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One of the main drivers of autism spectrum disorder is risk alleles within hundreds of genes, which may interact within shared but unknown protein complexes. Here we develop a scalable genome-editing-mediated approach to target 14 high-confidence autism risk genes within the mouse brain for proximity-based endogenous proteomics, achieving the identification of high-specificity spatial proteomes. The resulting native proximity proteomes are enriched for human genes dysregulated in the brain of autistic individuals, and reveal proximity interactions between proteins from high-confidence risk genes with those of lower-confidence that may provide new avenues to prioritize genetic risk. Importantly, the datasets are enriched for shared cellular functions and genetic interactions that may underlie the condition. We test this notion by spatial proteomics and CRISPR-based regulation of expression in two autism models, demonstrating functional interactions that modulate mechanisms of their dysregulation. Together, these results reveal native proteome networks in vivo relevant to autism, providing new inroads for understanding and manipulating the cellular drivers underpinning its etiology.
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Trastorno del Espectro Autista , Trastorno Autístico , Encéfalo , Modelos Animales de Enfermedad , Proteoma , Proteómica , Animales , Proteoma/metabolismo , Ratones , Humanos , Encéfalo/metabolismo , Proteómica/métodos , Trastorno Autístico/genética , Trastorno Autístico/metabolismo , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/genética , Fenotipo , Edición Génica , Masculino , Predisposición Genética a la Enfermedad , Ratones Endogámicos C57BL , Femenino , Sistemas CRISPR-CasRESUMEN
Activity-dependent neuroprotective protein (ADNP) syndrome is a rare neurodevelopmental disorder resulting in intellectual disability, developmental delay and autism spectrum disorder (ASD) and is due to mutations in the ADNP gene. Ketamine treatment has emerged as a promising therapeutic option for ADNP syndrome, showing safety and apparent behavioral improvements in a first open label study. However, the molecular perturbations induced by ketamine remain poorly understood. Here, we investigated the longitudinal effect of ketamine on the blood transcriptome of 10 individuals with ADNP syndrome. Transcriptomic profiling was performed before and at multiple time points after a single low-dose intravenous ketamine infusion (0.5 mg/kg). We show that ketamine triggers immediate and profound gene expression alterations, with specific enrichment of monocyte-related expression patterns. These acute alterations encompass diverse signaling pathways and co-expression networks, implicating upregulation of immune and inflammatory-related processes and down-regulation of RNA processing mechanisms and metabolism. Notably, these changes exhibit a transient nature, returning to baseline levels 24 hours to 1 week after treatment. These findings enhance our understanding of ketamine's molecular effects and lay the groundwork for further research elucidating its specific cellular and molecular targets. Moreover, they contribute to the development of therapeutic strategies for ADNP syndrome and potentially, ASD more broadly.
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Trastorno del Espectro Autista , Ketamina , Transcriptoma , Ketamina/farmacología , Ketamina/administración & dosificación , Ketamina/uso terapéutico , Humanos , Masculino , Transcriptoma/efectos de los fármacos , Niño , Femenino , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/sangre , Preescolar , Proteínas del Tejido Nervioso/genética , Discapacidad Intelectual/tratamiento farmacológico , Discapacidad Intelectual/genética , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/tratamiento farmacológico , Perfilación de la Expresión Génica , Adolescente , Proteínas de HomeodominioRESUMEN
Activity-dependent neuroprotective protein (ADNP) syndrome is a rare neurodevelopmental disorder resulting in intellectual disability, developmental delay and autism spectrum disorder (ASD) and is due to mutations in the ADNP gene. Ketamine treatment has emerged as a promising therapeutic option for ADNP syndrome, showing safety and apparent behavioral improvements in a first open label study. However, the molecular perturbations induced by ketamine remain poorly understood. Here, we investigated the longitudinal effect of ketamine on the blood transcriptome of 10 individuals with ADNP syndrome. Transcriptomic profiling was performed before and at multiple time points after a single low-dose intravenous ketamine infusion (0.5mg/kg). We show that ketamine triggers immediate and profound gene expression alterations, with specific enrichment of monocyte-related expression patterns. These acute alterations encompass diverse signaling pathways and co-expression networks, implicating up-regulation of immune and inflammatory-related processes and down-regulation of RNA processing mechanisms and metabolism. Notably, these changes exhibit a transient nature, returning to baseline levels 24 hours to 1 week after treatment. These findings enhance our understanding of ketamine's molecular effects and lay the groundwork for further research elucidating its specific cellular and molecular targets. Moreover, they contribute to the development of therapeutic strategies for ADNP syndrome and potentially, ASD more broadly.
