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1.
bioRxiv ; 2023 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-37205394

RESUMEN

Hyperexcitability in the orbitofrontal cortex (OFC) is a key clinical feature of anhedonic domains of Major Depressive Disorder (MDD). However, the cellular and molecular substrates underlying this dysfunction remain unknown. Here, cell-population-specific chromatin accessibility profiling in human OFC unexpectedly mapped genetic risk for MDD exclusively to non-neuronal cells, and transcriptomic analyses revealed significant glial dysregulation in this region. Characterization of MDD-specific cis-regulatory elements identified ZBTB7A - a transcriptional regulator of astrocyte reactivity - as an important mediator of MDD-specific chromatin accessibility and gene expression. Genetic manipulations in mouse OFC demonstrated that astrocytic Zbtb7a is both necessary and sufficient to promote behavioral deficits, cell-type-specific transcriptional and chromatin profiles, and OFC neuronal hyperexcitability induced by chronic stress - a major risk factor for MDD. These data thus highlight a critical role for OFC astrocytes in stress vulnerability and pinpoint ZBTB7A as a key dysregulated factor in MDD that mediates maladaptive astrocytic functions driving OFC hyperexcitability.

2.
Nat Neurosci ; 25(10): 1366-1378, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36171428

RESUMEN

To characterize the dysregulation of chromatin accessibility in Alzheimer's disease (AD), we generated 636 ATAC-seq libraries from neuronal and nonneuronal nuclei isolated from the superior temporal gyrus and entorhinal cortex of 153 AD cases and 56 controls. By analyzing a total of ~20 billion read pairs, we expanded the repertoire of known open chromatin regions (OCRs) in the human brain and identified cell-type-specific enhancer-promoter interactions. We show that interindividual variability in OCRs can be leveraged to identify cis-regulatory domains (CRDs) that capture the three-dimensional structure of the genome (3D genome). We identified AD-associated effects on chromatin accessibility, the 3D genome and transcription factor (TF) regulatory networks. For one of the most AD-perturbed TFs, USF2, we validated its regulatory effect on lysosomal genes. Overall, we applied a systematic approach to understanding the role of the 3D genome in AD. We provide all data as an online resource for widespread community-based analysis.


Asunto(s)
Enfermedad de Alzheimer , Cromatina , Enfermedad de Alzheimer/genética , Humanos , Regiones Promotoras Genéticas , Factores de Transcripción/genética
3.
Nat Genet ; 54(4): 508-517, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35393594

RESUMEN

The human brain forms functional networks of correlated activity, which have been linked with both cognitive and clinical outcomes. However, the genetic variants affecting brain function are largely unknown. Here, we used resting-state functional magnetic resonance images from 47,276 individuals to discover and validate common genetic variants influencing intrinsic brain activity. We identified 45 new genetic regions associated with brain functional signatures (P < 2.8 × 10-11), including associations to the central executive, default mode, and salience networks involved in the triple-network model of psychopathology. A number of brain activity-associated loci colocalized with brain disorders (e.g., the APOE ε4 locus with Alzheimer's disease). Variation in brain function was genetically correlated with brain disorders, such as major depressive disorder and schizophrenia. Together, our study provides a step forward in understanding the genetic architecture of brain functional networks and their genetic links to brain-related complex traits and disorders.


Asunto(s)
Enfermedad de Alzheimer , Trastorno Depresivo Mayor , Enfermedad de Alzheimer/genética , Encéfalo , Trastorno Depresivo Mayor/genética , Humanos , Imagen por Resonancia Magnética/métodos , Red Nerviosa
4.
Nat Neurosci ; 25(4): 474-483, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35332326

RESUMEN

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.


