Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
1.
Cell ; 187(13): 3390-3408.e19, 2024 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-38754421

RESUMEN

Clinical trials have identified ARID1A mutations as enriched among patients who respond favorably to immune checkpoint blockade (ICB) in several solid tumor types independent of microsatellite instability. We show that ARID1A loss in murine models is sufficient to induce anti-tumor immune phenotypes observed in ARID1A mutant human cancers, including increased CD8+ T cell infiltration and cytolytic activity. ARID1A-deficient cancers upregulated an interferon (IFN) gene expression signature, the ARID1A-IFN signature, associated with increased R-loops and cytosolic single-stranded DNA (ssDNA). Overexpression of the R-loop resolving enzyme, RNASEH2B, or cytosolic DNase, TREX1, in ARID1A-deficient cells prevented cytosolic ssDNA accumulation and ARID1A-IFN gene upregulation. Further, the ARID1A-IFN signature and anti-tumor immunity were driven by STING-dependent type I IFN signaling, which was required for improved responsiveness of ARID1A mutant tumors to ICB treatment. These findings define a molecular mechanism underlying anti-tumor immunity in ARID1A mutant cancers.


Asunto(s)
Linfocitos T CD8-positivos , Proteínas de Unión al ADN , Interferón Tipo I , Proteínas de la Membrana , Neoplasias , Transducción de Señal , Factores de Transcripción , Animales , Humanos , Ratones , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Línea Celular Tumoral , Proteínas de Unión al ADN/metabolismo , Exodesoxirribonucleasas/metabolismo , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Interferón Tipo I/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Ratones Endogámicos C57BL , Mutación , Neoplasias/inmunología , Neoplasias/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Factores de Transcripción/metabolismo , Masculino , Quimiocinas/genética , Quimiocinas/metabolismo
2.
Immunity ; 57(8): 1780-1795.e6, 2024 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-38843835

RESUMEN

Macrophages elicit immune responses to pathogens through induction of inflammatory genes. Here, we examined the role of three variants of the SWI/SNF nucleosome remodeling complex-cBAF, ncBAF, and PBAF-in the macrophage response to bacterial endotoxin (lipid A). All three SWI/SNF variants were prebound in macrophages and retargeted to genomic sites undergoing changes in chromatin accessibility following stimulation. Cooperative binding of all three variants associated with de novo chromatin opening and latent enhancer activation. Isolated binding of ncBAF and PBAF, in contrast, associated with activation and repression of active enhancers, respectively. Chemical and genetic perturbations of variant-specific subunits revealed pathway-specific regulation in the activation of lipid A response genes, corresponding to requirement for cBAF and ncBAF in inflammatory and interferon-stimulated gene (ISG) activation, respectively, consistent with differential engagement of SWI/SNF variants by signal-responsive transcription factors. Thus, functional diversity among SWI/SNF variants enables increased regulatory control of innate immune transcriptional programs, with potential for specific therapeutic targeting.


Asunto(s)
Ensamble y Desensamble de Cromatina , Proteínas Cromosómicas no Histona , Elementos de Facilitación Genéticos , Inflamación , Macrófagos , Factores de Transcripción , Macrófagos/inmunología , Macrófagos/metabolismo , Animales , Ratones , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas Cromosómicas no Histona/metabolismo , Proteínas Cromosómicas no Histona/genética , Inflamación/inmunología , Inflamación/genética , Elementos de Facilitación Genéticos/genética , Cromatina/metabolismo , Regulación de la Expresión Génica , Ratones Endogámicos C57BL , Inmunidad Innata , Humanos
3.
Immunity ; 56(6): 1303-1319.e5, 2023 06 13.
Artículo en Inglés | MEDLINE | ID: mdl-37315534

