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Polymer materials with multiple stimuli-responsive properties have demonstrated many potential and practical applications. By covalently introducing spiropyran (SP1) and spirothiopyran (STP) into the polyurethane backbone, photochromic, mechanochromic, and thermally discolored polymer materials have been prepared. In this work, we report for the first time that white light (violet, blue, and green light) above a certain intensity can activate STP to green color. Based on the above discovery, the polyurethane with SP1 and STP can exhibit reversible three-color changes (brown, green, and purple) in response to four stimuli: ultraviolet irradiation, white light irradiation, mechanical stress, and heat. The color-changing polymer materials have high color contrast and excellent reversibility, and can be used for reversible writing, anticounterfeiting and information encryption, etc.
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Neuropsychiatric genome-wide association studies (GWASs), including those for autism spectrum disorder and schizophrenia, show strong enrichment for regulatory elements in the developing brain. However, prioritizing risk genes and mechanisms is challenging without a unified regulatory atlas. Across 672 diverse developing human brains, we identified 15,752 genes harboring gene, isoform, and/or splicing quantitative trait loci, mapping 3739 to cellular contexts. Gene expression heritability drops during development, likely reflecting both increasing cellular heterogeneity and the intrinsic properties of neuronal maturation. Isoform-level regulation, particularly in the second trimester, mediated the largest proportion of GWAS heritability. Through colocalization, we prioritized mechanisms for about 60% of GWAS loci across five disorders, exceeding adult brain findings. Finally, we contextualized results within gene and isoform coexpression networks, revealing the comprehensive landscape of transcriptome regulation in development and disease.
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Processamento Alternativo , Encéfalo , Regulação da Expressão Gênica no Desenvolvimento , Transtornos Mentais , Humanos , Atlas como Assunto , Transtorno do Espectro Autista/genética , Encéfalo/metabolismo , Encéfalo/crescimento & desenvolvimento , Encéfalo/embriologia , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Locos de Características Quantitativas , Esquizofrenia/genética , Transcriptoma , Transtornos Mentais/genéticaRESUMO
BACKGROUND: Bipolar disorder (BD) is a multifactorial psychiatric illness affecting â¼1% of the global adult population. Lithium (Li), is the most effective mood stabilizer for BD but works only for a subset of patients and its mechanism of action remains largely elusive. METHODS: In the present study, we used iPSC-derived neurons from patients with BD who are responsive (LR) or not (LNR) to lithium. Combined electrophysiology, calcium imaging, biochemistry, transcriptomics, and phosphoproteomics were employed to provide mechanistic insights into neuronal hyperactivity in BD, investigate Li's mode of action, and identify alternative treatment strategies. FINDINGS: We show a selective rescue of the neuronal hyperactivity phenotype by Li in LR neurons, correlated with changes to Na+ conductance. Whole transcriptome sequencing in BD neurons revealed altered gene expression pathways related to glutamate transmission, alterations in cell signalling and ion transport/channel activity. We found altered Akt signalling as a potential therapeutic effect of Li in LR neurons from patients with BD, and that Akt activation mimics Li effect in LR neurons. Furthermore, the increased neural network activity observed in both LR & LNR neurons from patients with BD were reversed by AMP-activated protein kinase (AMPK) activation. INTERPRETATION: These results suggest potential for new treatment strategies in BD, such as Akt activators in LR cases, and the use of AMPK activators for LNR patients with BD. FUNDING: Supported by funding from ERA PerMed, Bell Brain Canada Mental Research Program and Brain & Behavior Research Foundation.
