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1.
PLoS Genet ; 19(10): e1010989, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37831723

RESUMEN

The effect of schizophrenia (SCZ) genetic risk on gene expression in brain remains elusive. A popular approach to this problem has been the application of gene co-expression network algorithms (e.g., WGCNA). To improve reliability with this method it is critical to remove unwanted sources of variance while also preserving biological signals of interest. In this WCGNA study of RNA-Seq data from postmortem prefrontal cortex (78 neurotypical donors, EUR ancestry), we tested the effects of SCZ genetic risk on co-expression networks. Specifically, we implemented a novel design in which gene expression was adjusted by linear regression models to preserve or remove variance explained by biological signal of interest (GWAS genomic scores for SCZ risk-(GS-SCZ), and genomic scores- GS of height (GS-Ht) as a negative control), while removing variance explained by covariates of non-interest. We calculated co-expression networks from adjusted expression (GS-SCZ and GS-Ht preserved or removed), and consensus between them (representative of a "background" network free of genomic scores effects). We then tested the overlap between GS-SCZ preserved modules and background networks reasoning that modules with reduced overlap would be most affected by GS-SCZ biology. Additionally, we tested these modules for convergence of SCZ risk (i.e., enrichment in PGC3 SCZ GWAS priority genes, enrichment in SCZ risk heritability and relevant biological ontologies. Our results highlight key aspects of GS-SCZ effects on brain co-expression networks, specifically: 1) preserving/removing SCZ genetic risk alters the co-expression modules; 2) biological pathways enriched in modules affected by GS-SCZ implicate processes of transcription, translation and metabolism that converge to influence synaptic transmission; 3) priority PGC3 SCZ GWAS genes and SCZ risk heritability are enriched in modules associated with GS-SCZ effects. Overall, our results indicate that gene co-expression networks that selectively integrate information about genetic risk can reveal novel combinations of biological pathways involved in schizophrenia.


Asunto(s)
Esquizofrenia , Humanos , Esquizofrenia/genética , Reproducibilidad de los Resultados , Predisposición Genética a la Enfermedad , Encéfalo/metabolismo , Genómica , Estudio de Asociación del Genoma Completo
2.
Genome Res ; 30(1): 1-11, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31852722

RESUMEN

Transcriptome compartmentalization by the nuclear membrane provides both stochastic and functional buffering of transcript activity in the cytoplasm, and has recently been implicated in neurodegenerative disease processes. Although many mechanisms regulating transcript compartmentalization are also prevalent in brain development, the extent to which subcellular localization differs as the brain matures has yet to be addressed. To characterize the nuclear and cytoplasmic transcriptomes during brain development, we sequenced both RNA fractions from homogenate prenatal and adult human postmortem cortex using poly(A)+ and Ribo-Zero library preparation methods. We find that while many genes are differentially expressed by fraction and developmental expression changes are similarly detectable in nuclear and cytoplasmic RNA, the compartmented transcriptomes become more distinct as the brain matures, perhaps reflecting increased utilization of nuclear retention as a regulatory strategy in adult brain. We examined potential mechanisms of this developmental divergence including alternative splicing, RNA editing, nuclear pore composition, RNA-binding protein motif enrichment, and RNA secondary structure. Intron retention is associated with greater nuclear abundance in a subset of transcripts, as is enrichment for several splicing factor binding motifs. Finally, we examined disease association with fraction-regulated gene sets and found nuclear-enriched genes were also preferentially enriched in gene sets associated with neurodevelopmental psychiatric disorders. These results suggest that although gene-level expression is globally comparable between fractions, nuclear retention of transcripts may play an underappreciated role in developmental regulation of gene expression in brain, particularly in genes whose dysregulation is related to neuropsychiatric disorders.


Asunto(s)
Núcleo Celular/metabolismo , Corteza Cerebral/metabolismo , Citoplasma/metabolismo , Predisposición Genética a la Enfermedad , Trastornos Mentales/genética , Trastornos Mentales/psicología , Transcriptoma , Factores de Edad , Empalme Alternativo , Biología Computacional/métodos , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Estudios de Asociación Genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Anotación de Secuencia Molecular , Edición de ARN
3.
Mol Psychiatry ; 25(4): 791-804, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-30478419