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BACKGROUND: Anorexia nervosa (AN) is a psychiatric disorder with complex etiology, with a significant portion of disease risk imparted by genetics. Traditional genome-wide association studies (GWAS) produce principal evidence for the association of genetic variants with disease. Transcriptomic imputation (TI) allows for the translation of those variants into regulatory mechanisms, which can then be used to assess the functional outcome of genetically regulated gene expression (GReX) in a broader setting through the use of phenome-wide association studies (pheWASs) in large and diverse clinical biobank populations with electronic health record phenotypes. METHODS: Here, we applied TI using S-PrediXcan to translate the most recent PGC-ED AN GWAS findings into AN-GReX. For significant genes, we imputed AN-GReX in the Mount Sinai BioMe™ Biobank and performed pheWASs on over 2000 outcomes to test the clinical consequences of aberrant expression of these genes. We performed a secondary analysis to assess the impact of body mass index (BMI) and sex on AN-GReX clinical associations. RESULTS: Our S-PrediXcan analysis identified 53 genes associated with AN, including what is, to our knowledge, the first-genetic association of AN with the major histocompatibility complex. AN-GReX was associated with autoimmune, metabolic, and gastrointestinal diagnoses in our biobank cohort, as well as measures of cholesterol, medications, substance use, and pain. Additionally, our analyses showed moderation of AN-GReX associations with measures of cholesterol and substance use by BMI, and moderation of AN-GReX associations with celiac disease by sex. CONCLUSIONS: Our BMI-stratified results provide potential avenues of functional mechanism for AN-genes to investigate further.
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Anorexia Nerviosa , Estudio de Asociación del Genoma Completo , Humanos , Anorexia Nerviosa/genética , Polimorfismo de Nucleótido Simple , Fenotipo , Transcriptoma , Predisposición Genética a la Enfermedad/genéticaRESUMEN
Posttranscriptional RNA modifications by adenosine-to-inosine (A-to-I) editing are abundant in the brain, yet elucidating functional sites remains challenging. To bridge this gap, we investigate spatiotemporal and genetically regulated A-to-I editing sites across prenatal and postnatal stages of human brain development. More than 10,000 spatiotemporally regulated A-to-I sites were identified that occur predominately in 3' UTRs and introns, as well as 37 sites that recode amino acids in protein coding regions with precise changes in editing levels across development. Hyper-edited transcripts are also enriched in the aging brain and stabilize RNA secondary structures. These features are conserved in murine and non-human primate models of neurodevelopment. Finally, thousands of cis-editing quantitative trait loci (edQTLs) were identified with unique regulatory effects during prenatal and postnatal development. Collectively, this work offers a resolved atlas linking spatiotemporal variation in editing levels to genetic regulatory effects throughout distinct stages of brain maturation.
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Inosina , Edición de ARN , Humanos , Animales , Ratones , Edición de ARN/genética , Inosina/genética , Adenosina/metabolismo , Primates , Regiones no Traducidas 3' , Encéfalo/metabolismo , Adenosina Desaminasa/metabolismoRESUMEN
Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.