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Proteínas Quinases Ativadas por AMP , Transtorno Bipolar , Células-Tronco Pluripotentes Induzidas , Neurônios , Proteínas Proto-Oncogênicas c-akt , Transtorno Bipolar/metabolismo , Transtorno Bipolar/tratamento farmacológico , Humanos , Neurônios/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Lítio/farmacologia , Lítio/uso terapêutico , Transdução de Sinais , Perfilação da Expressão Gênica , TranscriptomaRESUMO
Meditation-based interventions are novel and effective non-pharmacologic treatments for veterans with PTSD. We examined relationships between treatment response, early life trauma exposure, DNA polymorphisms, and methylation in the serotonin transporter (SLC6A4) and FK506-binding protein 5 (FKBP5) genes. DNA samples and clinical outcomes were examined in 72 veterans with PTSD who received meditation-based therapy in two separate studies of mindfulness-based stress reduction (MBSR) and Transcendental Meditation (TM). The PTSD Checklist was administered to assess symptoms at baseline and after 9 weeks of meditation intervention. We examined the SLC6A4 promoter (5HTTLPR_L/S insertion/deletion + rs25531_A/G) polymorphisms according to previously defined gene expression groups, and the FKBP5 variant rs1360780 previously associated with PTSD disease risk. Methylation for CpG sites of SLC6A4 (28 sites) and FKBP5 (45 sites) genes was quantified in DNA samples collected before and after treatment. The 5HTTLPR LALA high expression genotype was associated with greater symptom improvement in participants exposed to early life trauma (p = 0.015). Separately, pre to post-treatment change of DNA methylation in a group of nine FKBP5 CpG sites was associated with greater symptom improvement (OR = 2.8, 95% CI 1.1-7.1, p = 0.027). These findings build on a wealth of existing knowledge regarding epigenetic and genetic relationships with PTSD disease risk to highlight the potential importance of SLC6A4 and FKBP5 for treatment mechanisms and as biomarkers of symptom improvement.
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BACKGROUND AND HYPOTHESIS: The emergence of psychosis in ultra-high-risk subjects (UHR) is influenced by gene-environment interactions that rely on epigenetic mechanisms such as microRNAs. However, whether they can be relevant pathophysiological biomarkers of psychosis' onset remains unknown. STUDY DESIGN: We present a longitudinal study of microRNA expression, measured in plasma by high-throughput sequencing at baseline and follow-up, in a prospective cohort of 81 UHR, 35 of whom developed psychosis at follow-up (converters). We combined supervised machine learning and differential graph analysis to assess the relative weighted contribution of each microRNA variation to the difference in outcome and identify outcome-specific networks. We then applied univariate models to the resulting microRNA variations common to both strategies, to interpret them as a function of demographic and clinical covariates. STUDY RESULTS: We identified 207 microRNA variations that significantly contributed to the classification. The differential network analysis found 276 network-specific correlations of microRNA variations. The combination of both strategies identified 25 microRNAs, whose gene targets were overrepresented in cognition and schizophrenia genome-wide association studies findings. Interpretable univariate models further supported the relevance of miR-150-5p and miR-3191-5p variations in psychosis onset, independent of age, sex, cannabis use, and medication. CONCLUSIONS: In this first longitudinal study of microRNA variation during conversion to psychosis, we combined 2 methodologically independent data-driven strategies to identify a dynamic epigenetic signature of the emergence of psychosis that is pathophysiologically relevant.
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MicroRNAs , Transtornos Psicóticos , Humanos , Estudos Longitudinais , MicroRNAs/genética , Estudo de Associação Genômica Ampla , Estudos Prospectivos , Transtornos Psicóticos/genéticaRESUMO
Non-suicidal self-injury (NSSI) is highly prevalent among adolescents. The current study aimed to explore defense mechanisms and parental styles of adolescents with NSSI behaviors. The Egna Minnen Barndoms Uppfostran (EMBU [One's Memories of Upbringing]) and Defense Style Questionnaire (DSQ) were used to evaluate 31 participants with NSSI behaviors in the experimental group and 60 participants with non-NSSI behaviors in the control group. There were significant differences in Father Factors II, V, and VI, and Mother Factors III and IV on the EMBU between the experimental and control groups. On the DSQ, there were significant differences in immature defense mechanism, mature defense mechanism, and camouflage factors between the experimental and control groups. In the experimental group, Father Factors I and IV and Mother Factors I and V were significantly correlated with mature defense mechanism. Father Factor VI and Mother Factors III and IV were significantly correlated with immature defense mechanism. Father Factors II and V were significantly correlated with camouflage factors. Defense mechanisms and parental styles of participants in the experimental group were different than those of the control group, and immature parental styles affect the formation of defense mechanisms. [Journal of Psychosocial Nursing and Mental Health Services, 61(11), 17-22.].
