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1.
N Engl J Med ; 385(16): 1462-1473, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34644471

RESUMO

BACKGROUND: Experimental studies and small clinical trials have suggested that treatment with intranasal oxytocin may reduce social impairment in persons with autism spectrum disorder. Oxytocin has been administered in clinical practice to many children with autism spectrum disorder. METHODS: We conducted a 24-week, placebo-controlled phase 2 trial of intranasal oxytocin therapy in children and adolescents 3 to 17 years of age with autism spectrum disorder. Participants were randomly assigned in a 1:1 ratio, with stratification according to age and verbal fluency, to receive oxytocin or placebo, administered intranasally, with a total target dose of 48 international units daily. The primary outcome was the least-squares mean change from baseline on the Aberrant Behavior Checklist modified Social Withdrawal subscale (ABC-mSW), which includes 13 items (scores range from 0 to 39, with higher scores indicating less social interaction). Secondary outcomes included two additional measures of social function and an abbreviated measure of IQ. RESULTS: Of the 355 children and adolescents who underwent screening, 290 were enrolled. A total of 146 participants were assigned to the oxytocin group and 144 to the placebo group; 139 and 138 participants, respectively, completed both the baseline and at least one postbaseline ABC-mSW assessments and were included in the modified intention-to-treat analyses. The least-squares mean change from baseline in the ABC-mSW score (primary outcome) was -3.7 in the oxytocin group and -3.5 in the placebo group (least-squares mean difference, -0.2; 95% confidence interval, -1.5 to 1.0; P = 0.61). Secondary outcomes generally did not differ between the trial groups. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONS: This placebo-controlled trial of intranasal oxytocin therapy in children and adolescents with autism spectrum disorder showed no significant between-group differences in the least-squares mean change from baseline on measures of social or cognitive functioning over a period of 24 weeks. (Funded by the National Institute of Child Health and Human Development; SOARS-B ClinicalTrials.gov number, NCT01944046.).


Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Ocitocina/administração & dosagem , Comportamento Social , Administração Intranasal , Adolescente , Transtorno do Espectro Autista/psicologia , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Humanos , Análise dos Mínimos Quadrados , Masculino , Ocitocina/efeitos adversos , Ocitocina/uso terapêutico , Habilidades Sociais , Falha de Tratamento
2.
Behav Brain Funct ; 20(1): 14, 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38898502

RESUMO

BACKGROUND: Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with higher incidence in males and is characterized by atypical verbal/nonverbal communication, restricted interests that can be accompanied by repetitive behavior, and disturbances in social behavior. This study investigated brain mechanisms that contribute to sociability deficits and sex differences in an ASD animal model. METHODS: Sociability was measured in C58/J and C57BL/6J mice using the 3-chamber social choice test. Bulk RNA-Seq and snRNA-Seq identified transcriptional changes in C58/J and C57BL/6J amygdala within which DMRseq was used to measure differentially methylated regions in amygdala. RESULTS: C58/J mice displayed divergent social strata in the 3-chamber test. Transcriptional and pathway signatures revealed immune-related biological processes differ between C58/J and C57BL/6J amygdala. Hypermethylated and hypomethylated genes were identified in C58/J versus C57BL/6J amygdala. snRNA-Seq data in C58/J amygdala identified differential transcriptional signatures within oligodendrocytes and microglia characterized by increased ASD risk gene expression and predicted impaired myelination that was dependent on sex and sociability. RNA velocity, gene regulatory network, and cell communication analysis showed diminished oligodendrocyte/microglia differentiation. Findings were verified using Bulk RNA-Seq and demonstrated oxytocin's beneficial effects on myelin gene expression. LIMITATIONS: Our findings are significant. However, limitations can be noted. The cellular mechanisms linking reduced oligodendrocyte differentiation and reduced myelination to an ASD phenotype in C58/J mice need further investigation. Additional snRNA-Seq and spatial studies would determine if effects in oligodendrocytes/microglia are unique to amygdala or if this occurs in other brain regions. Oxytocin's effects need further examination to understand its' potential as an ASD therapeutic. CONCLUSIONS: Our work demonstrates the C58/J mouse model's utility in evaluating the influence of sex and sociability on the transcriptome in concomitant brain regions involved in ASD. Our single-nucleus transcriptome analysis elucidates potential pathological roles of oligodendrocytes and microglia in ASD. This investigation provides details regarding regulatory features disrupted in these cell types, including transcriptional gene dysregulation, aberrant cell differentiation, altered gene regulatory networks, and changes to key pathways that promote microglia/oligodendrocyte differentiation. Our studies provide insight into interactions between genetic risk and epigenetic processes associated with divergent affiliative behavior and lack of positive sociability.