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COVID-19 , Exoma , Humanos , Exoma/genética , Estudio de Asociación del Genoma Completo , COVID-19/genética , Predisposición Genética a la Enfermedad , Receptor Toll-Like 7/genética , SARS-CoV-2/genéticaRESUMEN
Activity-dependent neuroprotective protein (ADNP) syndrome is a rare genetic condition associated with intellectual disability and autism spectrum disorder. Preclinical evidence suggests that low-dose ketamine may induce expression of ADNP and that neuroprotective effects of ketamine may be mediated by ADNP. The goal of the proposed research was to evaluate the safety, tolerability, and behavioral outcomes of low-dose ketamine in children with ADNP syndrome. We also sought to explore the feasibility of using electrophysiological markers of auditory steady-state response and computerized eye tracking to assess biomarker sensitivity to treatment. This study utilized a single-dose (0.5 mg/kg), open-label design, with ketamine infused intravenously over 40 min. Ten children with ADNP syndrome ages 6 to 12 years were enrolled. Ketamine was generally well tolerated, and there were no serious adverse events. The most common adverse events were elation/silliness (50%), fatigue (40%), and increased aggression (40%). Using parent-report instruments to assess treatment effects, ketamine was associated with nominally significant improvement in a wide array of domains, including social behavior, attention deficit and hyperactivity, restricted and repetitive behaviors, and sensory sensitivities, a week after administration. Results derived from clinician-rated assessments aligned with findings from the parent reports. Overall, nominal improvement was evident based on the Clinical Global Impressions - Improvement scale, in addition to clinician-based scales reflecting key domains of social communication, attention deficit and hyperactivity, restricted and repetitive behaviors, speech, thinking, and learning, activities of daily living, and sensory sensitivities. Results also highlight the potential utility of electrophysiological measurement of auditory steady-state response and eye-tracking to index change with ketamine treatment. Findings are intended to be hypothesis generating and provide preliminary support for the safety and efficacy of ketamine in ADNP syndrome in addition to identifying useful endpoints for a ketamine clinical development program. However, results must be interpreted with caution given limitations of this study, most importantly the small sample size and absence of a placebo-control group.
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Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated with ASD at false discovery rate (FDR) ≤ 0.001 (185 at FDR ≤ 0.05). De novo PTVs, damaging missense variants and CNVs represented 57.5%, 21.1% and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD) (n = 91,605) yielded 373 genes associated with ASD/DD at FDR ≤ 0.001 (664 at FDR ≤ 0.05), some of which differed in relative frequency of mutation between ASD and DD cohorts. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells, whereas genes showing stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophrenia-associated genes, emphasizing that these neuropsychiatric disorders may share common pathways to risk.
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Trastorno del Espectro Autista , Trastorno Autístico , Trastorno del Espectro Autista/genética , Trastorno Autístico/genética , Variaciones en el Número de Copia de ADN/genética , Predisposición Genética a la Enfermedad , Humanos , MutaciónRESUMEN
Chromosomal organization, scaling from the 147-base pair (bp) nucleosome to megabase-ranging domains encompassing multiple transcriptional units, including heritability loci for psychiatric traits, remains largely unexplored in the human brain. In this study, we constructed promoter- and enhancer-enriched nucleosomal histone modification landscapes for adult prefrontal cortex from H3-lysine 27 acetylation and H3-lysine 4 trimethylation profiles, generated from 388 controls and 351 individuals diagnosed with schizophrenia (SCZ) or bipolar disorder (BD) (n = 739). We mapped thousands of cis-regulatory domains (CRDs), revealing fine-grained, 104-106-bp chromosomal organization, firmly integrated into Hi-C topologically associating domain stratification by open/repressive chromosomal environments and nuclear topography. Large clusters of hyper-acetylated CRDs were enriched for SCZ heritability, with prominent representation of regulatory sequences governing fetal development and glutamatergic neuron signaling. Therefore, SCZ and BD brains show coordinated dysregulation of risk-associated regulatory sequences assembled into kilobase- to megabase-scaling chromosomal domains.