RESUMEN

Schizophrenia polygenic risk is plausibly manifested by complex transcriptional dysregulation in the brain, involving networks of co-expressed and functionally related genes. The main purpose of this study was to identify and prioritize co-expressed gene sets in a hierarchical manner, based on the strength of the relationships with clinical diagnosis and with polygenic risk for schizophrenia. Weighted Gene Co-expression Network Analysis (WGCNA) was applied to RNA-quality-adjusted DLPFC RNA-Seq data from the LIBD Postmortem Human Brain Repository (90 controls, 74 schizophrenia cases; all Caucasians) to construct co-expression networks and detect "modules" of co-expressed genes. After multiple internal and external validation procedures, modules of selected interest were tested for enrichment in biological ontologies, for association with schizophrenia polygenic risk scores (PRSs) and with diagnosis, and also for enrichment in genes within the significant GWAS loci reported by the Psychiatric Genomic Consortium (PGC2). The association between schizophrenia genetic signals and modules of co-expression converged on one module showing not only a significant association with both diagnosis and PRS but also significant overlap with 36 PGC2 loci genes, deemed the strongest candidates for drug targets. This module contained many genes involved in synaptic signaling and neuroplasticity. Fifty-three PGC2 genes were in modules associated only with diagnosis and 59 in modules unrelated to diagnosis or PRS. Our study highlights complex relationships between gene co-expression networks in the brain and clinical state and polygenic risk for SCZ and provides a strategy for using this information in selecting and prioritizing potentially targetable gene sets for therapeutic drug development.


Asunto(s)
Redes Reguladoras de Genes/genética , Esquizofrenia/genética , Transcriptoma/genética , Adulto , Anciano , Anciano de 80 o más Años , Autopsia , Encéfalo/metabolismo , Femenino , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Genómica/métodos , Humanos , Masculino , Persona de Mediana Edad , Herencia Multifactorial/genética , Corteza Prefrontal/metabolismo , Población Blanca/genética
4.
Mol Psychiatry ; 25(4): 831-843, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-30635639

RESUMEN

Genome-wide association studies (GWAS) have identified many genomic loci associated with risk for schizophrenia, but unambiguous identification of the relationship between disease-associated variants and specific genes, and in particular their effect on risk conferring transcripts, has proven difficult. To better understand the specific molecular mechanism(s) at the schizophrenia locus in 11q25, we undertook cis expression quantitative trait loci (cis-eQTL) mapping for this 2 megabase genomic region using postmortem human brain samples. To comprehensively assess the effects of genetic risk upon local expression, we evaluated multiple transcript features: genes, exons, and exon-exon junctions in multiple brain regions-dorsolateral prefrontal cortex (DLPFC), hippocampus, and caudate. Genetic risk variants strongly associated with expression of SNX19 transcript features that tag multiple rare classes of SNX19 transcripts, whereas they only weakly affected expression of an exon-exon junction that tags the majority of abundant transcripts. The most prominent class of SNX19 risk-associated transcripts is predicted to be overexpressed, defined by an exon-exon splice junction between exons 8 and 10 (junc8.10) and that is predicted to encode proteins that lack the characteristic nexin C terminal domain. Risk alleles were also associated with either increased or decreased expression of multiple additional classes of transcripts. With RACE, molecular cloning, and long read sequencing, we found a number of novel SNX19 transcripts that further define the set of potential etiological transcripts. We explored epigenetic regulation of SNX19 expression and found that DNA methylation at CpG sites near the primary transcription start site and within exon 2 partially mediate the effects of risk variants on risk-associated expression. ATAC sequencing revealed that some of the most strongly risk-associated SNPs are located within a region of open chromatin, suggesting a nearby regulatory element is involved. These findings indicate a potentially complex molecular etiology, in which risk alleles for schizophrenia generate epigenetic alterations and dysregulation of multiple classes of SNX19 transcripts.


Asunto(s)
Esquizofrenia/genética , Nexinas de Clasificación/genética , Adulto , Alelos , Autopsia , Encéfalo/metabolismo , Cromatina/metabolismo , Mapeo Cromosómico/métodos , Metilación de ADN , Exones/genética , Femenino , Expresión Génica/genética , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Sitios de Carácter Cuantitativo/genética , Factores de Riesgo , Nexinas de Clasificación/metabolismo
5.
Mol Psychiatry ; 25(12): 3267-3277, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-30131587

