RESUMEN
Motivation: DNA methylation datasets are growing ever larger both in sample size and genome coverage. Novel computational solutions are required to efficiently handle these data. Results: We have developed meffil, an R package designed for efficient quality control, normalization and epigenome-wide association studies of large samples of Illumina Methylation BeadChip microarrays. A complete re-implementation of functional normalization minimizes computational memory without increasing running time. Incorporating fixed and random effects within functional normalization, and automated estimation of functional normalization parameters reduces technical variation in DNA methylation levels, thus reducing false positive rates and improving power. Support for normalization of datasets distributed across physically different locations without needing to share biologically-based individual-level data means that meffil can be used to reduce heterogeneity in meta-analyses of epigenome-wide association studies. Availability and implementation: https://github.com/perishky/meffil/. Supplementary information: Supplementary data are available at Bioinformatics online.
Asunto(s)
Metilación de ADN , Epigenómica , Conjuntos de Datos como Asunto , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
Reward-related memory is an important factor in cocaine seeking. One necessary signaling mechanism for long-term memory formation is the activation of poly(ADP-ribose) polymerase-1 (PARP-1), via poly(ADP-ribosyl)ation. We demonstrate herein that auto-poly(ADP-ribosyl)ation of activated PARP-1 was significantly pronounced during retrieval of cocaine-associated contextual memory, in the central amygdala (CeA) of rats expressing cocaine-conditioned place preference (CPP). Intra-CeA pharmacological and short hairpin RNA depletion of PARP-1 activity during cocaine-associated memory retrieval abolished CPP. In contrast, PARP-1 inhibition after memory retrieval did not affect CPP reconsolidation process and subsequent retrievals. Chromatin immunoprecipitation sequencing revealed that PARP-1 binding in the CeA is highly enriched in genes involved in neuronal signaling. We identified among PARP targets in CeA a single gene, yet uncharacterized and encoding a putative transposase inhibitor, at which PARP-1 enrichment markedly increases during cocaine-associated memory retrieval and positively correlates with CPP. Our findings have important implications for understanding drug-related behaviors, and suggest possible future therapeutic targets for drug abuse.
Asunto(s)
Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Poli(ADP-Ribosa) Polimerasas/genética , Factores de Ribosilacion-ADP/metabolismo , Amígdala del Cerebelo/metabolismo , Animales , Cocaína/efectos adversos , Cocaína/metabolismo , Cocaína/farmacología , Masculino , Memoria/efectos de los fármacos , Poli(ADP-Ribosa) Polimerasa-1/genética , Regiones Promotoras Genéticas/genética , Unión Proteica , Ratas , Ratas Sprague-Dawley , Transposasas/antagonistas & inhibidoresRESUMEN
Astrocytes are glial cells specific to the central nervous system and involved in numerous brain functions, including regulation of synaptic transmission and of immune reactions. There is mounting evidence suggesting astrocytic dysfunction in psychopathologies such as major depression, however, little is known about the underlying etiological mechanisms. Here we report a two-stage study investigating genome-wide DNA methylation associated with astrocytic markers in depressive psychopathology. We first characterized prefrontal cortex samples from 121 individuals (76 who died during a depressive episode and 45 healthy controls) for the astrocytic markers GFAP, ALDH1L1, SOX9, GLUL, SCL1A3, GJA1 and GJB6. A subset of 22 cases with consistently downregulated astrocytic markers was then compared with 17 matched controls using methylation binding domain-2 (MBD2) sequencing followed by validation with high-resolution melting and bisulfite Sanger sequencing. With these data, we generated a genome-wide methylation map unique to altered astrocyte-associated depressive psychopathology. The map revealed differentially methylated regions (DMRs) between cases and controls, the majority of which displayed reduced methylation levels in cases. Among intragenic DMRs, those found in GRIK2 (glutamate receptor, ionotropic kainate 2) and BEGAIN (brain-enriched guanylate kinase-associated protein) were most significant and also showed significant correlations with gene expression. Cell-sorted fractions were investigated and demonstrated an important non-neuronal contribution of methylation status in BEGAIN. Functional cell assays revealed promoter and enhancer-like properties in this region that were markedly decreased by methylation. Furthermore, a large number of our DMRs overlapped known Encyclopedia of DNA elements (ENCODE)-identified regulatory elements. Taken together, our data indicate significant differences in the methylation patterns specific to astrocytic dysfunction associated with depressive psychopathology, providing a potential framework for better understanding this disease phenotype.