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Trastorno Bipolar , Esquizofrenia , Adulto , Trastorno Bipolar/genética , Encéfalo , Cromatina , Humanos , Lisina/genética , Esquizofrenia/genéticaRESUMEN
Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
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Trastorno Bipolar/genética , Estudio de Asociación del Genoma Completo , Estudios de Casos y Controles , Cromosomas Humanos/genética , Predisposición Genética a la Enfermedad , Genoma Humano , Humanos , Complejo Mayor de Histocompatibilidad/genética , Herencia Multifactorial/genética , Fenotipo , Sitios de Carácter Cuantitativo/genética , Factores de RiesgoRESUMEN
Structural variants (SVs) contribute to many disorders, yet, functionally annotating them remains a major challenge. Here, we integrate SVs with RNA-sequencing from human post-mortem brains to quantify their dosage and regulatory effects. We show that genic and regulatory SVs exist at significantly lower frequencies than intergenic SVs. Functional impact of copy number variants (CNVs) stems from both the proportion of genic and regulatory content altered and loss-of-function intolerance of the gene. We train a linear model to predict expression effects of rare CNVs and use it to annotate regulatory disruption of CNVs from 14,891 independent genome-sequenced individuals. Pathogenic deletions implicated in neurodevelopmental disorders show significantly more extreme regulatory disruption scores and if rank ordered would be prioritized higher than using frequency or length alone. This work shows the deleteriousness of regulatory SVs, particularly those altering CTCF sites and provides a simple approach for functionally annotating the regulatory consequences of CNVs.
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Encéfalo/metabolismo , Variaciones en el Número de Copia de ADN , Regulación de la Expresión Génica , Variación Genética , Genoma Humano/genética , Autopsia/métodos , Encéfalo/patología , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Masculino , Trastornos del Neurodesarrollo/genética , Análisis de Secuencia de ARN/métodosRESUMEN
To reveal post-traumatic stress disorder (PTSD) genetic risk influences on tissue-specific gene expression, we use brain and non-brain transcriptomic imputation. We impute genetically regulated gene expression (GReX) in 29,539 PTSD cases and 166,145 controls from 70 ancestry-specific cohorts and identify 18 significant GReX-PTSD associations corresponding to specific tissue-gene pairs. The results suggest substantial genetic heterogeneity based on ancestry, cohort type (military versus civilian), and sex. Two study-wide significant PTSD associations are identified in European and military European cohorts; ZNF140 is predicted to be upregulated in whole blood, and SNRNP35 is predicted to be downregulated in dorsolateral prefrontal cortex, respectively. In peripheral leukocytes from 175 marines, the observed PTSD differential gene expression correlates with the predicted differences for these individuals, and deployment stress produces glucocorticoid-regulated expression changes that include downregulation of both ZNF140 and SNRNP35. SNRNP35 knockdown in cells validates its functional role in U12-intron splicing. Finally, exogenous glucocorticoids in mice downregulate prefrontal Snrnp35 expression.
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Corteza Prefrontal/metabolismo , Ribonucleoproteínas Nucleares Pequeñas/genética , Trastornos por Estrés Postraumático/genética , Animales , Estudios de Casos y Controles , Estudios de Cohortes , Dexametasona/farmacología , Regulación hacia Abajo/efectos de los fármacos , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Predisposición Genética a la Enfermedad , Humanos , Leucocitos/citología , Leucocitos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Personal Militar , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Proteínas Represoras/sangre , Proteínas Represoras/metabolismo , Ribonucleoproteínas Nucleares Pequeñas/antagonistas & inhibidores , Ribonucleoproteínas Nucleares Pequeñas/metabolismo , Trastornos por Estrés Postraumático/sangre , Trastornos por Estrés Postraumático/diagnósticoRESUMEN
Schizophrenia and bipolar disorder are serious mental illnesses that affect more than 2% of adults. While large-scale genetics studies have identified genomic regions associated with disease risk, less is known about the molecular mechanisms by which risk alleles with small effects lead to schizophrenia and bipolar disorder. In order to fill this gap between genetics and disease phenotype, we have undertaken a multi-cohort genomics study of postmortem brains from controls, individuals with schizophrenia and bipolar disorder. Here we present a public resource of functional genomic data from the dorsolateral prefrontal cortex (DLPFC; Brodmann areas 9 and 46) of 986 individuals from 4 separate brain banks, including 353 diagnosed with schizophrenia and 120 with bipolar disorder. The genomic data include RNA-seq and SNP genotypes on 980 individuals, and ATAC-seq on 269 individuals, of which 264 are a subset of individuals with RNA-seq. We have performed extensive preprocessing and quality control on these data so that the research community can take advantage of this public resource available on the Synapse platform at http://CommonMind.org .