RESUMEN

Cigarette smoking during pregnancy is a major public health concern. While there are well-described consequences in early child development, there is very little known about the effects of maternal smoking on human cortical biology during prenatal life. We therefore performed a genome-wide differential gene expression analysis using RNA sequencing (RNA-seq) on prenatal (N = 33; 16 smoking-exposed) as well as adult (N = 207; 57 active smokers) human postmortem prefrontal cortices. Smoking exposure during the prenatal period was directly associated with differential expression of 14 genes; in contrast, during adulthood, despite a much larger sample size, only two genes showed significant differential expression (FDR < 10%). Moreover, 1,315 genes showed significantly different exposure effects between maternal smoking during pregnancy and direct exposure in adulthood (FDR < 10%)-these differences were largely driven by prenatal differences that were enriched for pathways previously implicated in addiction and synaptic function. Furthermore, prenatal and age-dependent differentially expressed genes were enriched for genes implicated in non-syndromic autism spectrum disorder (ASD) and were differentially expressed as a set between patients with ASD and controls in postmortem cortical regions. These results underscore the enhanced sensitivity to the biological effect of smoking exposure in the developing brain and offer insight into how maternal smoking during pregnancy affects gene expression in the prenatal human cortex. They also begin to address the relationship between in utero exposure to smoking and the heightened risks for the subsequent development of neuropsychiatric disorders.


Asunto(s)
Trastorno del Espectro Autista , Efectos Tardíos de la Exposición Prenatal , Adulto , Encéfalo , Femenino , Humanos , Exposición Materna , Embarazo , Efectos Tardíos de la Exposición Prenatal/genética , Análisis de Secuencia de ARN , Fumar/efectos adversos , Fumar/genética , Transcriptoma/genética
6.
Proc Natl Acad Sci U S A ; 114(27): 7130-7135, 2017 07 03.
Artículo en Inglés | MEDLINE | ID: mdl-28634288

RESUMEN

RNA sequencing (RNA-seq) is a powerful approach for measuring gene expression levels in cells and tissues, but it relies on high-quality RNA. We demonstrate here that statistical adjustment using existing quality measures largely fails to remove the effects of RNA degradation when RNA quality associates with the outcome of interest. Using RNA-seq data from molecular degradation experiments of human primary tissues, we introduce a method-quality surrogate variable analysis (qSVA)-as a framework for estimating and removing the confounding effect of RNA quality in differential expression analysis. We show that this approach results in greatly improved replication rates (>3×) across two large independent postmortem human brain studies of schizophrenia and also removes potential RNA quality biases in earlier published work that compared expression levels of different brain regions and other diagnostic groups. Our approach can therefore improve the interpretation of differential expression analysis of transcriptomic data from human tissue.


Asunto(s)
ARN/análisis , Análisis de Secuencia de ARN/métodos , Algoritmos , Animales , Biología Computacional , Replicación del ADN , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Genotipo , Sustancia Gris , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN/genética , Esquizofrenia/genética , Esquizofrenia/metabolismo , Transcriptoma
7.
BMC Genomics ; 20(1): 513, 2019 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-31226924

RESUMEN

BACKGROUND: RNA sequencing offers advantages over other quantification methods for microRNA (miRNA), yet numerous biases make reliable quantification challenging. Previous evaluations of these biases have focused on adapter ligation bias with limited evaluation of reverse transcription bias or amplification bias. Furthermore, evaluations of the quantification of isomiRs (miRNA isoforms) or the influence of starting amount on performance have been very limited. No study had yet evaluated the quantification of isomiRs of altered length or compared the consistency of results derived from multiple moderate starting inputs. We therefore evaluated quantifications of miRNA and isomiRs using four library preparation kits, with various starting amounts, as well as quantifications following removal of duplicate reads using unique molecular identifiers (UMIs) to mitigate reverse transcription and amplification biases. RESULTS: All methods resulted in false isomiR detection; however, the adapter-free method tested was especially prone to false isomiR detection. We demonstrate that using UMIs improves accuracy and we provide a guide for input amounts to improve consistency. CONCLUSIONS: Our data show differences and limitations of current methods, thus raising concerns about the validity of quantification of miRNA and isomiRs across studies. We advocate for the use of UMIs to improve accuracy and reliability of miRNA quantifications.