Asunto(s)
Astrocitos/metabolismo , Metilación de ADN , Depresión , Regulación hacia Abajo , Corteza Prefrontal/metabolismo , Suicidio , Adulto , Aldehído Deshidrogenasa/genética , Estudios de Casos y Controles , Conexina 43/genética , Depresión/genética , Depresión/patología , Depresión/fisiopatología , Epigénesis Genética , Femenino , Estudio de Asociación del Genoma Completo , Proteína Ácida Fibrilar de la Glía/genética , Glutamato-Amoníaco Ligasa/genética , Humanos , Masculino , Persona de Mediana Edad , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH , Corteza Prefrontal/patología , Factor de Transcripción SOX9/genética , Adulto JovenRESUMEN
Background: Prior studies indicate that peer victimization (including bullying) is associated with higher risk for depression and suicidal ideation across the life course. However, molecular mechanisms underlying these associations remain unclear. This two-cohort study proposes to test whether epigenetic aging and pace of aging, as well as a DNA methylation marker of responsive to glucocorticoids, are associated to childhood peer victimization and later depressive symptoms, or suicidal ideation. Methods: Cohort 1: Epigenome-wide DNA methylation (EPIC array) was measured in saliva collected when participants were 10.47 years (standard deviation = 0.35) in a subsample of the Quebec Longitudinal Study of Child Development (QLSCD, n = 149 participants), with self-reported peer victimization at 6-8 years, depressive symptoms (mean symptoms, and dichotomized top 30% symptoms) and suicidal ideation at 15-17 years. Cohort 2: Epigenome-wide DNA methylation (EPIC array) was measured in blood collected from participants aged 45.13 years (standard deviation = 0.37) in a subsample of the 1958 British Birth cohort (1958BBC, n = 238 participants) with information on mother-reported peer victimization at 7-11 years, self-reported depressive symptoms at 50 years, and suicidal ideation at 45 years. Five epigenetic indices were derived: three indicators of epigenetic aging [Horvath's pan-tissue (Horvath1), Horvath's Skin-and-Blood (Horvath2), Pediatric-Buccal-Epigenetic age (PedBE)], pace of aging (DunedinPACE), and stress response reactivity (Epistress). Results: Peer victimization was not associated with the epigenetic indices in either cohort. In the QLSCD, higher PedBE epigenetic aging and a slower pace of aging as measured by DunedinPACE predicted higher depressive symptoms scores. In contrast, neither the Horvath1, or Horvath2 epigenetic age estimates, nor the Epistress score were associated with depressive symptoms in either cohort, and none of the epigenetic indices predicted suicidal ideation. Conclusion: The findings are consistent with epigenome-wide and candidate gene studies suggesting that these epigenetic indices did not relate to peer victimization, challenging the hypothesis that cumulative epigenetic aging indices could translate vulnerability to depressive symptoms and suicidal ideation following peer victimization. Since some indices of epigenetic aging and pace of aging signaled higher risk for depressive symptoms, future studies should pursue this investigation to further evaluate the robustness and generalization of these preliminary findings.
