RESUMEN
DNA has been known to be a potent immune stimulus for more than half a century. However, the underlying molecular mechanisms of DNA-triggered immune response have remained elusive until recent years. Cyclic GMP-AMP synthase (cGAS) is a major cytoplasmic DNA sensor in various types of cells that detect either invaded foreign DNA or aberrantly located self-DNA. Upon sensing of DNA, cGAS catalyzes the formation of cyclic GMP-AMP (cGAMP), which in turn activates the ER-localized adaptor protein MITA (also named STING) to elicit the innate immune response. The cGAS-MITA axis not only plays a central role in host defense against pathogen-derived DNA but also acts as a cellular stress response pathway by sensing aberrantly located self-DNA, which is linked to the pathogenesis of various human diseases. In this review, we summarize the spatial and temporal mechanisms of host defense to cytoplasmic DNA mediated by the cGAS-MITA axis and discuss the association of malfunctions of this axis with autoimmune and other diseases.
Asunto(s)
ADN/inmunología , Inmunidad Innata , Animales , Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/metabolismo , Autoinmunidad , Biomarcadores , Citoplasma/inmunología , Citoplasma/metabolismo , Susceptibilidad a Enfermedades , Interacciones Huésped-Patógeno/inmunología , Humanos , Evasión Inmune , Interferón Tipo I/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Nucleotidiltransferasas/metabolismoRESUMEN
Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are present in MS lesions yet lack myelin production. We found that oligodendrocytes in the lesions are epigenetically silenced. Developing a transgenic reporter labeling differentiated oligodendrocytes for phenotypic screening, we identified a small-molecule epigenetic-silencing-inhibitor (ESI1) that enhances myelin production and ensheathment. ESI1 promotes remyelination in animal models of demyelination and enables de novo myelinogenesis on regenerated CNS axons. ESI1 treatment lengthened myelin sheaths in human iPSC-derived organoids and augmented (re)myelination in aged mice while reversing age-related cognitive decline. Multi-omics revealed that ESI1 induces an active chromatin landscape that activates myelinogenic pathways and reprograms metabolism. Notably, ESI1 triggered nuclear condensate formation of master lipid-metabolic regulators SREBP1/2, concentrating transcriptional co-activators to drive lipid/cholesterol biosynthesis. Our study highlights the potential of targeting epigenetic silencing to enable CNS myelin regeneration in demyelinating diseases and aging.
Asunto(s)
Epigénesis Genética , Vaina de Mielina , Oligodendroglía , Remielinización , Animales , Vaina de Mielina/metabolismo , Humanos , Ratones , Remielinización/efectos de los fármacos , Oligodendroglía/metabolismo , Sistema Nervioso Central/metabolismo , Ratones Endogámicos C57BL , Rejuvenecimiento , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Organoides/metabolismo , Organoides/efectos de los fármacos , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/genética , Diferenciación Celular/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Masculino , Regeneración/efectos de los fármacos , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/genética , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/patologíaRESUMEN
Antigen receptor loci are organized into variable (V), diversity (D) and joining (J) gene segments that rearrange to generate antigen receptor repertoires. Here, we identified an enhancer (E34) in the murine immunoglobulin kappa (Igk) locus that instructed rearrangement of Vκ genes located in a sub-topologically associating domain, including a Vκ gene encoding for antibodies targeting bacterial phosphorylcholine. We show that E34 instructs the nuclear repositioning of the E34 sub-topologically associating domain from a recombination-repressive compartment to a recombination-permissive compartment that is marked by equivalent activating histone modifications. Finally, we found that E34-instructed Vκ-Jκ rearrangement was essential to combat Streptococcus pneumoniae but not methicillin-resistant Staphylococcus aureus or influenza infections. We propose that the merging of Vκ genes with Jκ elements is instructed by one-dimensional epigenetic information imposed by enhancers across Vκ and Jκ genomic regions. The data also reveal how enhancers generate distinct antibody repertoires that provide protection against lethal bacterial infection.