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Poder Familiar , Comportamento Autodestrutivo , Feminino , Humanos , Adolescente , Poder Familiar/psicologia , Relações Pais-Filho , Pais/psicologia , Mecanismos de DefesaRESUMO
Genomic regulatory elements active in the developing human brain are notably enriched in genetic risk for neuropsychiatric disorders, including autism spectrum disorder (ASD), schizophrenia, and bipolar disorder. However, prioritizing the specific risk genes and candidate molecular mechanisms underlying these genetic enrichments has been hindered by the lack of a single unified large-scale gene regulatory atlas of human brain development. Here, we uniformly process and systematically characterize gene, isoform, and splicing quantitative trait loci (xQTLs) in 672 fetal brain samples from unique subjects across multiple ancestral populations. We identify 15,752 genes harboring a significant xQTL and map 3,739 eQTLs to a specific cellular context. We observe a striking drop in gene expression and splicing heritability as the human brain develops. Isoform-level regulation, particularly in the second trimester, mediates the greatest proportion of heritability across multiple psychiatric GWAS, compared with eQTLs. Via colocalization and TWAS, we prioritize biological mechanisms for ~60% of GWAS loci across five neuropsychiatric disorders, nearly two-fold that observed in the adult brain. Finally, we build a comprehensive set of developmentally regulated gene and isoform co-expression networks capturing unique genetic enrichments across disorders. Together, this work provides a comprehensive view of genetic regulation across human brain development as well as the stage-and cell type-informed mechanistic underpinnings of neuropsychiatric disorders.
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Valproic acid (VPA) exposure as an environmental factor that confers risk of autism spectrum disorder (ASD), its functional mechanisms in the human brain remain unclear since relevant studies are currently restricted to two-dimensional cell cultures and animal models. To identify mechanisms by which VPA contribute to ASD risk in human, here we used human forebrain organoids (hFOs), in vitro derived three-dimensional cell cultures that recapitulate key human brain developmental features. We identified that VPA exposure in hFOs affected the expression of genes enriched in neural development, synaptic transmission, oxytocin signaling, calcium, and potassium signaling pathways, which have been implicated in ASD. Genes (e.g., CAMK4, CLCN4, DPP10, GABRB3, KCNB1, PRKCB, SCN1A, and SLC24A2) that affected by VPA were significantly overlapped with those dysregulated in brains or organoids derived from ASD patients, and known ASD risk genes, as well as genes in ASD risk-associated gene coexpression modules. Single-cell RNA sequencing analysis showed that VPA exposure affected the expression of genes in choroid plexus, excitatory neuron, immature neuron, and medial ganglionic eminence cells annotated in hFOs. Microelectrode array further identified that VPA exposure in hFOs disrupted synaptic transmission. Taken together, this study connects VPA exposure to ASD pathogenesis using hFOs, which is valuable for illuminating the etiology of ASD and screening for potential therapeutic targets.