Assuntos
Tonsila do Cerebelo , Transtorno do Espectro Autista , Camundongos Endogâmicos C57BL , Microglia , Oligodendroglia , Comportamento Social , Animais , Masculino , Microglia/metabolismo , Camundongos , Tonsila do Cerebelo/metabolismo , Feminino , Oligodendroglia/metabolismo , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Perfilação da Expressão Gênica/métodos , Fenótipo , Caracteres Sexuais , Transcriptoma , Modelos Animais de Doenças , Ocitocina/genética , Ocitocina/metabolismo
3.
Nat Commun ; 15(1): 7875, 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39285180

RESUMO

Dysregulation of master regulator c-MYC (MYC) plays a central role in hepatocellular carcinoma (HCC) and other cancers but remains an elusive target for therapeutic intervention. MYC expression is epigenetically modulated within naturally occurring DNA loop structures, Insulated Genomic Domains (IGDs). We present a therapeutic approach using an epigenomic controller (EC), a programmable epigenomic mRNA medicine, to precisely modify MYC IGD sub-elements, leading to methylation of MYC regulatory elements and durable downregulation of MYC mRNA transcription. Significant antitumor activity is observed in preclinical models of HCC treated with the MYC-targeted EC, as monotherapy or in combination with tyrosine kinase or immune checkpoint inhibitors. These findings pave the way for clinical development of MYC-targeting epigenomic controllers in HCC patients and provide a framework for programmable epigenomic mRNA therapeutics for cancer and other diseases.


Assuntos
Carcinoma Hepatocelular , Metilação de DNA , Regulação para Baixo , Epigenômica , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas , Proteínas Proto-Oncogênicas c-myc , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Humanos , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Animais , Camundongos , Linhagem Celular Tumoral , Regulação para Baixo/genética , Epigenômica/métodos , Epigênese Genética , Ensaios Antitumorais Modelo de Xenoenxerto , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Transcrição Gênica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
4.
bioRxiv ; 2024 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-38293238

RESUMO

Background: Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with higher incidence in males and is characterized by atypical verbal/nonverbal communication, restricted interests that can be accompanied by repetitive behavior, and disturbances in social behavior. This study investigated brain mechanisms that contribute to sociability deficits and sex differences in an ASD animal model. Methods: Sociability was measured in C58/J and C57BL/6J mice using the 3-chamber social choice test. Bulk RNA-Seq and snRNA-Seq identified transcriptional changes in C58/J and C57BL/6J amygdala within which DMRseq was used to measure differentially methylated regions in amygdala. Results: C58/J mice displayed divergent social strata in the 3-chamber test. Transcriptional and pathway signatures revealed immune-related biological processes differ between C58/J and C57BL/6J amygdala. Hypermethylated and hypomethylated genes were identified in C58/J versus C57BL/6J amygdala. snRNA-Seq data in C58/J amygdala identified differential transcriptional signatures within oligodendrocytes and microglia characterized by increased ASD risk gene expression and predicted impaired myelination that was dependent on sex and sociability. RNA velocity, gene regulatory network, and cell communication analysis showed diminished oligodendrocyte/microglia differentiation. Findings were verified using bulk RNA-Seq and demonstrated oxytocin's beneficial effects on myelin gene expression. Limitations: Our findings are significant. However, limitations can be noted. The cellular mechanisms linking reduced oligodendrocyte differentiation and reduced myelination to an ASD phenotype in C58/J mice need further investigation. Additional snRNA-Seq and spatial studies would determine if effects in oligodendrocytes/microglia are unique to amygdala or if this occurs in other brain regions. Oxytocin's effects need further examination to understand its potential as an ASD therapeutic. Conclusions: Our work demonstrates the C58/J mouse model's utility in evaluating the influence of sex and sociability on the transcriptome in concomitant brain regions involved in ASD. Our single-nucleus transcriptome analysis elucidates potential pathological roles of oligodendrocytes and microglia in ASD. This investigation provides details regarding regulatory features disrupted in these cell types, including transcriptional gene dysregulation, aberrant cell differentiation, altered gene regulatory networks, and changes to key pathways that promote microglia/oligodendrocyte differentiation. Our studies provide insight into interactions between genetic risk and epigenetic processes associated with divergent affiliative behavior and lack of positive sociability.