Asunto(s)
Análisis de Secuencia de ARN/normas , Animales , Sesgo , Humanos , Ratones , Isoformas de ARN , ARN Viral , Ratas , Reproducibilidad de los Resultados , Análisis de Secuencia de ARN/métodos
8.
Acta Neuropathol ; 137(4): 557-569, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30712078

RESUMEN

Late-onset Alzheimer's disease (AD) is a complex age-related neurodegenerative disorder that likely involves epigenetic factors. To better understand the epigenetic state associated with AD, we surveyed 420,852 DNA methylation (DNAm) sites from neurotypical controls (N = 49) and late-onset AD patients (N = 24) across four brain regions (hippocampus, entorhinal cortex, dorsolateral prefrontal cortex and cerebellum). We identified 858 sites with robust differential methylation collectively annotated to 772 possible genes (FDR < 5%, within 10 kb). These sites were overrepresented in AD genetic risk loci (p = 0.00655) and were enriched for changes during normal aging (p < 2.2 × 10-16), and nearby genes were enriched for processes related to cell-adhesion, immunity, and calcium homeostasis (FDR < 5%). To functionally validate these associations, we generated and analyzed corresponding transcriptome data to prioritize 130 genes within 10 kb of the differentially methylated sites. These 130 genes were differentially expressed between AD cases and controls and their expression was associated with nearby DNAm (p < 0.05). This integrated analysis implicates novel genes in Alzheimer's disease, such as ANKRD30B. These results highlight DNAm differences in Alzheimer's disease that have gene expression correlates, further implicating DNAm as an epigenetic mechanism underlying pathological molecular changes associated with AD. Furthermore, our framework illustrates the value of integrating epigenetic and transcriptomic data for understanding complex disease.


Asunto(s)
Enfermedad de Alzheimer/genética , Encéfalo/metabolismo , Metilación de ADN , Perfilación de la Expresión Génica , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Encéfalo/patología , Islas de CpG/genética , Bases de Datos Genéticas , Epigenómica , Femenino , Humanos , Masculino , Persona de Mediana Edad
9.
BMC Genet ; 17: 16, 2016 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-26738766

RESUMEN

BACKGROUND: The serotonin 2A receptor is widely implicated in genetic association studies and remains an important drug target for psychiatric, neurological, and cardiovascular conditions. RNA sequencing redefined the architecture of the serotonin 2A receptor gene (HTR2A), revealing novel mRNA transcript isoforms utilizing unannotated untranslated regions of the gene. Expression of these untranslated regions is modulated by common single nucleotide polymorphisms (SNPs), namely rs6311. Previous studies did not fully capture the complexity of the sense- and antisense-encoded transcripts with respect to novel exons in the HTR2A gene locus. Here, we comprehensively catalogued exons and RNA isoforms for both HTR2A and HTR2A-AS1 using RNA-Seq from human prefrontal cortex and multiple mouse tissues. We subsequently tested associations between expression of newfound gene features and common SNPs in humans. RESULTS: We find that the human HTR2A gene spans ~66 kilobases and consists of 7, rather than 4 exons. Furthermore, the revised human HTR2A-AS1 gene spans ~474 kilobases and consists of 18, rather than 3 exons. Three HTR2A exons directly overlap with HTR2A-AS1 exons, suggesting potential for complementary nucleotide interactions. The repertoire of possible mouse Htr2a splice isoforms is remarkably similar to humans and we also find evidence for overlapping sense-antisense transcripts in the same relative positions as the human transcripts. rs6311 and SNPs in high linkage disequilibrium are associated with HTR2A-AS1 expression, in addition to previously described associations with expression of the extended 5' untranslated region of HTR2A. CONCLUSIONS: Our proposed HTR2A and HTR2A-AS1 gene structures dramatically differ from current annotations, now including overlapping exons on the sense and anti-sense strands. We also find orthologous transcript isoforms expressed in mice, providing opportunities to elucidate the biological roles of the human isoforms using a model system. Associations between rs6311 and expression of HTR2A and HTR2A-AS1 suggest this polymorphism is capable of modulating the expression of the sense or antisense transcripts. Still unclear is whether these SNPs act directly on the expression of the sense or antisense transcripts and whether overlapping exons are capable of interacting through complimentary base-pairing. Additional studies are necessary to determine the extent and nature of interactions between the SNPs and the transcripts prior to interpreting these findings in the context of phenotypes associated with HTR2A.