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Transtorno do Espectro Autista , Transtorno Autístico , Efeitos Tardios da Exposição Pré-Natal , Animais , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Transtorno Autístico/metabolismo , Canais de Cloreto/metabolismo , Modelos Animais de Doenças , Humanos , Organoides/metabolismo , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Prosencéfalo/metabolismo , Ácido Valproico/efeitos adversosRESUMO
DNA methylation (DNAm) that occurs on promoter regions is primarily considered to repress gene expression. Previous studies indicated that DNAm could also show positive correlations with gene expression. Both DNAm and gene expression profiles are known to be tissue- and development-specific. This study aims to investigate how DNAm and gene expression are coordinated across different human tissues and developmental stages, as well as the biological significance of such correlations. By analyzing 2,239 samples with both DNAm and gene expression data in the same human subjects obtained from six published datasets, we evaluated the correlations between gene and CpG pairs (GCPs) at cis-regions and compared significantly correlated GCPs (cGCPs) across different tissues and brains at different age groups. A total of 37,363 cGCPs was identified in the six datasets; approximately 38% of the cGCPs were positively correlated. The majority (>90%) of cGCPs was tissue- or development-specific. We also observed that the correlation direction can be opposite in different tissues and ages. Further analysis highlights the importance of cGCPs for their cellular functions and potential roles in complex traits and human diseases. For instance, the early developmental brain possessed a highly unique set of cGCPs that were associated with neurogenesis and psychiatric disorders. By assessing the epigenetic factors involved in cGCPs, we discovered novel regulatory mechanisms of positive cGCPs distinct from negative cGCPs, which were related to multiple factors, such as H3K27me3, CTCF, and JARD2. The catalogue of cGCPs compiled can be used to guide functional interpretation of genetic and epigenetic studies.
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Metilação de DNA , Histonas , Encéfalo , Ilhas de CpG , Epigênese Genética , Epigenômica , Expressão Gênica , HumanosRESUMO
Psychosis frequently occurs during adolescence and young adulthood, possibly as a result of gene-environment interactions, mediated by epigenetic mechanisms such as DNA methylation. Methylation patterns can be leveraged to predict epigenetic age in order to identify anomalies in aging trajectories that may be associated with the emergence of psychosis. Thus, epigenetic age may provide a measurable surrogate of psychotic risk or psychosis' emergence, and shed light on the neurodevelopmental model of psychosis. In this study, we present the first longitudinal analysis of epigenetic age trajectory during conversion to psychosis in a population at ultra-high-risk, with available genome-wide methylation DNA at two time points, at baseline and after one year of follow-up (Nâ =â 38â ×â 2). After predicting epigenetic age, we computed epigenetic age gap as the cross-sectional difference between real age and predicted age, and (longitudinal) epigenetic age acceleration as the derivative of predicted age with respect to time. At baseline, future converters were 2.7 years younger than nonconverters and this difference disappeared at follow-up, when some converted to psychosis. This is because during conversion to psychosis, the epigenetic age of converters accelerated by 2.8 years/year compared to nonconverters. This acceleration was robust with a strictly positive 95% confidence interval, and held its significance after adjustment for age, sex, and cannabis intake. The methylation sites most associated with aging were on genes also linked with schizophrenia and neurodevelopmental disorders. This accelerated age trajectory, following a previous deceleration, may therefore reflect dysmaturational processes.
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Many psychiatric disorders are characterized by a strong sex difference, but the mechanisms behind sex-bias are not fully understood. DNA methylation plays important roles in regulating gene expression, ultimately impacting sexually different characteristics of the human brain. Most previous literature focused on DNA methylation alone without considering the regulatory network and its contribution to sex-bias of psychiatric disorders. Since DNA methylation acts in a complex regulatory network to connect genetic and environmental factors with high-order brain functions, we investigated the regulatory networks associated with different DNA methylation and assessed their contribution to the risks of psychiatric disorders. We compiled data from 1408 postmortem brain samples in 3 collections to identify sex-differentially methylated positions (DMPs) and regions (DMRs). We identified and replicated thousands of DMPs and DMRs. The DMR genes were enriched in neuronal related pathways. We extended the regulatory networks related to sex-differential methylation and psychiatric disorders by integrating methylation quantitative trait loci (meQTLs), gene expression, and protein-protein interaction data. We observed significant enrichment of sex-associated genes in psychiatric disorder-associated gene sets. We prioritized 2080 genes that were sex-biased and associated with psychiatric disorders, such as NRXN1, NRXN2, NRXN3, FDE4A, and SHANK2. These genes are enriched in synapse-related pathways and signaling pathways, suggesting that sex-differential genes of these neuronal pathways may cause the sex-bias of psychiatric disorders.