Asunto(s)
Cromatina , Staphylococcus aureus Resistente a Meticilina , Ratones , Animales , Cromatina/genética , Región Variable de Inmunoglobulina/genética , Cadenas kappa de Inmunoglobulina/genética , Staphylococcus aureus Resistente a Meticilina/genética , Linfocitos B , Epigénesis GenéticaRESUMEN
Microbial nucleic acids are major signatures of invading pathogens, and their recognition by various host pattern recognition receptors (PRRs) represents the first step toward an efficient innate immune response to clear the pathogens. The nucleic acid-sensing PRRs are localized at the plasma membrane, the cytosol, and/or various cellular organelles. Sensing of nucleic acids and signaling by PRRs involve recruitment of distinct signaling components, and PRRs are intensively regulated by cellular organelle trafficking. PRR-mediated innate immune responses are also heavily regulated by posttranslational modifications, including phosphorylation, polyubiquitination, sumoylation, and glutamylation. In this review, we focus on our current understanding of recognition of microbial nucleic acid by PRRs, particularly on their regulation by organelle trafficking and posttranslational modifications. We also discuss how sensing of self nucleic acids and dysregulation of PRR-mediated signaling lead to serious human diseases.
Asunto(s)
Interacciones Huésped-Patógeno/genética , Inmunidad Innata/genética , Ácidos Nucleicos/genética , Receptores de Reconocimiento de Patrones/genética , Bacterias/genética , Bacterias/patogenicidad , Citoplasma/inmunología , Citoplasma/microbiología , ADN Bacteriano/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Ácidos Nucleicos/inmunología , Procesamiento Proteico-Postraduccional/genética , Procesamiento Proteico-Postraduccional/inmunología , Receptores de Reconocimiento de Patrones/inmunología , Transducción de Señal/genéticaRESUMEN
It is well established that neutrophils adopt malleable polymorphonuclear shapes to migrate through narrow interstitial tissue spaces1-3. However, how polymorphonuclear structures are assembled remains unknown4. Here we show that in neutrophil progenitors, halting loop extrusion-a motor-powered process that generates DNA loops by pulling in chromatin5-leads to the assembly of polymorphonuclear genomes. Specifically, we found that in mononuclear neutrophil progenitors, acute depletion of the loop-extrusion loading factor nipped-B-like protein (NIPBL) induced the assembly of horseshoe, banded, ringed and hypersegmented nuclear structures and led to a reduction in nuclear volume, mirroring what is observed during the differentiation of neutrophils. Depletion of NIPBL also induced cell-cycle arrest, activated a neutrophil-specific gene program and conditioned a loss of interactions across topologically associating domains to generate a chromatin architecture that resembled that of differentiated neutrophils. Removing NIPBL resulted in enrichment for mega-loops and interchromosomal hubs that contain genes associated with neutrophil-specific enhancer repertoires and an inflammatory gene program. On the basis of these observations, we propose that in neutrophil progenitors, loop-extrusion programs produce lineage-specific chromatin architectures that permit the packing of chromosomes into geometrically confined lobular structures. Our data also provide a blueprint for the assembly of polymorphonuclear structures, and point to the possibility of engineering de novo nuclear shapes to facilitate the migration of effector cells in densely populated tumorigenic environments.
Asunto(s)
Movimiento Celular , Forma del Núcleo Celular , Neutrófilos , Puntos de Control del Ciclo Celular , Proteínas de Ciclo Celular/deficiencia , Proteínas de Ciclo Celular/metabolismo , Cromatina/química , Cromatina/metabolismo , Cromosomas/química , Cromosomas/metabolismo , Neutrófilos/citología , Neutrófilos/metabolismo , Conformación de Ácido Nucleico , Diferenciación Celular/genética , Inflamación/genética , Elementos de Facilitación Genéticos , Linaje de la Célula/genéticaRESUMEN
Chromosomes of eukaryotes adopt highly dynamic and complex hierarchical structures in the nucleus. The three-dimensional (3D) organization of chromosomes profoundly affects DNA replication, transcription and the repair of DNA damage. Thus, a thorough understanding of nuclear architecture is fundamental to the study of nuclear processes in eukaryotic cells. Recent years have seen rapid proliferation of technologies to investigate genome organization and function. Here, we review experimental and computational methodologies for 3D genome analysis, with special focus on recent advances in high-throughput chromatin conformation capture (3C) techniques and data analysis.