Asunto(s)
Trastorno Bipolar , Esquizofrenia , Adulto , Trastorno Bipolar/genética , Encéfalo , Cromatina , Humanos , Lisina/genética , Esquizofrenia/genética
6.
Science ; 372(6548)2021 06 18.
Artículo en Inglés | MEDLINE | ID: mdl-34140357

RESUMEN

Brain regions communicate with each other through tracts of myelinated axons, commonly referred to as white matter. We identified common genetic variants influencing white matter microstructure using diffusion magnetic resonance imaging of 43,802 individuals. Genome-wide association analysis identified 109 associated loci, 30 of which were detected by tract-specific functional principal components analysis. A number of loci colocalized with brain diseases, such as glioma and stroke. Genetic correlations were observed between white matter microstructure and 57 complex traits and diseases. Common variants associated with white matter microstructure altered the function of regulatory elements in glial cells, particularly oligodendrocytes. This large-scale tract-specific study advances the understanding of the genetic architecture of white matter and its genetic links to a wide spectrum of clinical outcomes.


Asunto(s)
Variación Genética , Sustancia Blanca/fisiología , Sustancia Blanca/ultraestructura , Encéfalo/anatomía & histología , Encéfalo/fisiología , Encefalopatías/genética , Cognición , Imagen de Difusión por Resonancia Magnética , Imagen de Difusión Tensora , Femenino , Genoma Humano , Estudio de Asociación del Genoma Completo , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Masculino , Trastornos Mentales/genética , Herencia Multifactorial , Vías Nerviosas , Neuroglía/fisiología , Neuronas/fisiología , Análisis de Componente Principal , Sitios de Carácter Cuantitativo , Factores de Riesgo , Sustancia Blanca/diagnóstico por imagen
7.
Nat Commun ; 11(1): 5581, 2020 11 04.
Artículo en Inglés | MEDLINE | ID: mdl-33149216

RESUMEN

The chromatin landscape of human brain cells encompasses key information to understanding brain function. Here we use ATAC-seq to profile the chromatin structure in four distinct populations of cells (glutamatergic neurons, GABAergic neurons, oligodendrocytes, and microglia/astrocytes) from three different brain regions (anterior cingulate cortex, dorsolateral prefrontal cortex, and primary visual cortex) in human postmortem brain samples. We find that chromatin accessibility varies greatly by cell type and, more moderately, by brain region, with glutamatergic neurons showing the largest regional variability. Transcription factor footprinting implicates cell-specific transcriptional regulators and infers cell-specific regulation of protein-coding genes, long intergenic noncoding RNAs and microRNAs. In vivo transgenic mouse experiments validate the cell type specificity of several of these human-derived regulatory sequences. We find that open chromatin regions in glutamatergic neurons are enriched for neuropsychiatric risk variants, particularly those associated with schizophrenia. Integration of cell-specific chromatin data with a bulk tissue study of schizophrenia brains increases statistical power and confirms that glutamatergic neurons are most affected. These findings illustrate the utility of studying the cell-type-specific epigenome in complex tissues like the human brain, and the potential of such approaches to better understand the genetic basis of human brain function.


Asunto(s)
Astrocitos/metabolismo , Cromatina/metabolismo , Neuronas GABAérgicas/metabolismo , Microglía/metabolismo , Neuronas/metabolismo , Oligodendroglía/metabolismo , Esquizofrenia/metabolismo , Animales , Cromatina/genética , Epigénesis Genética , Regulación de la Expresión Génica/genética , Giro del Cíngulo/citología , Giro del Cíngulo/metabolismo , Humanos , Ratones , Ratones Transgénicos , MicroARNs/metabolismo , Corteza Prefrontal/citología , Corteza Prefrontal/metabolismo , Regiones Promotoras Genéticas , ARN Largo no Codificante/metabolismo , Factores de Riesgo , Esquizofrenia/genética , Factores de Transcripción/metabolismo , Corteza Visual/citología , Corteza Visual/metabolismo
8.
Nat Commun ; 11(1): 4634, 2020 09 14.
Artículo en Inglés | MEDLINE | ID: mdl-32929078