Asunto(s)
ADN sin Sentido , Exones , Receptor de Serotonina 5-HT2A/genética , Empalme Alternativo , Animales , Humanos , Ratones , Polimorfismo de Nucleótido Simple , Corteza Prefrontal/metabolismo , Sitios de Empalme de ARN , Esquizofrenia/genética , Alineación de Secuencia , Transcripción Genética
10.
J Appl Toxicol ; 35(7): 766-80, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25378103

RESUMEN

Formalin-fixed, paraffin-embedded (FFPE) pathology specimens represent a potentially vast resource for transcriptomic-based biomarker discovery. We present here a comparison of results from a whole transcriptome RNA-Seq analysis of RNA extracted from fresh frozen and FFPE livers. The samples were derived from rats exposed to aflatoxin B1 (AFB1 ) and a corresponding set of control animals. Principal components analysis indicated that samples were separated in the two groups representing presence or absence of chemical exposure, both in fresh frozen and FFPE sample types. Sixty-five percent of the differentially expressed transcripts (AFB1 vs. controls) in fresh frozen samples were also differentially expressed in FFPE samples (overlap significance: P < 0.0001). Genomic signature and gene set analysis of AFB1 differentially expressed transcript lists indicated highly similar results between fresh frozen and FFPE at the level of chemogenomic signatures (i.e., single chemical/dose/duration elicited transcriptomic signatures), mechanistic and pathology signatures, biological processes, canonical pathways and transcription factor networks. Overall, our results suggest that similar hypotheses about the biological mechanism of toxicity would be formulated from fresh frozen and FFPE samples. These results indicate that phenotypically anchored archival specimens represent a potentially informative resource for signature-based biomarker discovery and mechanistic characterization of toxicity.


Asunto(s)
Perfilación de la Expresión Génica/métodos , Hígado/efectos de los fármacos , Análisis de Secuencia de ARN/métodos , Toxicogenética/métodos , Aflatoxina B1/toxicidad , Animales , Biomarcadores Farmacológicos/análisis , Formaldehído , Congelación , Regulación de la Expresión Génica/efectos de los fármacos , Hígado/patología , Masculino , Ratas , Ratas Endogámicas F344
11.
Nat Commun ; 15(1): 4220, 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38760338

RESUMEN

When somatic cells acquire complex karyotypes, they often are removed by the immune system. Mutant somatic cells that evade immune surveillance can lead to cancer. Neurons with complex karyotypes arise during neurotypical brain development, but neurons are almost never the origin of brain cancers. Instead, somatic mutations in neurons can bring about neurodevelopmental disorders, and contribute to the polygenic landscape of neuropsychiatric and neurodegenerative disease. A subset of human neurons harbors idiosyncratic copy number variants (CNVs, "CNV neurons"), but previous analyses of CNV neurons are limited by relatively small sample sizes. Here, we develop an allele-based validation approach, SCOVAL, to corroborate or reject read-depth based CNV calls in single human neurons. We apply this approach to 2,125 frontal cortical neurons from a neurotypical human brain. SCOVAL identifies 226 CNV neurons, which include a subclass of 65 CNV neurons with highly aberrant karyotypes containing whole or substantial losses on multiple chromosomes. Moreover, we find that CNV location appears to be nonrandom. Recurrent regions of neuronal genome rearrangement contain fewer, but longer, genes.


Asunto(s)
Variaciones en el Número de Copia de ADN , Mosaicismo , Neuronas , Humanos , Neuronas/metabolismo , Alelos
12.
Nat Neurosci ; 27(6): 1064-1074, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38769152

RESUMEN

Ancestral differences in genomic variation affect the regulation of gene expression; however, most gene expression studies have been limited to European ancestry samples or adjusted to identify ancestry-independent associations. Here, we instead examined the impact of genetic ancestry on gene expression and DNA methylation in the postmortem brain tissue of admixed Black American neurotypical individuals to identify ancestry-dependent and ancestry-independent contributions. Ancestry-associated differentially expressed genes (DEGs), transcripts and gene networks, while notably not implicating neurons, are enriched for genes related to the immune response and vascular tissue and explain up to 26% of heritability for ischemic stroke, 27% of heritability for Parkinson disease and 30% of heritability for Alzheimer's disease. Ancestry-associated DEGs also show general enrichment for the heritability of diverse immune-related traits but depletion for psychiatric-related traits. We also compared Black and non-Hispanic white Americans, confirming most ancestry-associated DEGs. Our results delineate the extent to which genetic ancestry affects differences in gene expression in the human brain and the implications for brain illness risk.