RESUMEN

CD8+ T cells provide host protection against pathogens by differentiating into distinct effector and memory cell subsets, but how chromatin is site-specifically remodeled during their differentiation is unclear. Due to its critical role in regulating chromatin and enhancer accessibility through its nucleosome remodeling activities, we investigated the role of the canonical BAF (cBAF) chromatin remodeling complex in antiviral CD8+ T cells during infection. ARID1A, a subunit of cBAF, was recruited early after activation and established de novo open chromatin regions (OCRs) at enhancers. Arid1a deficiency impaired the opening of thousands of activation-induced enhancers, leading to loss of TF binding, dysregulated proliferation and gene expression, and failure to undergo terminal effector differentiation. Although Arid1a was dispensable for circulating memory cell formation, tissue-resident memory (Trm) formation was strongly impaired. Thus, cBAF governs the enhancer landscape of activated CD8+ T cells that orchestrates TF recruitment and activity and the acquisition of specific effector and memory differentiation states.


Asunto(s)
Linfocitos T CD8-positivos , Secuencias Reguladoras de Ácidos Nucleicos , Cromatina , Nucleosomas , Antivirales
4.
Proc Natl Acad Sci U S A ; 119(1)2022 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-34983841

RESUMEN

Macrophages induce a number of inflammatory response genes in response to stimulation with microbial ligands. In response to endotoxin Lipid A, a gene-activation cascade of primary followed by secondary-response genes is induced. Epigenetic state is an important regulator of the kinetics, specificity, and mechanism of gene activation of these two classes. In particular, SWI/SNF chromatin-remodeling complexes are required for the induction of secondary-response genes, but not primary-response genes, which generally exhibit open chromatin. Here, we show that a recently discovered variant of the SWI/SNF complex, the noncanonical BAF complex (ncBAF), regulates secondary-response genes in the interferon (IFN) response pathway. Inhibition of bromodomain-containing protein 9 (BRD9), a subunit of the ncBAF complex, with BRD9 bromodomain inhibitors (BRD9i) or a degrader (dBRD9) led to reduction in a number of interferon-stimulated genes (ISGs) following stimulation with endotoxin lipid A. BRD9-dependent genes overlapped highly with a subset of genes differentially regulated by BET protein inhibition with JQ1 following endotoxin stimulation. We find that the BET protein BRD4 is cobound with BRD9 in unstimulated macrophages and corecruited upon stimulation to ISG promoters along with STAT1, STAT2, and IRF9, components of the ISGF3 complex activated downstream of IFN-alpha receptor stimulation. In the presence of BRD9i or dBRD9, STAT1-, STAT2-, and IRF9-binding is reduced, in some cases with reduced binding of BRD4. These results demonstrate a specific role for BRD9 and the ncBAF complex in ISG activation and identify an activity for BRD9 inhibitors and degraders in dampening endotoxin- and IFN-dependent gene expression.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Interferones/metabolismo , Activación de Macrófagos/efectos de los fármacos , Factores de Transcripción/metabolismo , Antivirales/farmacología , Proteínas de Ciclo Celular/genética , Ensamble y Desensamble de Cromatina/efectos de los fármacos , Humanos , Subunidad gamma del Factor 3 de Genes Estimulados por el Interferón/metabolismo , Interferón-alfa/farmacología , Interferones/genética , Interferones/farmacología , Regiones Promotoras Genéticas/efectos de los fármacos , Dominios Proteicos , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT2/metabolismo , Factores de Transcripción/genética , Activación Transcripcional/efectos de los fármacos
5.
Int J Mol Sci ; 21(18)2020 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-32948023

RESUMEN

Cardiovascular diseases are the leading cause of death worldwide, and as rates continue to increase, discovering mechanisms and therapeutic targets become increasingly important. An underlying cause of most cardiovascular diseases is believed to be excess reactive oxygen or nitrogen species. Glutathione, the most abundant cellular antioxidant, plays an important role in the body's reaction to oxidative stress by forming reversible disulfide bridges with a variety of proteins, termed glutathionylation (GSylation). GSylation can alter the activity, function, and structure of proteins, making it a major regulator of cellular processes. Glutathione-protein mixed disulfide bonds are regulated by glutaredoxins (Glrxs), thioltransferase members of the thioredoxin family. Glrxs reduce GSylated proteins and make them available for another redox signaling cycle. Glrxs and GSylation play an important role in cardiovascular diseases, such as myocardial ischemia and reperfusion, cardiac hypertrophy, peripheral arterial disease, and atherosclerosis. This review primarily concerns the role of GSylation and Glrxs, particularly glutaredoxin-1 (Glrx), in cardiovascular diseases and the potential of Glrx as therapeutic agents.