RESUMEN
BACKGROUND: Smoking remains one of the leading preventable causes of death. Smoking leaves a strong signature on the blood methylome as shown in multiple studies using the Infinium HumanMethylation450 BeadChip. Here, we explore novel blood methylation smoking signals on the Illumina MethylationEPIC BeadChip (EPIC) array, which also targets novel CpG-sites in enhancers. METHOD: A smoking-methylation meta-analysis was carried out using EPIC DNA methylation profiles in 1407 blood samples from four UK population-based cohorts, including the MRC National Survey for Health and Development (NSHD) or 1946 British birth cohort, the National Child Development Study (NCDS) or 1958 birth cohort, the 1970 British Cohort Study (BCS70), and the TwinsUK cohort (TwinsUK). The overall discovery sample included 269 current, 497 former, and 643 never smokers. Replication was pursued in 3425 trans-ethnic samples, including 2325 American Indian individuals participating in the Strong Heart Study (SHS) in 1989-1991 and 1100 African-American participants in the Genetic Epidemiology Network of Arteriopathy Study (GENOA). RESULTS: Altogether 952 CpG-sites in 500 genes were differentially methylated between smokers and never smokers after Bonferroni correction. There were 526 novel smoking-associated CpG-sites only profiled by the EPIC array, of which 486 (92%) replicated in a meta-analysis of the American Indian and African-American samples. Novel CpG sites mapped both to genes containing previously identified smoking-methylation signals and to 80 novel genes not previously linked to smoking, with the strongest novel signal in SLAMF7. Comparison of former versus never smokers identified that 37 of these sites were persistently differentially methylated after cessation, where 16 represented novel signals only profiled by the EPIC array. We observed a depletion of smoking-associated signals in CpG islands and an enrichment in enhancer regions, consistent with previous results. CONCLUSION: This study identified novel smoking-associated signals as possible biomarkers of exposure to smoking and may help improve our understanding of smoking-related disease risk.
Asunto(s)
Estudio de Asociación del Genoma Completo/métodos , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/genética , Fumar Tabaco/sangre , Fumar Tabaco/genética , Negro o Afroamericano/genética , Anciano , Estudios de Casos y Controles , Estudios de Cohortes , Islas de CpG , Metilación de ADN , Exposición a Riesgos Ambientales/efectos adversos , Epigénesis Genética , Epigenoma , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Fumadores/estadística & datos numéricos , Fumar Tabaco/etnología , Reino Unido/epidemiología , Población Blanca/genética , Indio Americano o Nativo de Alaska/genéticaRESUMEN
BACKGROUND: Risk behaviours in adolescence are linked to poor educational attainment and health and other outcomes in young adulthood. We explored whether there are molecular mechanisms associated with the development, or the result, of multiple risk behaviours (MRBs). METHODS: MRBs (antisocial behaviour and delinquency, traffic-related risk behaviour, risky sexual behaviour, lack of exercise) and their sumscore were characterized based on self-reported questions at age 7 and 17 within the ARIES subsample of the ALSPAC birth cohort, and were linked to DNA methylation at over 485,000 CpG sites at ages 0,7 and 17. Associations were determined for participants with complete data (n = 227-575). RESULTS: There was weak evidence of associations between cumulative MRBs and methylation at cg01783492 and cg16720578 at age 17. DNA methylation at age 17 was associated with risky sexual behaviour (cg22883332), lack of exercise (cg03152353, cg20056908, cg20571116) and substance use (cg02188400, cg13906377). No associations between DNA methylation and individual risk behaviours at age 7 were observed. DNA methylation at age 7 might predispose for traffic-related risk behaviour (cg24683561) and substance use (cg08761410) at age 17. LIMITATIONS: Main limitations are absence of information on directly measured blood cell type proportions and tissue specificity, and a modest sample size. CONCLUSIONS: Cumulative MRB in late adolescence was associated with effects on DNA methylation. More specifically, risky sexual behaviour and sedentary behaviour are associated with changes in DNA methylation, while DNA methylation in childhood may predict later traffic-related risky behaviour. For substance use effects in both temporal directions were observed.
Asunto(s)
Conducta del Adolescente , Envejecimiento/genética , Metilación de ADN , Trastornos Mentales/genética , Asunción de Riesgos , Adolescente , Envejecimiento/psicología , Conducción de Automóvil/psicología , Niño , Femenino , Humanos , Masculino , Trastornos Mentales/psicología , Conducta Sedentaria , Conducta Sexual , Trastornos Relacionados con Sustancias/genética , Trastornos Relacionados con Sustancias/psicología , Adulto JovenRESUMEN
Childhood adversity affects later health, but the underlying molecular mechanisms are unclear. Although there is some evidence from animal models and case-control studies of a role for DNA methylation, evidence from human population-based studies is limited. In two cohorts (mothers from the Avon Longitudinal Study of Parents and Children, ALSPAC, n = 780 and women from the MRC National Survey of Health and Development, NSHD, n = 552), we assessed the association of seven adverse childhood experiences (ACEs: parental physical illness, parental mental illness, parental death, parental separation, suboptimal maternal bonding, childhood illness and child maltreatment) as well as their combination (ACE score) with genome-wide DNA methylation levels measured using the Illumina Infinium HumanMethylation450 BeadChip in peripheral blood at mean age 47 years (ALSPAC) and in buccal cells at age 53 years (NSHD). CpG sites with a genome-wide false discovery rate (FDR) below 0.05 and differentially methylated regions (DMRs) with one-step Sidák correction p-values below 0.05 in each cohort were examined in the other cohort. No individual CpG sites replicated across cohorts. However, nine DMRs replicated across cohorts respectively associated with the ACE score (one region), parental mental illness (two regions), parental physical illness (three regions) and parental death (three regions). These observations indicate that some adverse childhood experiences, notably those related to parental health, may leave imprints on peripheral DNA methylation that persist to mid-life.
Asunto(s)
Experiencias Adversas de la Infancia , Metilación de ADN , Epigénesis Genética , Estudios de Cohortes , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The aim of the study was to investigate whether maternal mid-pregnancy 25-hydroxyvitamin D concentrations are associated with cord blood DNA methylation. DNA methylation was assessed using the Illumina HumanMethylation450 BeadChip, and maternal plasma 25-hydroxyvitamin D was measured in 819 mothers/newborn pairs participating in the Norwegian Mother and Child Cohort (MoBa) and 597 mothers/newborn pairs participating in the Avon Longitudinal Study of Parents and Children (ALSPAC). Across 473,731CpG DNA methylation sites in cord blood DNA, none were strongly associated with maternal 25-hydroxyvitamin D after adjusting for multiple tests (false discovery rate (FDR)>0.5; 473,731 tests). A meta-analysis of the results from both cohorts, using the Fisher method for combining p-values, also did not strengthen findings (FDR>0.2). Further exploration of a set of CpG sites in the proximity of four a priori defined candidate genes (CYP24A1, CYP27B1, CYP27A1 and CYP2R1) did not result in any associations with FDR<0.05 (56 tests). In this large genome wide assessment of the potential influence of maternal vitamin D status on DNA methylation, we did not find any convincing associations in 1416 newborns. If true associations do exist, their identification might require much larger consortium studies, expanded genomic coverage, investigation of alternative cell types or measurements of 25-hydroxyvitamin D at different gestational time points.
Asunto(s)
ADN/sangre , Embarazo/sangre , Adulto , Estudios de Cohortes , Sistema Enzimático del Citocromo P-450/genética , ADN/genética , Metilación de ADN , Femenino , Sangre Fetal/fisiología , Feto/fisiología , Ácido Fólico , Genoma Humano , Humanos , Vitamina D/análogos & derivadosRESUMEN
Epigenetic processes have been implicated in addiction; yet, it remains unclear whether these represent a risk factor and/or a consequence of substance use. Here, we believe we conducted the first genome-wide, longitudinal study to investigate whether DNA methylation patterns in early life prospectively associate with substance use in adolescence. The sample comprised of 244 youth (51% female) from the Avon Longitudinal Study of Parents and Children (ALSPAC), with repeated assessments of DNA methylation (Illumina 450k array; cord blood at birth, whole blood at age 7) and substance use (tobacco, alcohol and cannabis use; age 14-18). We found that, at birth, epigenetic variation across a tightly interconnected genetic network (n=65 loci; q<0.05) associated with greater levels of substance use during adolescence, as well as an earlier age of onset amongst users. Associations were specific to the neonatal period and not observed at age 7. Key annotated genes included PACSIN1, NEUROD4 and NTRK2, implicated in neurodevelopmental processes. Several of the identified loci were associated with known methylation quantitative trait loci, and consequently likely to be under significant genetic control. Collectively, these 65 loci were also found to partially mediate the effect of prenatal maternal tobacco smoking on adolescent substance use. Together, findings lend novel insights into epigenetic correlates of substance use, highlight birth as a potentially sensitive window of biological vulnerability and provide preliminary evidence of an indirect epigenetic pathway linking prenatal tobacco exposure and adolescent substance use.