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Trastorno Bipolar , Esquizofrenia , Trastorno Bipolar/genética , Trastorno Bipolar/patología , Estudios de Cohortes , Epigenómica , Humanos , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Esquizofrenia/genética , Esquizofrenia/patología , TranscriptomaRESUMEN
With the rapid growth of the aging population, exploring the biological basis of aging and related molecular mechanisms has become an important topic in modern scientific research. Aging can cause multiple organ function attenuations, leading to the occurrence and development of various age-related metabolic, nervous system, and cardiovascular diseases. In addition, aging is closely related to the occurrence and development of tumors. Although a number of studies have used various mouse models to study aging, further research is needed to associate mouse and human aging at the molecular level. In this paper, we systematically assessed the relationship between human and mouse aging by comparing multi-tissue age-related gene expression sets. We compared 18 human and mouse tissues, and found 9 significantly correlated tissue pairs. Functional analysis also revealed some terms related to aging in human and mouse. And we performed a crosswise comparison of homologous age-related genes with 18 tissues in human and mouse respectively, and found that human Brain_Cortex was significantly correlated with Brain_Hippocampus, which was also found in mouse. In addition, we focused on comparing four brain-related tissues in human and mouse, and found a gene-GFAP-related to aging in both human and mouse.
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Envejecimiento/genética , Corteza Cerebral/metabolismo , Hipocampo/metabolismo , Transcriptoma , Adulto , Anciano , Algoritmos , Animales , Bases de Datos Genéticas , Proteína Ácida Fibrilar de la Glía/genética , Humanos , Ratones , RNA-SeqRESUMEN
Alkali bees (Nomia melanderi) are solitary relatives of the halictine bees, which have become an important model for the evolution of social behavior, but for which few solitary comparisons exist. These ground-nesting bees defend their developing offspring against pathogens and predators, and thus exhibit some of the key traits that preceded insect sociality. Alkali bees are also efficient native pollinators of alfalfa seed, which is a crop of major economic value in the United States. We sequenced, assembled, and annotated a high-quality draft genome of 299.6 Mbp for this species. Repetitive content makes up more than one-third of this genome, and previously uncharacterized transposable elements are the most abundant type of repetitive DNA. We predicted 10,847 protein coding genes, and identify 479 of these undergoing positive directional selection with the use of population genetic analysis based on low-coverage whole genome sequencing of 19 individuals. We found evidence of recent population bottlenecks, but no significant evidence of population structure. We also identify 45 genes enriched for protein translation and folding, transcriptional regulation, and triglyceride metabolism evolving slower in alkali bees compared to other halictid bees. These resources will be useful for future studies of bee comparative genomics and pollinator health research.