Asunto(s)
Enfermedades Cardiovasculares/metabolismo , Glutarredoxinas/fisiología , Glutatión/metabolismo , Procesamiento Proteico-Postraduccional , Animales , Antioxidantes/metabolismo , Enfermedades Cardiovasculares/tratamiento farmacológico , Cisteína/análogos & derivados , Cisteína/química , Cisteína/metabolismo , Disulfuros/metabolismo , Células Endoteliales/metabolismo , Glucosa/metabolismo , Glutarredoxinas/deficiencia , Glutarredoxinas/uso terapéutico , Homeostasis , Humanos , Metabolismo de los Lípidos/fisiología , Ratones , Ratones Noqueados , Miocitos Cardíacos/metabolismo , Oxidación-Reducción , Estrés Oxidativo , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de Oxígeno/metabolismo
6.
Science ; 381(6664): 1316-1323, 2023 09 22.
Artículo en Inglés | MEDLINE | ID: mdl-37733872

RESUMEN

Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of complex I (CI) and complex II (CII), the gatekeepers for initiating electron flow, remains unclear. In this work, we report that the loss of CII, but not that of CI, reduces melanoma tumor growth by increasing antigen presentation and T cell-mediated killing. This is driven by succinate-mediated transcriptional and epigenetic activation of major histocompatibility complex-antigen processing and presentation (MHC-APP) genes independent of interferon signaling. Furthermore, knockout of methylation-controlled J protein (MCJ), to promote electron entry preferentially through CI, provides proof of concept of ETC rewiring to achieve antitumor responses without side effects associated with an overall reduction in mitochondrial respiration in noncancer cells. Our results may hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion.


Asunto(s)
Antígenos de Neoplasias , Complejo II de Transporte de Electrones , Complejo I de Transporte de Electrón , Mitocondrias , Neoplasias , Humanos , Presentación de Antígeno , Antígenos de Neoplasias/inmunología , Complejo I de Transporte de Electrón/genética , Complejo I de Transporte de Electrón/metabolismo , Complejo II de Transporte de Electrones/genética , Complejo II de Transporte de Electrones/metabolismo , Electrones , Técnicas de Inactivación de Genes , Histonas/metabolismo , Proteínas del Choque Térmico HSP40/genética , Melanoma/inmunología , Melanoma/patología , Metilación , Mitocondrias/enzimología , Neoplasias/inmunología , Neoplasias/patología , Línea Celular Tumoral
7.
Nat Commun ; 13(1): 3243, 2022 06 10.
Artículo en Inglés | MEDLINE | ID: mdl-35688811

RESUMEN

Cerebral organoids can be used to gain insights into cell type specific processes perturbed by genetic variants associated with neuropsychiatric disorders. However, robust and scalable phenotyping of organoids remains challenging. Here, we perform RNA sequencing on 71 samples comprising 1,420 cerebral organoids from 25 donors, and describe a framework (Orgo-Seq) to integrate bulk RNA and single-cell RNA sequence data. We apply Orgo-Seq to 16p11.2 deletions and 15q11-13 duplications, two loci associated with autism spectrum disorder, to identify immature neurons and intermediate progenitor cells as critical cell types for 16p11.2 deletions. We further applied Orgo-Seq to identify cell type-specific driver genes. Our work presents a quantitative phenotyping framework to integrate multi-transcriptomic datasets for the identification of cell types and cell type-specific co-expressed driver genes associated with neuropsychiatric disorders.


Asunto(s)
Trastorno del Espectro Autista , Trastorno Autístico , Discapacidad Intelectual , Trastorno del Espectro Autista/genética , Trastorno Autístico/genética , Deleción Cromosómica , Trastornos de los Cromosomas , Cromosomas Humanos Par 16 , Humanos , Discapacidad Intelectual/genética , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Transcriptoma/genética
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA