In addition to the above, being an open source, CleanBSequences is a flexible tool that has the potential to be used in future improvements to respond to new problems.


Assuntos
Biologia Computacional , Marcadores Genéticos/genética , Biologia Molecular/métodos , Software , Epigenômica/métodos , Genômica/métodos , Anotação de Sequência Molecular/métodos , Alinhamento de Sequência/métodos , Análise de Sequência/métodos , Transcriptoma/genética
11.
PLoS Comput Biol ; 16(4): e1007771, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32255787

RESUMO

Biomedical research studies have generated large multi-omic datasets to study complex diseases like Alzheimer's disease (AD). An important aim of these studies is the identification of candidate genes that demonstrate congruent disease-related alterations across the different data types measured by the study. We developed a new method to detect such candidate genes in large multi-omic case-control studies that measure multiple data types in the same set of samples. The method is based on a gene-centric integrative coefficient quantifying to what degree consistent differences are observed in the different data types. For statistical inference, a Bayesian hierarchical model is used to study the distribution of the integrative coefficient. The model employs a conditional autoregressive prior to integrate a functional gene network and to share information between genes known to be functionally related. We applied the method to an AD dataset consisting of histone acetylation, DNA methylation, and RNA transcription data from human cortical tissue samples of 233 subjects, and we detected 816 genes with consistent differences between persons with AD and controls. The findings were validated in protein data and in RNA transcription data from two independent AD studies. Finally, we found three subnetworks of jointly dysregulated genes within the functional gene network which capture three distinct biological processes: myeloid cell differentiation, protein phosphorylation and synaptic signaling. Further investigation of the myeloid network indicated an upregulation of this network in early stages of AD prior to accumulation of hyperphosphorylated tau and suggested that increased CSF1 transcription in astrocytes may contribute to microglial activation in AD. Thus, we developed a method that integrates multiple data types and external knowledge of gene function to detect candidate genes, applied the method to an AD dataset, and identified several disease-related genes and processes demonstrating the usefulness of the integrative approach.


Assuntos
Doença de Alzheimer , Biologia Computacional/métodos , Epigenômica/métodos , Perfilação da Expressão Gênica/métodos , Transcriptoma/genética , Algoritmos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Teorema de Bayes , Estudos de Casos e Controles , Diferenciação Celular/genética , Bases de Dados Genéticas , Redes Reguladoras de Genes/genética , Humanos
12.
Nat Genet ; 52(5): 525-533, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32313247

RESUMO

Polyploidy is an evolutionary innovation for many animals and all flowering plants, but its impact on selection and domestication remains elusive. Here we analyze genome evolution and diversification for all five allopolyploid cotton species, including economically important Upland and Pima cottons. Although these polyploid genomes are conserved in gene content and synteny, they have diversified by subgenomic transposon exchanges that equilibrate genome size, evolutionary rate heterogeneities and positive selection between homoeologs within and among lineages. These differential evolutionary trajectories are accompanied by gene-family diversification and homoeolog expression divergence among polyploid lineages. Selection and domestication drive parallel gene expression similarities in fibers of two cultivated cottons, involving coexpression networks and N6-methyladenosine RNA modifications. Furthermore, polyploidy induces recombination suppression, which correlates with altered epigenetic landscapes and can be overcome by wild introgression. These genomic insights will empower efforts to manipulate genetic recombination and modify epigenetic landscapes and target genes for crop improvement.


Assuntos
Genoma de Planta/genética , Gossypium/genética , Fibra de Algodão , Domesticação , Epigenômica/métodos , Evolução Molecular , Regulação da Expressão Gênica de Plantas/genética , Genômica/métodos , Filogenia , Poliploidia
13.
PLoS One ; 15(4): e0230930, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32267870

RESUMO

Human epidemiological studies have shown that paternal aging as one of the risk factors for neurodevelopmental disorders, such as autism, in offspring. A recent study has suggested that factors other than de novo mutations due to aging can influence the biology of offspring. Here, we focused on epigenetic alterations in sperm that can influence developmental programs in offspring. In this study, we qualitatively and semiquantitatively evaluated histone modification patterns in male germline cells throughout spermatogenesis based on immunostaining of testes taken from young (3 months old) and aged (12 months old) mice. Although localization patterns were not obviously changed between young and aged testes, some histone modification showed differences in their intensity. Among histone modifications that repress gene expression, histone H3 lysine 9 trimethylation (H3K9me3) was decreased in the male germline cells of the aged testis, while H3K27me2/3 was increased. The intensity of H3K27 acetylation (ac), an active mark, was lower/higher depending on the stages in the aged testis. Interestingly, H3K27ac was detected on the putative sex chromosomes of round spermatids, while other chromosomes were occupied by a repressive mark, H3K27me3. Among other histone modifications that activate gene expression, H3K4me2 was drastically decreased in the male germline cells of the aged testis. In contrast, H3K79me3 was increased in M-phase spermatocytes, where it accumulates on the sex chromosomes. Therefore, aging induced alterations in the amount of histone modifications and in the differences of patterns for each modification. Moreover, histone modifications on the sex chromosomes and on other chromosomes seems to be differentially regulated by aging. These findings will help elucidate the epigenetic mechanisms underlying the influence of paternal aging on offspring development.


Assuntos
Histonas/genética , Meiose/genética , Espermatócitos/fisiologia , Espermatogênese/genética , Testículo/fisiologia , Acetilação , Animais , Epigênese Genética/genética , Epigenômica/métodos , Expressão Gênica/genética , Código das Histonas/genética , Humanos , Lisina/genética , Masculino , Metilação , Camundongos , Processamento de Proteína Pós-Traducional/genética , Cromossomos Sexuais/genética , Espermátides/fisiologia
14.
Am J Hum Genet ; 106(4): 513-524, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32243819

RESUMO

The identification of functional regions in the noncoding human genome is difficult but critical in order to gain understanding of the role noncoding variation plays in gene regulation in human health and disease. We describe here a co-localization approach that aims to identify constrained sequences that co-localize with tissue- or cell-type-specific regulatory regions, and we show that the resulting score is particularly well suited for the identification of rare regulatory variants. For 127 tissues and cell types in the ENCODE/Roadmap Epigenomics Project, we provide catalogs of putative tissue- or cell-type-specific regulatory regions under sequence constraint. We use the newly developed co-localization score for brain tissues to score de novo mutations in whole genomes from 1,902 individuals affected with autism spectrum disorder (ASD) and their unaffected siblings in the Simons Simplex Collection. We show that noncoding de novo mutations near genes co-expressed in midfetal brain with high confidence ASD risk genes, and near FMRP gene targets are more likely to be in co-localized regions if they occur in ASD probands versus in their unaffected siblings. We also observed a similar enrichment for mutations near lincRNAs, previously shown to co-express with ASD risk genes. Additionally, we provide strong evidence that prioritized de novo mutations in autism probands point to a small set of well-known ASD genes, the disruption of which produces relevant mouse phenotypes such as abnormal social investigation and abnormal discrimination/associative learning, unlike the de novo mutations in unaffected siblings. The genome-wide co-localization results are available online.


Assuntos
Regulação da Expressão Gênica/genética , Genoma Humano/genética , Transtorno do Espectro Autista/genética , Epigenômica/métodos , Humanos , Mutação/genética , Fenótipo , Irmãos , Sequenciamento Completo do Genoma/métodos
15.
Proc Natl Acad Sci U S A ; 117(18): 10003-10014, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32300008

RESUMO

Transcription factors (TFs) enact precise regulation of gene expression through site-specific, genome-wide binding. Common methods for TF-occupancy profiling, such as chromatin immunoprecipitation, are limited by requirement of TF-specific antibodies and provide only end-point snapshots of TF binding. Alternatively, TF-tagging techniques, in which a TF is fused to a DNA-modifying enzyme that marks TF-binding events across the genome as they occur, do not require TF-specific antibodies and offer the potential for unique applications, such as recording of TF occupancy over time and cell type specificity through conditional expression of the TF-enzyme fusion. Here, we create a viral toolkit for one such method, calling cards, and demonstrate that these reagents can be delivered to the live mouse brain and used to report TF occupancy. Further, we establish a Cre-dependent calling cards system and, in proof-of-principle experiments, show utility in defining cell type-specific TF profiles and recording and integrating TF-binding events across time. This versatile approach will enable unique studies of TF-mediated gene regulation in live animal models.