RESUMEN

The current opioid epidemic necessitates a better understanding of human addiction neurobiology to develop efficacious treatment approaches. Here, we perform genome-wide assessment of chromatin accessibility of the human striatum in heroin users and matched controls. Our study reveals distinct neuronal and non-neuronal epigenetic signatures, and identifies a locus in the proximity of the gene encoding tyrosine kinase FYN as the most affected region in neurons. FYN expression, kinase activity and the phosphorylation of its target Tau are increased by heroin use in the post-mortem human striatum, as well as in rats trained to self-administer heroin and primary striatal neurons treated with chronic morphine in vitro. Pharmacological or genetic manipulation of FYN activity significantly attenuates heroin self-administration and responding for drug-paired cues in rodents. Our findings suggest that striatal FYN is an important driver of heroin-related neurodegenerative-like pathology and drug-taking behavior, making FYN a promising therapeutic target for heroin use disorder.


Asunto(s)
Cromatina/metabolismo , Cuerpo Estriado/enzimología , Dependencia de Heroína/enzimología , Terapia Molecular Dirigida , Proteínas Proto-Oncogénicas c-fyn/metabolismo , Animales , Secuencia de Bases , Conducta Animal/efectos de los fármacos , Señales (Psicología) , Genoma , Células HEK293 , Heroína/efectos adversos , Humanos , Masculino , Neuronas/metabolismo , Fosforilación/efectos de los fármacos , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas c-fyn/antagonistas & inhibidores , Ratas Long-Evans , Autoadministración , Transcripción Genética/efectos de los fármacos , Proteínas tau/metabolismo
9.
Sci Data ; 6(1): 180, 2019 09 24.
Artículo en Inglés | MEDLINE | ID: mdl-31551426

RESUMEN

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 .


Asunto(s)
Trastorno Bipolar , Esquizofrenia , Trastorno Bipolar/genética , Trastorno Bipolar/patología , Estudios de Cohortes , Epigenómica , Humanos , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Esquizofrenia/genética , Esquizofrenia/patología , Transcriptoma
10.
Mol Psychiatry ; 24(11): 1685-1695, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-29740122

RESUMEN

Transcription at enhancers is a widespread phenomenon which produces so-called enhancer RNA (eRNA) and occurs in an activity-dependent manner. However, the role of eRNA and its utility in exploring disease-associated changes in enhancer function, and the downstream coding transcripts that they regulate, is not well established. We used transcriptomic and epigenomic data to interrogate the relationship of eRNA transcription to disease status and how genetic variants alter enhancer transcriptional activity in the human brain. We combined RNA-seq data from 537 postmortem brain samples from the CommonMind Consortium with cap analysis of gene expression and enhancer identification, using the assay for transposase-accessible chromatin followed by sequencing (ATACseq). We find 118 differentially transcribed eRNAs in schizophrenia and identify schizophrenia-associated gene/eRNA co-expression modules. Perturbations of a key module are associated with the polygenic risk scores. Furthermore, we identify genetic variants affecting expression of 927 enhancers, which we refer to as enhancer expression quantitative loci or eeQTLs. Enhancer expression patterns are consistent across studies, including differentially expressed eRNAs and eeQTLs. Combining eeQTLs with a genome-wide association study of schizophrenia identifies a genetic variant that alters enhancer function and expression of its target gene, GOLPH3L. Our novel approach to analyzing enhancer transcription is adaptable to other large-scale, non-poly-A depleted, RNA-seq studies.