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Metilação de DNA , Transtornos Mentais , Encéfalo , Ilhas de CpG/genética , Metilação de DNA/genética , Epigênese Genética , Feminino , Humanos , Masculino , Transtornos Mentais/genética , Locos de Características QuantitativasRESUMO
This retrospective study assessed the efficacy and safety of 1% topical clotrimazole cream for the treatment of patients with tinea cruris (TC).We included 86 patients with confirmed TC for the presence of fungal hyphae. Of those, 43 patients received 1% topical clotrimazole cream for a total of 4 consecutive weeks, and were assigned to an experimental group. The other 43 patients underwent 1% topical butenafine cream for a total of 2 consecutive weeks, and were allocated to a control group. The efficacy and safety were measured and analyzed after 4 weeks treatment.After treatment, patients in both groups achieved better improvements in erythema (Pâ<â.01), scaling (Pâ<â.01), itching (Pâ<â.01), and KOH-negative results (Pâ<â.01), compared with those in patients before the treatment. However, there were not significant differences in erythema (Pâ=â.61), scaling (Pâ=â.57), itching (Pâ=â.47), and KOH-negative results (Pâ=â.67) between 2 groups. In addition, no treatment-related adverse events were recorded in both groups.Both 1% topical clotrimazole and butenafine cream are found to be effective and safe for patients with TC. However, there is not significant difference in efficacy and safety between two groups.
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Antifúngicos/uso terapêutico , Benzilaminas/uso terapêutico , Clotrimazol/uso terapêutico , Naftalenos/uso terapêutico , Tinea Cruris/tratamento farmacológico , Administração Cutânea , Adulto , Antifúngicos/efeitos adversos , Benzilaminas/efeitos adversos , Clotrimazol/efeitos adversos , Eritema/microbiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Naftalenos/efeitos adversos , Prurido/microbiologia , Estudos Retrospectivos , Creme para a Pele/uso terapêutico , Tinea Cruris/complicações , Adulto JovemRESUMO
BACKGROUND: This study is designed to systematically assess the psychological impact of high-quality nursing care (HQNC) on patients with esophageal cancer during perioperative period (ECPP). METHODS: Several electronic databases will be searched to collect randomized controlled trials (RCTs) or case-control studies (CCSs) on HQNC in the management of ECPP from inception to present: Cochrane Library, PUBMED, EMBASE, SinoMed, Web of Science, WANGFANG, and China National Knowledge Infrastructure. We will not apply any language limitation to all literature searches. Two authors will independently perform literature selection, data extraction and literature quality evaluation. All disagreements will be resolved by a third author through discussion. Cochrane risk of bias tool will be employed to assess trial quality, and RevMan 5.3 software will be utilized to carry out statistical analysis. RESULTS: This study will summarize the current evidence to appraise of the psychological impact of HQNC in the management of ECPP. CONCLUSION: The findings of this study may help to explicit whether HQNC is effective on psychological problem in ECPP. It will also provide scientific evidence for the clinical practice and future researches. STUDY REGISTRATION: INPLASY202080071.