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Cromatina/ultraestructura , Animales , Mapeo Cromosómico , Cromosomas/ultraestructura , Simulación por Computador , Humanos , Modelos MolecularesRESUMEN
Genome-wide mapping of chromatin interactions at high resolution remains experimentally and computationally challenging. Here we used a low-input "easy Hi-C" protocol to map the 3D genome architecture in human neurogenesis and brain tissues and also demonstrated that a rigorous Hi-C bias-correction pipeline (HiCorr) can significantly improve the sensitivity and robustness of Hi-C loop identification at sub-TAD level, especially the enhancer-promoter (E-P) interactions. We used HiCorr to compare the high-resolution maps of chromatin interactions from 10 tissue or cell types with a focus on neurogenesis and brain tissues. We found that dynamic chromatin loops are better hallmarks for cellular differentiation than compartment switching. HiCorr allowed direct observation of cell-type- and differentiation-specific E-P aggregates spanning large neighborhoods, suggesting a mechanism that stabilizes enhancer contacts during development. Interestingly, we concluded that Hi-C loop outperforms eQTL in explaining neurological GWAS results, revealing a unique value of high-resolution 3D genome maps in elucidating the disease etiology.
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Cromatina/metabolismo , Elementos de Facilitación Genéticos , Regulación del Desarrollo de la Expresión Génica , Redes Reguladoras de Genes , Genoma Humano , Neurogénesis/genética , Regiones Promotoras Genéticas , Adulto , Línea Celular , Cerebro/citología , Cerebro/crecimiento & desarrollo , Cerebro/metabolismo , Cromatina/ultraestructura , Mapeo Cromosómico , Feto , Histonas/genética , Histonas/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Proteínas del Tejido Nervioso/clasificación , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Neuronas/citología , Neuronas/metabolismo , Lóbulo Temporal/citología , Lóbulo Temporal/crecimiento & desarrollo , Lóbulo Temporal/metabolismo , Factores de Transcripción/clasificación , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Mitochondria play essential roles in cancer cell adaptation to hypoxia, but the underlying mechanisms remain elusive. Through mitochondrial proteomic profiling, we here find that the prolyl hydroxylase EglN1 (PHD2) accumulates on mitochondria under hypoxia. EglN1 substrate-binding region in the ß2ß3 loop is responsible for its mitochondrial translocation and contributes to breast tumor growth. Furthermore, we identify AMP-activated protein kinase alpha (AMPKα) as an EglN1 substrate on mitochondria. The EglN1-AMPKα interaction is essential for their mutual mitochondrial translocation. After EglN1 prolyl-hydroxylates AMPKα under normoxia, they rapidly dissociate following prolyl-hydroxylation, leading to their immediate release from mitochondria. In contrast, hypoxia results in constant EglN1-AMPKα interaction and their accumulation on mitochondria, leading to the formation of a Ca2+ /calmodulin-dependent protein kinase 2 (CaMKK2)-EglN1-AMPKα complex to activate AMPKα phosphorylation, ensuring metabolic homeostasis and breast tumor growth. Our findings identify EglN1 as an oxygen-sensitive metabolic checkpoint signaling hypoxic stress to mitochondria through its ß2ß3 loop region, suggesting a potential therapeutic target for breast cancer.
Asunto(s)
Proteínas Quinasas Activadas por AMP , Neoplasias de la Mama , Femenino , Humanos , Proteínas Quinasas Activadas por AMP/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Hipoxia , Prolina Dioxigenasas del Factor Inducible por Hipoxia/genética , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Mitocondrias/metabolismo , ProteómicaRESUMEN
Recognition of viral RNA by the retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) initiates innate antiviral immune response. How the binding of viral RNA to and activation of the RLRs are regulated remains enigmatic. In this study, we identified ZCCHC3 as a positive regulator of the RLRs including RIG-I and MDA5. ZCCHC3 deficiency markedly inhibited RNA virus-triggered induction of downstream antiviral genes, and ZCCHC3-deficient mice were more susceptible to RNA virus infection. ZCCHC3 was associated with RIG-I and MDA5 and functions in two distinct processes for regulation of RIG-I and MDA5 activities. ZCCHC3 bound to dsRNA and enhanced the binding of RIG-I and MDA5 to dsRNA. ZCCHC3 also recruited the E3 ubiquitin ligase TRIM25 to the RIG-I and MDA5 complexes to facilitate its K63-linked polyubiquitination and activation. Thus, ZCCHC3 is a co-receptor for RIG-I and MDA5, which is critical for RLR-mediated innate immune response to RNA virus.