5.
Autism Res ; 16(3): 502-523, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36609850

RESUMO

Oxytocin (OT), the brain's most abundant neuropeptide, plays an important role in social salience and motivation. Clinical trials of the efficacy of OT in autism spectrum disorder (ASD) have reported mixed results due in part to ASD's complex etiology. We investigated whether genetic and epigenetic variation contribute to variable endogenous OT levels that modulate sensitivity to OT therapy. To carry out this analysis, we integrated genome-wide profiles of DNA-methylation, transcriptional activity, and genetic variation with plasma OT levels in 290 participants with ASD enrolled in a randomized controlled trial of OT. Our analysis identified genetic variants with novel association with plasma OT, several of which reside in known ASD risk genes. We also show subtle but statistically significant association of plasma OT levels with peripheral transcriptional activity and DNA-methylation profiles across several annotated gene sets. These findings broaden our understanding of the effects of the peripheral oxytocin system and provide novel genetic candidates for future studies to decode the complex etiology of ASD and its interaction with OT signaling and OT-based interventions. LAY SUMMARY: Oxytocin (OT) is an abundant chemical produced by neurons that plays an important role in social interaction and motivation. We investigated whether genetic and epigenetic factors contribute to variable OT levels in the blood. To this, we integrated genetic, gene expression, and non-DNA regulated (epigenetic) signatures with blood OT levels in 290 participants with autism enrolled in an OT clinical trial. We identified genetic association with plasma OT, several of which reside in known autism risk genes. We also show statistically significant association of plasma OT levels with gene expression and epigenetic across several gene pathways. These findings broaden our understanding of the factors that influence OT levels in the blood for future studies to decode the complex presentation of autism and its interaction with OT and OT-based treatment.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Humanos , Criança , Adolescente , Transtorno do Espectro Autista/metabolismo , Ocitocina , Transtorno Autístico/genética , Metilação de DNA/genética , Epigênese Genética
6.
PLoS One ; 13(3): e0194233, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29529098

RESUMO

Despite much progress, few genetic findings for schizophrenia have been assessed by functional validation experiments at the molecular level. We previously reported evidence for genetic linkage of broadly defined schizophrenia to chromosome 17q25 in a sample of 24 multiplex families. 2,002 SNPs under this linkage peak were analyzed for evidence of linkage disequilibrium using the posterior probability of linkage (PPL) framework. SNP rs1060120 produced the strongest evidence for association, with a PPLD|L score of 0.21. This SNP is located within the 3'UTR of the histone gene H3F3B and colocalizes with potential gene target miR-616. A custom miRNA target prediction program predicted that the binding of miR-616 to H3F3B transcripts would be altered by the allelic variants of rs1060120. We used dual luciferase assays to experimentally validate this interaction. The rs1060120 A allele significantly reduced luciferase expression, indicating a stronger interaction with miR-616 than the G allele (p = 0.000412). These results provide functional validation that this SNP could alter schizophrenia epigenetic mechanisms thereby contributing to schizophrenia-related disease risk.


Assuntos
Sítios de Ligação , Histonas/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Interferência de RNA , RNA Mensageiro/genética , Esquizofrenia/genética , Regiões 3' não Traduzidas , Alelos , Expressão Gênica , Genes Reporter , Estudos de Associação Genética , Genótipo , Humanos , Desequilíbrio de Ligação , Fenótipo , Esquizofrenia/diagnóstico
7.
JCI Insight ; 3(23)2018 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-30518695

RESUMO

OXTR modulates a variety of behaviors in mammals, including social memory and recognition. Genetic and epigenetic dysregulation of OXTR has been suggested to be implicated in neuropsychiatric disorders, including autism spectrum disorder (ASD). While the involvement of DNA methylation is suggested, the mechanism underlying epigenetic regulation of OXTR is largely unknown. This has hampered the experimental design and interpretation of the results of epigenetic studies of OXTR in neuropsychiatric disorders. From the generation and characterization of a new line of Tet1 mutant mice - by deleting the largest coding exon 4 (Tet1Δe4) - we discovered for the first time to our knowledge that Oxtr has an array of mRNA isoforms and a complex transcriptional regulation. Select isoforms of Oxtr are significantly reduced in the brain of Tet1Δe4-/- mice. Accordingly, CpG islands of Oxtr are hypermethylated during early development and persist into adulthood. Consistent with the reduced express of OXTR, Tet1Δe4-/- mice display impaired maternal care, social behavior, and synaptic responses to oxytocin stimulation. Our findings elucidate a mechanism mediated by TET1 protein in regulating Oxtr expression by preventing DNA hypermethylation of Oxtr. The discovery of epigenetic dysregulation of Oxtr in TET1-deficient mouse brain supports the necessity of a reassessment of existing findings and a value of future studies of OXTR in neuropsychiatric disorders.


Assuntos
Proteínas de Ligação a DNA/genética , Epigênese Genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Proto-Oncogênicas/genética , Receptores de Ocitocina/genética , Animais , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Comportamento Animal/fisiologia , Encéfalo/metabolismo , Metilação de DNA , Proteínas de Ligação a DNA/metabolismo , Éxons , Feminino , Histonas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Proteínas Proto-Oncogênicas/metabolismo , Isoformas de RNA/metabolismo , Receptores de Ocitocina/metabolismo , Comportamento Social , Transcriptoma
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