Asunto(s)
Negro o Afroamericano , Encéfalo , Metilación de ADN , Humanos , Negro o Afroamericano/genética , Encéfalo/metabolismo , Femenino , Masculino , Población Blanca/genética , Autopsia , Expresión Génica/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/etnología , Anciano , Persona de Mediana Edad
13.
Nat Commun ; 15(1): 3980, 2024 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-38730231

RESUMEN

Schizophrenia is a complex neuropsychiatric disorder with sexually dimorphic features, including differential symptomatology, drug responsiveness, and male incidence rate. Prior large-scale transcriptome analyses for sex differences in schizophrenia have focused on the prefrontal cortex. Analyzing BrainSeq Consortium data (caudate nucleus: n = 399, dorsolateral prefrontal cortex: n = 377, and hippocampus: n = 394), we identified 831 unique genes that exhibit sex differences across brain regions, enriched for immune-related pathways. We observed X-chromosome dosage reduction in the hippocampus of male individuals with schizophrenia. Our sex interaction model revealed 148 junctions dysregulated in a sex-specific manner in schizophrenia. Sex-specific schizophrenia analysis identified dozens of differentially expressed genes, notably enriched in immune-related pathways. Finally, our sex-interacting expression quantitative trait loci analysis revealed 704 unique genes, nine associated with schizophrenia risk. These findings emphasize the importance of sex-informed analysis of sexually dimorphic traits, inform personalized therapeutic strategies in schizophrenia, and highlight the need for increased female samples for schizophrenia analyses.


Asunto(s)
Núcleo Caudado , Corteza Prefontal Dorsolateral , Hipocampo , Sitios de Carácter Cuantitativo , Esquizofrenia , Caracteres Sexuales , Humanos , Esquizofrenia/genética , Esquizofrenia/metabolismo , Femenino , Masculino , Hipocampo/metabolismo , Núcleo Caudado/metabolismo , Corteza Prefontal Dorsolateral/metabolismo , Adulto , Transcriptoma , Perfilación de la Expresión Génica , Factores Sexuales , Cromosomas Humanos X/genética , Corteza Prefrontal/metabolismo
14.
Transl Psychiatry ; 14(1): 52, 2024 Jan 23.
Artículo en Inglés | MEDLINE | ID: mdl-38263132

RESUMEN

The lateral septum (LS), a GABAergic structure located in the basal forebrain, is implicated in social behavior, learning, and memory. We previously demonstrated that expression of tropomyosin kinase receptor B (TrkB) in LS neurons is required for social novelty recognition. To better understand molecular mechanisms by which TrkB signaling controls behavior, we locally knocked down TrkB in LS and used bulk RNA-sequencing to identify changes in gene expression downstream of TrkB. TrkB knockdown induces upregulation of genes associated with inflammation and immune responses, and downregulation of genes associated with synaptic signaling and plasticity. Next, we generated one of the first atlases of molecular profiles for LS cell types using single nucleus RNA-sequencing (snRNA-seq). We identified markers for the septum broadly, and the LS specifically, as well as for all neuronal cell types. We then investigated whether the differentially expressed genes (DEGs) induced by TrkB knockdown map to specific LS cell types. Enrichment testing identified that downregulated DEGs are broadly expressed across neuronal clusters. Enrichment analyses of these DEGs demonstrated that downregulated genes are uniquely expressed in the LS, and associated with either synaptic plasticity or neurodevelopmental disorders. Upregulated genes are enriched in LS microglia, associated with immune response and inflammation, and linked to both neurodegenerative disease and neuropsychiatric disorders. In addition, many of these genes are implicated in regulating social behaviors. In summary, the findings implicate TrkB signaling in the LS as a critical regulator of gene networks associated with psychiatric disorders that display social deficits, including schizophrenia and autism, and with neurodegenerative diseases, including Alzheimer's.


Asunto(s)
Enfermedades Neurodegenerativas , Proteínas Quinasas , Humanos , Transducción de Señal , Inflamación , ARN
15.
Sci Rep ; 14(1): 3291, 2024 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-38332235

RESUMEN

Primary human trophoblast stem cells (TSCs) and TSCs derived from human pluripotent stem cells (hPSCs) can potentially model placental processes in vitro. Yet, the pluripotent states and factors involved in the differentiation of hPSCs to TSCs remain poorly understood. In this study, we demonstrate that the primed pluripotent state can generate TSCs by activating pathways such as Epidermal Growth Factor (EGF) and Wingless-related integration site (WNT), and by suppressing tumor growth factor beta (TGFß), histone deacetylases (HDAC), and Rho-associated protein kinase (ROCK) signaling pathways, all without the addition of exogenous Bone morphogenetic protein 4 (BMP4)-a condition we refer to as the TS condition. We characterized this process using temporal single-cell RNA sequencing to compare TS conditions with differentiation protocols involving BMP4 activation alone or BMP4 activation in conjunction with WNT inhibition. The TS condition consistently produced a stable, proliferative cell type that closely mimics first-trimester placental cytotrophoblasts, marked by the activation of endogenous retroviral genes and the absence of amnion expression. This was observed across multiple cell lines, including various primed induced pluripotent stem cell (iPSC) and embryonic stem cell (ESC) lines. Primed-derived TSCs can proliferate for over 30 passages and further specify into multinucleated syncytiotrophoblasts and extravillous trophoblast cells. Our research establishes that the differentiation of primed hPSCs to TSC under TS conditions triggers the induction of TMSB4X, BMP5/7, GATA3, and TFAP2A without progressing through a naive state. These findings propose that the primed hPSC state is part of a continuum of potency with the capacity to differentiate into TSCs through multiple routes.