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Abejas/genética , Genoma de los Insectos , Anotación de Secuencia Molecular , Secuenciación Completa del Genoma , Animales , Femenino , Genética de Población , Masculino , FilogeniaRESUMEN
Social challenges like territorial intrusions evoke behavioral responses in widely diverging species. Recent work has showed that evolutionary "toolkits"-genes and modules with lineage-specific variations but deep conservation of function-participate in the behavioral response to social challenge. Here, we develop a multispecies computational-experimental approach to characterize such a toolkit at a systems level. Brain transcriptomic responses to social challenge was probed via RNA-seq profiling in three diverged species-honey bees, mice and three-spined stickleback fish-following a common methodology, allowing fair comparisons across species. Data were collected from multiple brain regions and multiple time points after social challenge exposure, achieving anatomical and temporal resolution substantially greater than previous work. We developed statistically rigorous analyses equipped to find homologous functional groups among these species at the levels of individual genes, functional and coexpressed gene modules, and transcription factor subnetworks. We identified six orthogroups involved in response to social challenge, including groups represented by mouse genes Npas4 and Nr4a1, as well as common modulation of systems such as transcriptional regulators, ion channels, G-protein-coupled receptors and synaptic proteins. We also identified conserved coexpression modules enriched for mitochondrial fatty acid metabolism and heat shock that constitute the shared neurogenomic response. Our analysis suggests a toolkit wherein nuclear receptors, interacting with chaperones, induce transcriptional changes in mitochondrial activity, neural cytoarchitecture and synaptic transmission after social challenge. It shows systems-level mechanisms that have been repeatedly co-opted during evolution of analogous behaviors, thus advancing the genetic toolkit concept beyond individual genes.
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Evolución Molecular , Genética Conductual/métodos , Genómica/métodos , Conducta Social , Análisis de Sistemas , Animales , Abejas , Encéfalo/metabolismo , Encéfalo/fisiología , Femenino , Redes Reguladoras de Genes , Genoma , Masculino , Ratones , Smegmamorpha , TranscriptomaRESUMEN
Risk variants for schizophrenia affect more than 100 genomic loci, yet cell- and tissue-specific roles underlying disease liability remain poorly characterized. We have generated for two cortical areas implicated in psychosis, the dorsolateral prefrontal cortex and anterior cingulate cortex, 157 reference maps from neuronal, neuron-depleted and bulk tissue chromatin for two histone marks associated with active promoters and enhancers, H3-trimethyl-Lys4 (H3K4me3) and H3-acetyl-Lys27 (H3K27ac). Differences between neuronal and neuron-depleted chromatin states were the major axis of variation in histone modification profiles, followed by substantial variability across subjects and cortical areas. Thousands of significant histone quantitative trait loci were identified in neuronal and neuron-depleted samples. Risk variants for schizophrenia, depressive symptoms and neuroticism were significantly over-represented in neuronal H3K4me3 and H3K27ac landscapes. Our Resource, sponsored by PsychENCODE and CommonMind, highlights the critical role of cell-type-specific signatures at regulatory and disease-associated noncoding sequences in the human frontal lobe.
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Epigénesis Genética/genética , Lóbulo Frontal/metabolismo , Lóbulo Frontal/patología , Histonas/genética , Esquizofrenia/genética , Esquizofrenia/metabolismo , Enfermedad de Alzheimer/genética , Mapeo Encefálico , Cromatina/genética , Depresión/genética , Depresión/patología , Escolaridad , Predisposición Genética a la Enfermedad/genética , Variación Genética , Estudio de Asociación del Genoma Completo , Giro del Cíngulo/patología , Humanos , Trastornos Neuróticos/genética , Trastornos Neuróticos/patología , Corteza Prefrontal/patología , RiesgoRESUMEN
Causal genes and variants within genome-wide association study (GWAS) loci can be identified by integrating GWAS statistics with expression quantitative trait loci (eQTL) and determining which variants underlie both GWAS and eQTL signals. Most analyses, however, consider only the marginal eQTL signal, rather than dissect this signal into multiple conditionally independent signals for each gene. Here we show that analyzing conditional eQTL signatures, which could be important under specific cellular or temporal contexts, leads to improved fine mapping of GWAS associations. Using genotypes and gene expression levels from post-mortem human brain samples (n = 467) reported by the CommonMind Consortium (CMC), we find that conditional eQTL are widespread; 63% of genes with primary eQTL also have conditional eQTL. In addition, genomic features associated with conditional eQTL are consistent with context-specific (e.g., tissue-, cell type-, or developmental time point-specific) regulation of gene expression. Integrating the 2014 Psychiatric Genomics Consortium schizophrenia (SCZ) GWAS and CMC primary and conditional eQTL data reveals 40 loci with strong evidence for co-localization (posterior probability > 0.8), including six loci with co-localization of conditional eQTL. Our co-localization analyses support previously reported genes, identify novel genes associated with schizophrenia risk, and provide specific hypotheses for their functional follow-up.