Asunto(s)
Elementos de Facilitación Genéticos/genética , Esquizofrenia/genética , Esquizofrenia/metabolismo , Adulto , Estudios de Casos y Controles , Cromatina/genética , Femenino , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica/genética , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino , Persona de Mediana Edad , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Corteza Prefrontal , Regiones Promotoras Genéticas/genética , Sitios de Carácter Cuantitativo/genética , ARN/genética , ARN no Traducido/genética , Transcripción Genética/genética
11.
Sci Data ; 5: 180185, 2018 09 11.
Artículo en Inglés | MEDLINE | ID: mdl-30204156

RESUMEN

Alzheimer's disease (AD) affects half the US population over the age of 85 and is universally fatal following an average course of 10 years of progressive cognitive disability. Genetic and genome-wide association studies (GWAS) have identified about 33 risk factor genes for common, late-onset AD (LOAD), but these risk loci fail to account for the majority of affected cases and can neither provide clinically meaningful prediction of development of AD nor offer actionable mechanisms. This cohort study generated large-scale matched multi-Omics data in AD and control brains for exploring novel molecular underpinnings of AD. Specifically, we generated whole genome sequencing, whole exome sequencing, transcriptome sequencing and proteome profiling data from multiple regions of 364 postmortem control, mild cognitive impaired (MCI) and AD brains with rich clinical and pathophysiological data. All the data went through rigorous quality control. Both the raw and processed data are publicly available through the Synapse software platform.


Asunto(s)
Enfermedad de Alzheimer , Proteoma , Transcriptoma , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Disfunción Cognitiva/genética , Estudios de Cohortes , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genómica , Humanos , Proteómica
12.
Nat Neurosci ; 21(8): 1126-1136, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-30038276

RESUMEN

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.


Asunto(s)
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 , Riesgo
14.
Genome Res ; 28(8): 1243-1252, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29945882

RESUMEN

Most common genetic risk variants associated with neuropsychiatric disease are noncoding and are thought to exert their effects by disrupting the function of cis regulatory elements (CREs), including promoters and enhancers. Within each cell, chromatin is arranged in specific patterns to expose the repertoire of CREs required for optimal spatiotemporal regulation of gene expression. To further understand the complex mechanisms that modulate transcription in the brain, we used frozen postmortem samples to generate the largest human brain and cell-type-specific open chromatin data set to date. Using the Assay for Transposase Accessible Chromatin followed by sequencing (ATAC-seq), we created maps of chromatin accessibility in two cell types (neurons and non-neurons) across 14 distinct brain regions of five individuals. Chromatin structure varies markedly by cell type, with neuronal chromatin displaying higher regional variability than that of non-neurons. Among our findings is an open chromatin region (OCR) specific to neurons of the striatum. When placed in the mouse, a human sequence derived from this OCR recapitulates the cell type and regional expression pattern predicted by our ATAC-seq experiments. Furthermore, differentially accessible chromatin overlaps with the genetic architecture of neuropsychiatric traits and identifies differences in molecular pathways and biological functions. By leveraging transcription factor binding analysis, we identify protein-coding and long noncoding RNAs (lncRNAs) with cell-type and brain region specificity. Our data provide a valuable resource to the research community and we provide this human brain chromatin accessibility atlas as an online database "Brain Open Chromatin Atlas (BOCA)" to facilitate interpretation.


Asunto(s)
Encéfalo/metabolismo , Cromatina/genética , Elementos Reguladores de la Transcripción/genética , Animales , Regulación de la Expresión Génica/genética , Humanos , Ratones , Regiones Promotoras Genéticas , Unión Proteica , Análisis de Secuencia de ADN , Transposasas
15.
Sci Rep ; 8(1): 8868, 2018 06 11.
Artículo en Inglés | MEDLINE | ID: mdl-29892006

RESUMEN

Elucidating brain cell type specific gene expression patterns is critical towards a better understanding of how cell-cell communications may influence brain functions and dysfunctions. We set out to compare and contrast five human and murine cell type-specific transcriptome-wide RNA expression data sets that were generated within the past several years. We defined three measures of brain cell type-relative expression including specificity, enrichment, and absolute expression and identified corresponding consensus brain cell "signatures," which were well conserved across data sets. We validated that the relative expression of top cell type markers are associated with proxies for cell type proportions in bulk RNA expression data from postmortem human brain samples. We further validated novel marker genes using an orthogonal ATAC-seq dataset. We performed multiscale coexpression network analysis of the single cell data sets and identified robust cell-specific gene modules. To facilitate the use of the cell type-specific genes for cell type proportion estimation and deconvolution from bulk brain gene expression data, we developed an R package, BRETIGEA. In summary, we identified a set of novel brain cell consensus signatures and robust networks from the integration of multiple datasets and therefore transcend limitations related to technical issues characteristic of each individual study.


Asunto(s)
Bases de Datos de Ácidos Nucleicos , Células Endoteliales/metabolismo , Neuroglía/metabolismo , Neuronas/metabolismo , Lóbulo Temporal , Transcriptoma , Animales , Conjuntos de Datos como Asunto , Células Endoteliales/citología , Femenino , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Marcadores Genéticos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Neuroglía/citología , Neuronas/citología , Análisis de la Célula Individual , Lóbulo Temporal/citología , Lóbulo Temporal/metabolismo
17.
Hum Mol Genet ; 26(10): 1942-1951, 2017 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-28335009

RESUMEN

Open chromatin provides access to DNA-binding proteins for the correct spatiotemporal regulation of gene expression. Mapping chromatin accessibility has been widely used to identify the location of cis regulatory elements (CREs) including promoters and enhancers. CREs show tissue- and cell-type specificity and disease-associated variants are often enriched for CREs in the tissues and cells that pertain to a given disease. To better understand the role of CREs in neuropsychiatric disorders we applied the Assay for Transposase Accessible Chromatin followed by sequencing (ATAC-seq) to neuronal and non-neuronal nuclei isolated from frozen postmortem human brain by fluorescence-activated nuclear sorting (FANS). Most of the identified open chromatin regions (OCRs) are differentially accessible between neurons and non-neurons, and show enrichment with known cell type markers, promoters and enhancers. Relative to those of non-neurons, neuronal OCRs are more evolutionarily conserved and are enriched in distal regulatory elements. Transcription factor (TF) footprinting analysis identifies differences in the regulome between neuronal and non-neuronal cells and ascribes putative functional roles to a number of non-coding schizophrenia (SCZ) risk variants. Among the identified variants is a Single Nucleotide Polymorphism (SNP) proximal to the gene encoding SNX19. In vitro experiments reveal that this SNP leads to an increase in transcriptional activity. As elevated expression of SNX19 has been associated with SCZ, our data provide evidence that the identified SNP contributes to disease. These results represent the first analysis of OCRs and TF-binding sites in distinct populations of postmortem human brain cells and further our understanding of the regulome and the impact of neuropsychiatric disease-associated genetic risk variants.


Asunto(s)
Cromatina/patología , Regiones Promotoras Genéticas/genética , Esquizofrenia/fisiopatología , Encéfalo/metabolismo , Mapeo Encefálico/métodos , Cromatina/metabolismo , Inmunoprecipitación de Cromatina/métodos , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/fisiología , Elementos de Facilitación Genéticos/genética , Expresión Génica/genética , Estudio de Asociación del Genoma Completo , Humanos , Polimorfismo de Nucleótido Simple/genética , Regiones Promotoras Genéticas/fisiología , Esquizofrenia/genética , Nexinas de Clasificación/genética , Nexinas de Clasificación/metabolismo , Factores de Transcripción/genética
18.
Genome Med ; 8(1): 53, 2016 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-27142060