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Neoplasias Esofágicas/enfermagem , Assistência Perioperatória/psicologia , Qualidade da Assistência à Saúde , Revisões Sistemáticas como Assunto , Humanos , Projetos de PesquisaRESUMO
The molecular mechanism for colorectal cancer to develop remains unelucidated. To find biomarkers related to colorectal cancer development, we analyzed the gene expression profile of 380 colorectal cancer patients and 51 healthy controls by R software. Finally, 1579 upregulated differential expression genes (DEGs) and 3218 downregulated DEGs were identified. Then, the top 20 upregulated DEGs were compared with 181 upregulated DEGs that we reported previously, and 11 overlapped DEGs were found. NFE2L3 (nuclear factor, erythroid 2-like 3) was among those overlapped DEGs and was rarely reported in colorectal cancer. Real-time polymerase chain reaction (PCR) results showed that higher NFE2L3 expression levels were identified in paired tumor samples than in paratumor samples (48 paired samples). Flow cytometry analysis revealed that the cell cycle was arrested at the G0/G1 phase after inhibition of NFE2L3 in both HCT116 and SW480 cell lines. Western blot detection showed that CCND1 and phosphorylated Rb transcriptional corepressor 1 at ser-807/811 (pRb1-ser807/811) expression levels were downregulated when NFE2L3 was inhibited in those two cell lines. A significant positive correlation was observed between NFE2L3 and CCND1 expression levels in colorectal tissue samples. These evidences indicate that downregulation of NFE2L3 induces cell cycle arrest at the G0/G1 phase through downregulation of CCND1 and pRb1-ser807/811.
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Fatores de Transcrição de Zíper de Leucina Básica/genética , Neoplasias Colorretais/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Ciclina D1/genética , Ciclina D1/metabolismo , Regulação para Baixo , Células HCT116 , Humanos , Proteínas Salivares Ricas em Prolina/genética , Proteínas Salivares Ricas em Prolina/metabolismoRESUMO
Summary: Gene expression changes over the lifespan and varies among different tissues or cell types. Gene co-expression also changes by sex, age, different tissues or cell types. However, gene expression under the normal state and gene co-expression in the human brain has not been fully defined and quantified. Here we present a database named Brain EXPression Database (BrainEXP) which provides spatiotemporal expression of individual genes and co-expression in normal human brains. BrainEXP consists of 4567 samples from 2863 healthy individuals gathered from existing public databases and our own data, in either microarray or RNA-Seq library types. We mainly provide two analysis results based on the large dataset: (i) basic gene expression across specific brain regions, age ranges and sexes; (ii) co-expression analysis from different platforms. Availability and implementation: http://www.brainexp.org/. Supplementary information: Supplementary data are available at Bioinformatics online.
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Encéfalo/crescimento & desenvolvimento , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Biologia Computacional , Humanos , RNA , Análise de Sequência de RNARESUMO
Schizophrenia and bipolar disorder are complex psychiatric diseases with risks contributed by multiple genes. Dysregulation of gene expression has been implicated in these disorders, but little is known about such dysregulation in the human brain. We analyzed three transcriptome datasets from 394 postmortem brain tissue samples from patients with schizophrenia or bipolar disorder or from healthy control individuals without a known history of psychiatric disease. We built genome-wide coexpression networks that included microRNAs (miRNAs). We identified a coexpression network module that was differentially expressed in the brain tissue from patients compared to healthy control individuals. This module contained genes that were principally involved in glial and neural cell genesis and glial cell differentiation, and included schizophrenia risk genes carrying rare variants. This module included five miRNAs and 545 mRNAs, with six transcription factors serving as hub genes in this module. We found that the most connected transcription factor gene POU3F2, also identified on a genome-wide association study for bipolar disorder, could regulate the miRNA hsa-miR-320e and other putative target mRNAs. These regulatory relationships were replicated using PsychENCODE/BrainGVEX datasets and validated by knockdown and overexpression experiments in SH-SY5Y cells and human neural progenitor cells in vitro. Thus, we identified a brain gene expression module that was enriched for rare coding variants in genes associated with schizophrenia and that contained the putative bipolar disorder risk gene POU3F2 The transcription factor POU3F2 may be a key regulator of gene expression in this disease-associated gene coexpression module.