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Estudio de Asociación del Genoma Completo , Corteza Prefrontal/patología , Sitios de Carácter Cuantitativo/genética , Esquizofrenia/genética , Células Cultivadas , Epigénesis Genética , Genoma Humano , HumanosRESUMEN
Agonistic encounters are powerful effectors of future behavior, and the ability to learn from this type of social challenge is an essential adaptive trait. We recently identified a conserved transcriptional program defining the response to social challenge across animal species, highly enriched in transcription factor (TF), energy metabolism, and developmental signaling genes. To understand the trajectory of this program and to uncover the most important regulatory influences controlling this response, we integrated gene expression data with the chromatin landscape in the hypothalamus, frontal cortex, and amygdala of socially challenged mice over time. The expression data revealed a complex spatiotemporal patterning of events starting with neural signaling molecules in the frontal cortex and ending in the modulation of developmental factors in the amygdala and hypothalamus, underpinned by a systems-wide shift in expression of energy metabolism-related genes. The transcriptional signals were correlated with significant shifts in chromatin accessibility and a network of challenge-associated TFs. Among these, the conserved metabolic and developmental regulator ESRRA was highlighted for an especially early and important regulatory role. Cell-type deconvolution analysis attributed the differential metabolic and developmental signals in this social context primarily to oligodendrocytes and neurons, respectively, and we show that ESRRA is expressed in both cell types. Localizing ESRRA binding sites in cortical chromatin, we show that this nuclear receptor binds both differentially expressed energy-related and neurodevelopmental TF genes. These data link metabolic and neurodevelopmental signaling to social challenge, and identify key regulatory drivers of this process with unprecedented tissue and temporal resolution.
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Cromatina/metabolismo , Regulación del Desarrollo de la Expresión Génica , Neuronas/metabolismo , Receptores de Estrógenos/genética , Estrés Psicológico/genética , Factores de Transcripción/genética , Conducta Agonística , Amígdala del Cerebelo/metabolismo , Amígdala del Cerebelo/fisiopatología , Animales , Cromatina/ultraestructura , Metabolismo Energético/genética , Lóbulo Frontal/metabolismo , Lóbulo Frontal/fisiopatología , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Hipotálamo/metabolismo , Hipotálamo/fisiopatología , Masculino , Ratones , Neuronas/citología , Oligodendroglía/citología , Oligodendroglía/metabolismo , Unión Proteica , Receptores de Estrógenos/metabolismo , Transducción de Señal , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatología , Factores de Transcripción/metabolismo , Transcripción Genética , Receptor Relacionado con Estrógeno ERRalfaRESUMEN
Histone citrullination regulates diverse cellular processes. Here, we report that SMARCAD1 preferentially associates with H3 arginine 26 citrullination (H3R26Cit) peptides present on arrays composed of 384 histone peptides harboring distinct post-transcriptional modifications. Among ten histone modifications assayed by ChIP-seq, H3R26Cit exhibited the most extensive genomewide co-localization with SMARCAD1 binding. Increased Smarcad1 expression correlated with naive pluripotency in pre-implantation embryos. In the presence of LIF, Smarcad1 knockdown (KD) embryonic stem cells lost naive state phenotypes but remained pluripotent, as suggested by morphology, gene expression, histone modifications, alkaline phosphatase activity, energy metabolism, embryoid bodies, teratoma, and chimeras. The majority of H3R26Cit ChIP-seq peaks occupied by SMARCAD1 were associated with increased levels of H3K9me3 in Smarcad1 KD cells. Inhibition of H3Cit induced H3K9me3 at the overlapping regions of H3R26Cit peaks and SMARCAD1 peaks. These data suggest a model in which SMARCAD1 regulates naive pluripotency by interacting with H3R26Cit and suppressing heterochromatin formation.