RESUMEN

BACKGROUND: The bromodomain containing 1 (BRD1) gene has been implicated with transcriptional regulation, brain development, and susceptibility to schizophrenia and bipolar disorder. To advance the understanding of BRD1 and its role in mental disorders, we characterized the protein and chromatin interactions of the BRD1 isoforms, BRD1-S and BRD1-L. METHODS: Stable human cell lines expressing epitope tagged BRD1-S and BRD1-L were generated and used as discovery systems for identifying protein and chromatin interactions. Protein-protein interactions were identified using co-immunoprecipitation followed by mass spectrometry and chromatin interactions were identified using chromatin immunoprecipitation followed by next generation sequencing. Gene expression profiles and differentially expressed genes were identified after upregulating and downregulating BRD1 expression using microarrays. The presented functional molecular data were integrated with human genomic and transcriptomic data using available GWAS, exome-sequencing datasets as well as spatiotemporal transcriptomic datasets from the human brain. RESULTS: We present several novel protein interactions of BRD1, including isoform-specific interactions as well as proteins previously implicated with mental disorders. By BRD1-S and BRD1-L chromatin immunoprecipitation followed by next generation sequencing we identified binding to promoter regions of 1540 and 823 genes, respectively, and showed correlation between BRD1-S and BRD1-L binding and regulation of gene expression. The identified BRD1 interaction network was found to be predominantly co-expressed with BRD1 mRNA in the human brain and enriched for pathways involved in gene expression and brain function. By interrogation of large datasets from genome-wide association studies, we further demonstrate that the BRD1 interaction network is enriched for schizophrenia risk. CONCLUSION: Our results show that BRD1 interacts with chromatin remodeling proteins, e.g. PBRM1, as well as histone modifiers, e.g. MYST2 and SUV420H1. We find that BRD1 primarily binds in close proximity to transcription start sites and regulates expression of numerous genes, many of which are involved with brain development and susceptibility to mental disorders. Our findings indicate that BRD1 acts as a regulatory hub in a comprehensive schizophrenia risk network which plays a role in many brain regions throughout life, implicating e.g. striatum, hippocampus, and amygdala at mid-fetal stages.


Asunto(s)
Encéfalo/metabolismo , Trastornos Mentales/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Mapeo de Interacción de Proteínas/métodos , Proteoma/metabolismo , Encéfalo/crecimiento & desarrollo , Línea Celular , Ensamble y Desensamble de Cromatina , Inmunoprecipitación de Cromatina , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Histona Acetiltransferasas , Chaperonas de Histonas , Humanos , Espectrometría de Masas , Regiones Promotoras Genéticas , Isoformas de Proteínas/metabolismo , Proteoma/genética
19.
Cell Rep ; 15(5): 1024-1036, 2016 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-27117414

RESUMEN

Converging evidence indicates that microRNAs (miRNAs) may contribute to disease risk for schizophrenia (SZ). We show that microRNA-9 (miR-9) is abundantly expressed in control neural progenitor cells (NPCs) but also significantly downregulated in a subset of SZ NPCs. We observed a strong correlation between miR-9 expression and miR-9 regulatory activity in NPCs as well as between miR-9 levels/activity, neural migration, and diagnosis. Overexpression of miR-9 was sufficient to ameliorate a previously reported neural migration deficit in SZ NPCs, whereas knockdown partially phenocopied aberrant migration in control NPCs. Unexpectedly, proteomic- and RNA sequencing (RNA-seq)-based analysis revealed that these effects were mediated primarily by small changes in expression of indirect miR-9 targets rather than large changes in direct miR-9 targets; these indirect targets are enriched for migration-associated genes. Together, these data indicate that aberrant levels and activity of miR-9 may be one of the many factors that contribute to SZ risk, at least in a subset of patients.


Asunto(s)
Regulación de la Expresión Génica , MicroARNs/genética , Células-Madre Neurales/metabolismo , Esquizofrenia/genética , Esquizofrenia/patología , Estudios de Casos y Controles , Movimiento Celular/genética , Perfilación de la Expresión Génica , Estudios de Asociación Genética , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , MicroARNs/metabolismo , Modelos Biológicos , Anotación de Secuencia Molecular , Células-Madre Neurales/patología , Neuronas/metabolismo , Proteoma/metabolismo , Factores de Transcripción/metabolismo
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