Asunto(s)
Células Madre Pluripotentes Inducidas , Células Madre Pluripotentes , Humanos , Femenino , Embarazo , Placenta , Diferenciación Celular/genética , Trofoblastos/metabolismo , Proteína Morfogenética Ósea 5/metabolismo
16.
bioRxiv ; 2024 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-38463979

RESUMEN

Importance: Habenula (Hb) pathophysiology is involved in many neuropsychiatric disorders, including schizophrenia. Deep brain stimulation and pharmacological targeting of the Hb are emerging as promising therapeutic treatments. However, little is known about the cell type-specific transcriptomic organization of the human Hb or how it is altered in schizophrenia. Objective: To define the molecular neuroanatomy of the human habenula and identify transcriptomic changes in individuals with schizophrenia compared to neurotypical controls. Design Setting and Participants: This study utilized Hb-enriched postmortem human brain tissue. Single nucleus RNA-sequencing (snRNA-seq) and single molecule fluorescent in situ hybridization (smFISH) experiments were conducted to identify molecularly defined Hb cell types and map their spatial location (n=3-7 donors). Bulk RNA-sequencing and cell type deconvolution were used to investigate transcriptomic changes in Hb-enriched tissue from 35 individuals with schizophrenia and 33 neurotypical controls. Gene expression changes associated with schizophrenia in the Hb were compared to those previously identified in the dorsolateral prefrontal cortex (DLPFC), hippocampus, and caudate. Main Outcomes and Measures: Semi-supervised snRNA-seq cell type clustering. Transcript visualization and quantification of smFISH probes. Bulk RNA-seq cell type deconvolution using reference snRNA-seq data. Schizophrenia-associated gene differential expression analysis adjusting for Hb and thalamus fractions, RNA degradation-associated quality surrogate variables, and other covariates. Cross-brain region schizophrenia-associated gene expression comparison. Results: snRNA-seq identified 17 cell type clusters across 16,437 nuclei, including 3 medial and 7 lateral Hb populations. Cell types were conserved with those identified in a rodent model. smFISH for cell type marker genes validated snRNA-seq Hb cell types and depicted the spatial organization of subpopulations. Bulk RNA-seq analyses yielded 45 schizophrenia-associated differentially expressed genes (FDR < 0.05), with 32 (71%) unique to Hb-enriched tissue. Conclusions: These results identify topographically organized cell types with distinct molecular signatures in the human Hb. They further demonstrate unique transcriptomic changes in the epithalamus associated with schizophrenia, thereby providing molecular insights into the role of Hb in neuropsychiatric disorders.

17.
Exp Mol Med ; 56(4): 975-986, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38609519

RESUMEN

We explored the genomic events underlying central neurocytoma (CN), a rare neoplasm of the central nervous system, via multiomics approaches, including whole-exome sequencing, bulk and single-nuclei RNA sequencing, and methylation sequencing. We identified FGFR3 hypomethylation leading to FGFR3 overexpression as a major event in the ontogeny of CN that affects crucial downstream events, such as aberrant PI3K-AKT activity and neuronal development pathways. Furthermore, we found similarities between CN and radial glial cells based on analyses of gene markers and CN tumor cells and postulate that CN tumorigenesis is due to dysregulation of radial glial cell differentiation into neurons. Our data demonstrate the potential role of FGFR3 as one of the leading drivers of tumorigenesis in CN.