Asunto(s)
Consumo de Bebidas Alcohólicas/genética , Metilación de ADN , Epigénesis Genética/genética , Genoma Humano/genética , Abuso de Marihuana/genética , Fumar/genética , Adolescente , Niño , Preescolar , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Lactante , Recién Nacido , Estudios Longitudinales , Masculino , Proteínas del Tejido Nervioso/genética , Embarazo , Estudios Prospectivos , RiesgoRESUMEN
Exposure to early-life stress (ELS) may heighten the risk for psychopathology at adulthood. Here, in order to identify common genes that may keep the memory of ELS through changes in their methylation status, we intersected methylome analyses performed in different tissues and time points in rats, non-human primates and humans, all characterized by ELS. We identified Ankyrin-3 (Ank3), a scaffolding protein with a strong genetic association for psychiatric disorders, as a gene persistently affected by stress exposure. In rats, Ank3 methylation and mRNA changes displayed a specific temporal profile during the postnatal development. Moreover, exposure to prenatal stress altered the interaction of ankyrin-G, the protein encoded by Ank3 enriched in the post-synaptic compartment, with PSD95. Notably, to model in humans a gene by early stress interplay on brain phenotypes during cognitive performance, we demonstrated an interaction between functional variation in Ank3 gene and obstetric complications on working memory in healthy adult subjects. Our data suggest that alterations of Ank3 expression and function may contribute to the effects of ELS on the development of psychiatric disorders.
Asunto(s)
Ancirinas/genética , Modelos Animales de Enfermedad , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Acontecimientos que Cambian la Vida , Trastornos Mentales/genética , Efectos Tardíos de la Exposición Prenatal/genética , Animales , Trastorno Bipolar/genética , Estudios de Cohortes , Metilación de ADN , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Recién Nacido , Macaca mulatta , Masculino , Memoria a Corto Plazo , Fenotipo , Embarazo , Regiones Promotoras Genéticas/genética , Ratas , Esquizofrenia/genéticaRESUMEN
Depression affects 10-15% of pregnant women and has been associated with preterm delivery and later developmental, behavioural and learning disabilities. We tested the hypothesis that maternal depression is associated with DNA methylation alterations in maternal T lymphocytes, neonatal cord blood T lymphocytes and adult offspring hippocampi. Genome-wide DNA methylation of CD3+ T lymphocytes isolated from 38 antepartum maternal and 44 neonatal cord blood samples were analyzed using Illumina Methylation 450 K microarrays. Previously obtained methylation data sets using methylated DNA immunoprecipitation and array-hybridization of 62 postmortem hippocampal samples of adult males were re-analyzed to test associations with history of maternal depression. We found 145 (false discovery rate (FDR) q<0.05) and 2520 (FDR q<0.1) differentially methylated CG-sites in cord blood T lymphocytes of neonates from the maternal depression group as compared with the control group. However, no significant DNA methylation differences were detected in the antepartum maternal T lymphocytes of our preliminary data set. We also detected 294 differentially methylated probes (FDR q<0.1) in hippocampal samples associated with history of maternal depression. We observed a significant overlap (P=0.002) of 33 genes with changes in DNA methylation in T lymphocytes of neonates and brains of adult offspring. Many of these genes are involved in immune system functions. Our results show that DNA methylation changes in offspring associated with maternal depression are detectable at birth in the immune system and persist to adulthood in the brain. This is consistent with the hypothesis that system-wide epigenetic changes are involved in life-long responses to maternal depression in the offspring.