Assuntos
Cromatina/genética , Elementos de DNA Transponíveis/genética , Proteínas de Ligação a DNA/genética , Epigenômica/métodos , Fatores de Transcrição/genética , Algoritmos , Animais , Anticorpos/genética , Sítios de Ligação/genética , Cromatina/virologia , Dependovirus/genética , Regulação da Expressão Gênica/genética , Genoma/genética , Humanos , Integrases/genética , Camundongos , Distribuição Tecidual/genética
16.
Nat Commun ; 11(1): 1238, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32144264

RESUMO

An improved understanding of etiological mechanisms in Parkinson's disease (PD) is urgently needed because the number of affected individuals is projected to increase rapidly as populations age. We present results from a blood-based methylome-wide association study of PD involving meta-analysis of 229 K CpG probes in 1,132 cases and 999 controls from two independent cohorts. We identify two previously unreported epigenome-wide significant associations with PD, including cg06690548 on chromosome 4. We demonstrate that cg06690548 hypermethylation in PD is associated with down-regulation of the SLC7A11 gene and show this is consistent with an environmental exposure, as opposed to medications or genetic factors with effects on DNA methylation or gene expression. These findings are notable because SLC7A11 codes for a cysteine-glutamate anti-porter regulating levels of the antioxidant glutathione, and it is a known target of the environmental neurotoxin ß-methylamino-L-alanine (BMAA). Our study identifies the SLC7A11 gene as a plausible biological target in PD.


Assuntos
Sistema y+ de Transporte de Aminoácidos/metabolismo , Cromossomos Humanos Par 4/genética , Metilação de DNA , Doença de Parkinson/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sistema y+ de Transporte de Aminoácidos/genética , Austrália , Estudos de Casos e Controles , Ilhas de CpG/genética , Regulação para Baixo , Epigenômica/métodos , Feminino , Glutationa/metabolismo , Voluntários Saudáveis , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Nova Zelândia , Doença de Parkinson/sangue , Doença de Parkinson/patologia
17.
Nat Rev Mol Cell Biol ; 21(3): 137-150, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32020082

RESUMO

Ageing is characterized by the functional decline of tissues and organs and the increased risk of ageing-associated disorders. Several 'rejuvenating' interventions have been proposed to delay ageing and the onset of age-associated decline and disease to extend healthspan and lifespan. These interventions include metabolic manipulation, partial reprogramming, heterochronic parabiosis, pharmaceutical administration and senescent cell ablation. As the ageing process is associated with altered epigenetic mechanisms of gene regulation, such as DNA methylation, histone modification and chromatin remodelling, and non-coding RNAs, the manipulation of these mechanisms is central to the effectiveness of age-delaying interventions. This Review discusses the epigenetic changes that occur during ageing and the rapidly increasing knowledge of how these epigenetic mechanisms have an effect on healthspan and lifespan extension, and outlines questions to guide future research on interventions to rejuvenate the epigenome and delay ageing processes.


Assuntos
Envelhecimento/genética , Epigênese Genética/genética , Rejuvenescimento/fisiologia , Animais , Montagem e Desmontagem da Cromatina/genética , Metilação de DNA/genética , Epigenoma/genética , Epigenômica/métodos , Regulação da Expressão Gênica/genética , Código das Histonas/genética , Humanos , Longevidade/genética
18.
Nucleic Acids Res ; 48(8): e43, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32086521

RESUMO

Quantitative comparison of epigenomic data across multiple cell types or experimental conditions is a promising way to understand the biological functions of epigenetic modifications. However, differences in sequencing depth and signal-to-noise ratios in the data from different experiments can hinder our ability to identify real biological variation from raw epigenomic data. Proper normalization is required prior to data analysis to gain meaningful insights. Most existing methods for data normalization standardize signals by rescaling either background regions or peak regions, assuming that the same scale factor is applicable to both background and peak regions. While such methods adjust for differences in sequencing depths, they do not address differences in the signal-to-noise ratios across different experiments. We developed a new data normalization method, called S3norm, that normalizes the sequencing depths and signal-to-noise ratios across different data sets simultaneously by a monotonic nonlinear transformation. We show empirically that the epigenomic data normalized by our method, compared to existing methods, can better capture real biological variation, such as impact on gene expression regulation.


Assuntos
Epigenômica/métodos , Análise de Sequência de DNA/métodos , Expressão Gênica , Código das Histonas , RNA-Seq , Software
19.
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
20.
Cancer Cell ; 37(2): 147-156, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-32049045

RESUMO

Metabolic pathways must be adapted to support cell processes required for transformation and cancer progression. Amino acid metabolism is deregulated in many cancers, with changes in branched-chain amino acid metabolism specifically affecting cancer cell state as well as systemic metabolism in individuals with malignancy. This review highlights key concepts surrounding the current understanding of branched-chain amino acid metabolism and its role in cancer.


Assuntos
Aminoácidos de Cadeia Ramificada/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias/metabolismo , Epigenômica/métodos , Humanos , Isoleucina/metabolismo , Leucina/metabolismo
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