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Encéfalo/metabolismo , Redes Reguladoras de Genes , Proteínas de Homeodomínio/metabolismo , Transtornos Mentais/genética , Fatores do Domínio POU/metabolismo , Diferenciação Celular/genética , Proliferação de Células/genética , Bases de Dados Genéticas , Regulação da Expressão Gênica , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Proteínas de Homeodomínio/genética , Humanos , Células-Tronco Neurais/metabolismo , Fatores do Domínio POU/genética , Mudanças Depois da Morte , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos TestesRESUMO
A number of studies indicate that rare copy number variations (CNVs) contribute to the risk of schizophrenia (SCZ). Most of these studies have focused on protein-coding genes residing in the CNVs. Here, we investigated long noncoding RNAs (lncRNAs) within 10 SCZ risk-associated CNV deletion regions (CNV-lncRNAs) and examined their potential contribution to SCZ risk. We used RNA sequencing transcriptome data derived from postmortem brain tissue from control individuals without psychiatric disease as part of the PsychENCODE BrainGVEX and Developmental Capstone projects. We carried out weighted gene coexpression network analysis to identify protein-coding genes coexpressed with CNV-lncRNAs in the human brain. We identified one neuronal function-related coexpression module shared by both datasets. This module contained a lncRNA called DGCR5 within the 22q11.2 CNV region, which was identified as a hub gene. Protein-coding genes associated with SCZ genome-wide association study signals, de novo mutations, or differential expression were also contained in this neuronal module. Using DGCR5 knockdown and overexpression experiments in human neural progenitor cells derived from human induced pluripotent stem cells, we identified a potential role for DGCR5 in regulating certain SCZ-related genes.
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Regulação da Expressão Gênica , RNA Longo não Codificante/metabolismo , Esquizofrenia/genética , Adulto , Encéfalo/patologia , Variações do Número de Cópias de DNA/genética , Humanos , Anotação de Sequência Molecular , Fases de Leitura Aberta/genética , RNA Longo não Codificante/genética , Fatores de RiscoRESUMO
DNA methylation has been an important area of research in the study of molecular mechanism to psychiatric disorders. Recent evidence has suggested that abnormalities in global methylation, methylation of genes, and pathways could play a role in the etiology of many forms of mental illness. In this article, we review the mechanisms of DNA methylation, including the genetic and environmental factors affecting methylation changes. We report and discuss major findings regarding DNA methylation in psychiatric patients, both within the context of global methylation studies and gene-specific methylation studies. Finally, we discuss issues surrounding data quality improvement, the limitations of current methylation analysis methods, and the possibility of using DNA methylation-based treatment for psychiatric disorders in the future.
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Metilação de DNA/genética , Transtornos Mentais/genética , Encéfalo/metabolismo , Encéfalo/patologia , Estudos de Associação Genética , Predisposição Genética para Doença , Genoma Humano , HumanosRESUMO
Familial cortical myoclonic tremor with epilepsy is an autosomal dominant neurodegenerative disease, characterized by cortical tremor and epileptic seizures. Although four subtypes (types 1-4) mapped on different chromosomes (8q24, 2p11.1-q12.2, 5p15.31-p15.1 and 3q26.32-3q28) have been reported, the causative gene has not yet been identified. Here, we report the genetic study in a cohort of 20 Chinese pedigrees with familial cortical myoclonic tremor with epilepsy. Linkage and haplotype analysis in 11 pedigrees revealed maximum two-point logarithm of the odds (LOD) scores from 1.64 to 3.77 (LOD scores in five pedigrees were >3.0) in chromosomal region 8q24 and narrowed the candidate region to an interval of 4.9 Mb. Using whole-genome sequencing, long-range polymerase chain reaction and repeat-primed polymerase chain reaction, we identified an intronic pentanucleotide (TTTCA)n insertion in the SAMD12 gene as the cause, which co-segregated with the disease among the 11 pedigrees mapped on 8q24 and additional seven unmapped pedigrees. Only two pedigrees did not contain the (TTTCA)n insertion. Repeat-primed polymerase chain reaction revealed that the sizes of (TTTCA)n insertion in all affected members were larger than 105 repeats. The same pentanucleotide insertion (ATTTCATTTC)58 has been reported to form RNA foci resulting in neurotoxicity in spinocerebellar ataxia type 37, which suggests the similar pathogenic process in familial cortical myoclonic tremor with epilepsy type 1.