Asunto(s)
Metilación de ADN/inmunología , Trastorno Depresivo/inmunología , Sangre Fetal/inmunología , Hipocampo/inmunología , Madres/psicología , Linfocitos T/inmunología , Adulto , Epigénesis Genética/inmunología , Femenino , Humanos , EmbarazoRESUMEN
This study of the yellow fever French neurotropic vaccine strain from the Institut Pasteur (FNV-IP) demonstrates that this viral genome is not as stable as that of the 17D-204 vaccine virus. FNV-IP was plaque-purified three times and then passaged eight times in Vero cells. Viral populations from the second and eighth passage post purification were sequenced and compared to the published sequences of FNV-IP. The passage-2 viral population had 31 nucleotide and nine amino acid changes compared to the parental virus while the passage-8 virus had six additional nucleotide changes encoding a single amino acid substitution. The plaque-purified virus also had two sequence deletions in the 3'-noncoding region. The plaque purification resulted in selection of a passage-2 virus that had a mouse LD(50) of 20 pfu/ml, 67-fold greater than parental FNV-IP which had an LD(50) of 0.3 pfu/ml. Subsequent passage in Vero cells resulted in a passage-8 virus which had increased neurovirulence with an LD(50) of 3.2 pfu/ml. The only amino acid difference between the passage-2 and passage-8 viruses was at amino acid 638 of NS5 which lies within domain V of the RNA-dependent-RNA polymerase. Overall, these data indicate that FNV-IP virus has an inherently less stable genome than 17D vaccine virus and a variable viral population.
Asunto(s)
Mutación , Virus de la Fiebre Amarilla/genética , Virus de la Fiebre Amarilla/patogenicidad , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Chlorocebus aethiops , ADN Viral/genética , Genes Virales , Ratones , Enfermedades del Sistema Nervioso/etiología , Células Vero , Virulencia/genética , Cultivo de Virus , Fiebre Amarilla/etiología , Vacuna contra la Fiebre Amarilla/genéticaRESUMEN
Deer tick virus (DTV) is a recently recognized North American virus isolated from Ixodes dammini ticks. Nucleotide sequencing of fragments of structural and non-structural protein genes suggested that this virus was most closely related to the tick-borne flavivirus Powassan (POW), which causes potentially fatal encephalitis in humans. To determine whether DTV represents a new and distinct member of the Flavivirus genus of the family Flaviviridae, we sequenced the structural protein genes and 5' and 3' non-coding regions of this virus. In addition, we compared the reactivity of DTV and POW in hemagglutination inhibition tests with a panel of polyclonal and monoclonal antisera, and performed cross-neutralization experiments using anti-DTV antisera. Nucleotide sequencing revealed a high degree of homology between DTV and POW at both nucleotide (>80% homology) and amino acid (>90% homology) levels, and the two viruses were indistinguishable in serological assays and mouse neuroinvasiveness. On the basis of these results, we suggest that DTV should be classified as a genotype of POW virus.
Asunto(s)
Virus de la Encefalitis Transmitidos por Garrapatas/genética , Ixodes/virología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Chlorocebus aethiops , ADN Viral , Ciervos/parasitología , Virus de la Encefalitis Transmitidos por Garrapatas/clasificación , Virus de la Encefalitis Transmitidos por Garrapatas/aislamiento & purificación , Virus de la Encefalitis Transmitidos por Garrapatas/patogenicidad , Genotipo , Macaca mulatta , Ratones , Datos de Secuencia Molecular , Análisis de Secuencia de ADN , Homología de Secuencia de Aminoácido , Homología de Secuencia de Ácido Nucleico , Infestaciones por Garrapatas/parasitología , Infestaciones por Garrapatas/veterinaria , Células Vero , VirulenciaRESUMEN
Jatobal (JAT) virus was isolated in 1985 from a carnivore (Nasua nasua) in Tucuruí, Pará state, Brazil and was classified as a distinct member of the Simbu serogroup of the Bunyavirus genus, family Bunyaviridae on the basis of neutralization tests. On the basis of nucleotide sequencing, we have found that the small (S) RNA of JAT virus is very similar (>95% identity) to that of Oropouche (ORO) virus, in particular, the Peruvian genotype of ORO virus. In comparison, limited nucleotide sequencing of the G2 protein gene, encoded by the middle (M) RNA, of JAT and ORO viruses, revealed relatively little identity (<66%) between these two viruses. Neutralization tests confirmed the lack of cross-reactivity between the viruses. These results suggest that JAT virus is a reassortant containing the S RNA of ORO virus. JAT virus was attenuated in hamsters compared to ORO virus suggesting that the S RNA of ORO virus is not directly involved in hamster virulence.