Asunto(s)
Metilación de ADN , Células Ependimogliales , Neurocitoma , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos , Humanos , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/metabolismo , Neurocitoma/genética , Neurocitoma/patología , Neurocitoma/metabolismo , Células Ependimogliales/metabolismo , Células Ependimogliales/patología , Regulación Neoplásica de la Expresión Génica
18.
Nat Commun ; 15(1): 3342, 2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38688917

RESUMEN

The polygenic architecture of schizophrenia implicates several molecular pathways involved in synaptic function. However, it is unclear how polygenic risk funnels through these pathways to translate into syndromic illness. Using tensor decomposition, we analyze gene co-expression in the caudate nucleus, hippocampus, and dorsolateral prefrontal cortex of post-mortem brain samples from 358 individuals. We identify a set of genes predominantly expressed in the caudate nucleus and associated with both clinical state and genetic risk for schizophrenia that shows dopaminergic selectivity. A higher polygenic risk score for schizophrenia parsed by this set of genes predicts greater dopamine synthesis in the striatum and greater striatal activation during reward anticipation. These results translate dopamine-linked genetic risk variation into in vivo neurochemical and hemodynamic phenotypes in the striatum that have long been implicated in the pathophysiology of schizophrenia.


Asunto(s)
Cuerpo Estriado , Dopamina , Esquizofrenia , Humanos , Dopamina/metabolismo , Dopamina/biosíntesis , Esquizofrenia/genética , Esquizofrenia/metabolismo , Masculino , Femenino , Cuerpo Estriado/metabolismo , Adulto , Núcleo Caudado/metabolismo , Transducción de Señal , Persona de Mediana Edad , Hipocampo/metabolismo , Herencia Multifactorial , Predisposición Genética a la Enfermedad , Corteza Prefontal Dorsolateral/metabolismo , Recompensa
19.
Science ; 384(6698): eadh3707, 2024 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-38781393

RESUMEN

The molecular pathology of stress-related disorders remains elusive. Our brain multiregion, multiomic study of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) included the central nucleus of the amygdala, hippocampal dentate gyrus, and medial prefrontal cortex (mPFC). Genes and exons within the mPFC carried most disease signals replicated across two independent cohorts. Pathways pointed to immune function, neuronal and synaptic regulation, and stress hormones. Multiomic factor and gene network analyses provided the underlying genomic structure. Single nucleus RNA sequencing in dorsolateral PFC revealed dysregulated (stress-related) signals in neuronal and non-neuronal cell types. Analyses of brain-blood intersections in >50,000 UK Biobank participants were conducted along with fine-mapping of the results of PTSD and MDD genome-wide association studies to distinguish risk from disease processes. Our data suggest shared and distinct molecular pathology in both disorders and propose potential therapeutic targets and biomarkers.


Asunto(s)
Encéfalo , Trastorno Depresivo Mayor , Sitios Genéticos , Trastornos por Estrés Postraumático , Femenino , Humanos , Masculino , Amígdala del Cerebelo/metabolismo , Biomarcadores/metabolismo , Encéfalo/metabolismo , Trastorno Depresivo Mayor/genética , Redes Reguladoras de Genes , Estudio de Asociación del Genoma Completo , Neuronas/metabolismo , Corteza Prefrontal/metabolismo , Trastornos por Estrés Postraumático/genética , Biología de Sistemas , Análisis de Expresión Génica de una Sola Célula , Mapeo Cromosómico
20.
bioRxiv ; 2023 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-37425939

RESUMEN

The lateral septum (LS), a GABAergic structure located in the basal forebrain, is implicated in social behavior, learning and memory. We previously demonstrated that expression of tropomyosin kinase receptor B (TrkB) in LS neurons is required for social novelty recognition. To better understand molecular mechanisms by which TrkB signaling controls behavior, we locally knocked down TrkB in LS and used bulk RNA-sequencing to identify changes in gene expression downstream of TrkB. TrkB knockdown induces upregulation of genes associated with inflammation and immune responses, and downregulation of genes associated with synaptic signaling and plasticity. Next, we generated one of the first atlases of molecular profiles for LS cell types using single nucleus RNA-sequencing (snRNA-seq). We identified markers for the septum broadly, and the LS specifically, as well as for all neuronal cell types. We then investigated whether the differentially expressed genes (DEGs) induced by TrkB knockdown map to specific LS cell types. Enrichment testing identified that downregulated DEGs are broadly expressed across neuronal clusters. Enrichment analyses of these DEGs demonstrated that downregulated genes are uniquely expressed in the LS, and associated with either synaptic plasticity or neurodevelopmental disorders. Upregulated genes are enriched in LS microglia, associated with immune response and inflammation, and linked to both neurodegenerative disease and neuropsychiatric disorders. In addition, many of these genes are implicated in regulating social behaviors. In summary, the findings implicate TrkB signaling in the LS as a critical regulator of gene networks associated with psychiatric disorders that display social deficits, including schizophrenia and autism, and with neurodegenerative diseases, including Alzheimer's.

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