Asunto(s)
Infecciones por Bunyaviridae/virología , ARN Viral/genética , Virus Reordenados/genética , Virus Simbu/genética , Virus Simbu/patogenicidad , Secuencia de Aminoácidos , Animales , Infecciones por Bunyaviridae/fisiopatología , Cricetinae , Femenino , Mesocricetus , Datos de Secuencia Molecular , Pruebas de Neutralización , Nucleocápside/genética , Nucleocápside/metabolismo , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/metabolismo , VirulenciaRESUMEN
Textrema hopkinsi gen. et sp. n. is described from Micropterus salmoides from central Texas. Textrema is most similar to the genus Multigonotylus but differs in having a single gomotyl. The new genus is placed in the family Cryptogonimidae.
Asunto(s)
Peces/parasitología , Trematodos/clasificación , Animales , Texas , Trematodos/anatomía & histologíaRESUMEN
Ivermectin, given in a single subcutaneous dose of 200 micrograms/kg, was evaluated for its efficacy against Dirofilaria immitis microfilariae in a trial with naturally infected dogs. Sodium thiacetarsamide (2.2 mg/kg) was administered twice daily for 2 days to 2 groups of 10 dogs. Two weeks later, 1 group was treated with ivermectin, and the other group was given the vehicle. Microfilariae were not detected (by blood sample concentration techniques) in 90% of the dogs 21 days after they were treated with ivermectin. Microfilariae were not detected in samples of any dog at days 28 and 35. However, 1 dog (not the one positive at day 21) had a detectable microfilaria at day 42. One dog with pretreatment ascites, exercise-induced cough, and high microfilaremial count was anorectic and depressed 2 days after treatment with ivermectin; the clinical signs were resolved 4 days later.
Asunto(s)
Antihelmínticos/farmacología , Dirofilaria immitis/efectos de los fármacos , Dirofilariasis/veterinaria , Enfermedades de los Perros/tratamiento farmacológico , Filaricidas/farmacología , Filarioidea/efectos de los fármacos , Lactonas/farmacología , Animales , Dirofilariasis/tratamiento farmacológico , Perros , Filaricidas/uso terapéutico , Ivermectina , Lactonas/uso terapéutico , Microfilarias/efectos de los fármacosRESUMEN
5-Hydroxymethylcytosine (5hmC) is abundant in the brain, suggesting an important role in epigenetic control of neuronal functions. In this paper, we show that 5hmC and 5-methylcytosine (5mC) levels are coordinately distributed in gene promoters of the rhesus macaque prefrontal cortex. Although promoter hydroxymethylation and methylation are overall negatively correlated with expression, a subset of highly expressed genes involved in specific cerebral functions is associated with high levels of 5mC and 5hmC. These relationships were also observed in the mouse cortex. Furthermore, we found that early-life maternal deprivation is associated, in the adult monkey cortex, with DNA hydroxymethylation changes of promoters of genes related to neurological functions and psychological disorders. These results reveal that early social adversity triggers variations in brain DNA hydroxymethylation that could be detected in adulthood.
Asunto(s)
5-Metilcitosina/metabolismo , Citosina/análogos & derivados , Metilación de ADN , Epigénesis Genética , Privación Materna , Corteza Prefrontal/metabolismo , Animales , Citosina/metabolismo , Bases de Datos Genéticas , Lóbulo Frontal/metabolismo , Expresión Génica , Macaca mulatta , Metilación , Ratones Endogámicos C57BL , Análisis de Secuencia por Matrices de Oligonucleótidos , Regiones Promotoras GenéticasRESUMEN
Sleep is critical for normal brain function and mental health. However, the molecular mechanisms mediating the impact of sleep loss on both cognition and the sleep electroencephalogram remain mostly unknown. Acute sleep loss impacts brain gene expression broadly. These data contributed to current hypotheses regarding the role for sleep in metabolism, synaptic plasticity and neuroprotection. These changes in gene expression likely underlie increased sleep intensity following sleep deprivation (SD). Here we tested the hypothesis that epigenetic mechanisms coordinate the gene expression response driven by SD. We found that SD altered the cortical genome-wide distribution of two major epigenetic marks: DNA methylation and hydroxymethylation. DNA methylation differences were enriched in gene pathways involved in neuritogenesis and synaptic plasticity, whereas large changes (>4000 sites) in hydroxymethylation where observed in genes linked to cytoskeleton, signaling and neurotransmission, which closely matches SD-dependent changes in the transcriptome. Moreover, this epigenetic remodeling applied to elements previously linked to sleep need (for example, Arc and Egr1) and synaptic partners of Neuroligin-1 (Nlgn1; for example, Dlg4, Nrxn1 and Nlgn3), which we recently identified as a regulator of sleep intensity following SD. We show here that Nlgn1 mutant mice display an enhanced slow-wave slope during non-rapid eye movement sleep following SD but this mutation does not affect SD-dependent changes in gene expression, suggesting that the Nlgn pathway acts downstream to mechanisms triggering gene expression changes in SD. These data reveal that acute SD reprograms the epigenetic landscape, providing a unique molecular route by which sleep can impact brain function and health.
Asunto(s)
Corteza Cerebral/metabolismo , Metilación de ADN/fisiología , Genoma/genética , Plasticidad Neuronal/genética , Privación de Sueño/metabolismo , Transcriptoma/genética , Animales , Moléculas de Adhesión Celular Neuronal/genética , Corteza Cerebral/fisiopatología , Metilación de ADN/genética , Electroencefalografía , Epigénesis Genética/genética , Epigénesis Genética/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Privación de Sueño/fisiopatología , Fases del Sueño/genética , Fases del Sueño/fisiologíaRESUMEN
Early life stress (ELS) is associated with increased vulnerability for diseases in later life, including psychiatric disorders. Animal models and human studies suggest that this effect is mediated by epigenetic mechanisms. In humans, epigenetic studies to investigate the influence of ELS on psychiatric phenotypes are limited by the inaccessibility of living brain tissue. Due to the tissue-specific nature of epigenetic signatures, it is impossible to determine whether ELS induced epigenetic changes in accessible peripheral cells, for example, blood lymphocytes, reflect epigenetic changes in the brain. To overcome these limitations, we applied a cross-species approach involving: (i) the analysis of CD34+ cells from human cord blood; (ii) the examination of blood-derived CD3+ T cells of newborn and adolescent nonhuman primates (Macaca mulatta); and (iii) the investigation of the prefrontal cortex of adult rats. Several regions in MORC1 (MORC family CW-type zinc finger 1; previously known as: microrchidia (mouse) homolog) were differentially methylated in response to ELS in CD34+ cells and CD3+ T cells derived from the blood of human and monkey neonates, as well as in CD3+ T cells derived from the blood of adolescent monkeys and in the prefrontal cortex of adult rats. MORC1 is thus the first identified epigenetic marker of ELS to be present in blood cell progenitors at birth and in the brain in adulthood. Interestingly, a gene-set-based analysis of data from a genome-wide association study of major depressive disorder (MDD) revealed an association of MORC1 with MDD.
Asunto(s)
Metilación de ADN/genética , Trastorno Depresivo Mayor/genética , Epigénesis Genética/genética , Estudio de Asociación del Genoma Completo , Estrés Psicológico/complicaciones , Animales , Animales Recién Nacidos , Estudios de Cohortes , Femenino , Sangre Fetal/citología , Predisposición Genética a la Enfermedad/genética , Humanos , Recién Nacido , Macaca mulatta , Corteza Prefrontal/metabolismo , Embarazo , Especificidad de la Especie , Células Madre , Linfocitos T/metabolismoRESUMEN
Epidemiological studies suggest that a father's diet can influence offspring health. A proposed mechanism for paternal transmission of environmental information is via the sperm epigenome. The epigenome includes heritable information such as DNA methylation. We hypothesize that the dietary supply of methyl donors will alter epigenetic reprogramming in sperm. Here we feed male mice either a folate-deficient or folate-sufficient diet throughout life. Paternal folate deficiency is associated with increased birth defects in the offspring, which include craniofacial and musculoskeletal malformations. Genome-wide DNA methylation analysis and the subsequent functional analysis identify differential methylation in sperm of genes implicated in development, chronic diseases such as cancer, diabetes, autism and schizophrenia. While >300 genes are differentially expressed in offspring placenta, only two correspond to genes with differential methylation in sperm. This model suggests epigenetic transmission may involve sperm histone H3 methylation or DNA methylation and that adequate paternal dietary folate is essential for offspring health.