Asunto(s)
Proteína 58 DEAD Box/metabolismo , Infecciones por Virus ARN/inmunología , Virus ARN/fisiología , ARN Viral/metabolismo , Proteínas de Unión al ARN/metabolismo , Animales , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Proteínas de Unión al ADN/metabolismo , Regulación Viral de la Expresión Génica , Células HEK293 , Humanos , Inmunidad Innata , Helicasa Inducida por Interferón IFIH1/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Unión Proteica , ARN Viral/inmunología , Proteínas de Unión al ARN/genética , Células THP-1 , Factores de Transcripción/metabolismo , UbiquitinaciónRESUMEN
Chemical reactions represent a class of quantum problems that challenge both the current theoretical understanding and computational capabilities1. Reactions that occur at ultralow temperatures provide an ideal testing ground for quantum chemistry and scattering theories, because they can be experimentally studied with unprecedented control2, yet display dynamics that are highly complex3. Here we report the full product state distribution for the reaction 2KRb â K2 + Rb2. Ultracold preparation of the reactants allows us complete control over their initial quantum degrees of freedom, whereas state-resolved, coincident detection of both products enables the probability of scattering into each of the 57 allowed rotational state-pairs to be measured. Our results show an overall agreement with a state-counting model based on statistical theory4-6, but also reveal several deviating state-pairs. In particular, we observe a strong suppression of population in the state-pair closest to the exoergicity limit as a result of the long-range potential inhibiting the escape of products. The completeness of our measurements provides a benchmark for quantum dynamics calculations beyond the current state of the art.
RESUMEN
Hi-C data are commonly normalized using single sample processing methods, with focus on comparisons between regions within a given contact map. Here, we aim to compare contact maps across different samples. We demonstrate that unwanted variation, of likely technical origin, is present in Hi-C data with replicates from different individuals, and that properties of this unwanted variation change across the contact map. We present band-wise normalization and batch correction, a method for normalization and batch correction of Hi-C data and show that it substantially improves comparisons across samples, including in a quantitative trait loci analysis as well as differential enrichment across cell types.
Asunto(s)
Sitios de Carácter Cuantitativo , Humanos , Biología ComputacionalRESUMEN
Lineage-specific epigenomic changes during human corticogenesis have been difficult to study owing to challenges with sample availability and tissue heterogeneity. For example, previous studies using single-cell RNA sequencing identified at least 9 major cell types and up to 26 distinct subtypes in the dorsal cortex alone1,2. Here we characterize cell-type-specific cis-regulatory chromatin interactions, open chromatin peaks, and transcriptomes for radial glia, intermediate progenitor cells, excitatory neurons, and interneurons isolated from mid-gestational samples of the human cortex. We show that chromatin interactions underlie several aspects of gene regulation, with transposable elements and disease-associated variants enriched at distal interacting regions in a cell-type-specific manner. In addition, promoters with increased levels of chromatin interactivity-termed super-interactive promoters-are enriched for lineage-specific genes, suggesting that interactions at these loci contribute to the fine-tuning of transcription. Finally, we develop CRISPRview, a technique that integrates immunostaining, CRISPR interference, RNAscope, and image analysis to validate cell-type-specific cis-regulatory elements in heterogeneous populations of primary cells. Our findings provide insights into cell-type-specific gene expression patterns in the developing human cortex and advance our understanding of gene regulation and lineage specification during this crucial developmental window.
Asunto(s)
Células/clasificación , Células/metabolismo , Corteza Cerebral/citología , Corteza Cerebral/embriología , Epigenoma , Epigenómica , Organogénesis/genética , Sistemas CRISPR-Cas , Linaje de la Célula/genética , Células Cultivadas , Cromatina/genética , Cromatina/metabolismo , Elementos Transponibles de ADN , Histonas/química , Histonas/metabolismo , Humanos , Imagenología Tridimensional , Metilación , Herencia Multifactorial/genética , Polimorfismo de Nucleótido Simple/genética , Regiones Promotoras Genéticas/genética , Elementos Reguladores de la Transcripción , Reproducibilidad de los Resultados , Transcripción GenéticaRESUMEN
BACKGROUND: Proximity to urban blue and green spaces has been associated with improved cardiovascular health; however, few studies have examined the role of race and socioeconomic status in these associations. METHODS: Data were from the CARDIA study (Coronary Artery Risk Development in Young Adults). We included longitudinal measurements (1985-1986 to 2010-2011) of blue and green spaces, including percentage of blue space cover, distance to the nearest river, green space cover, and distance to the nearest major park. Presence of coronary artery calcification (CAC) was measured with noncontrast cardiac computed tomography in 2010 to 2011. The associations of blue and green spaces with CAC were assessed with generalized estimating equation regression with adjustment for demographics, individual and neighborhood socioeconomic status, health-related behaviors, and other health conditions. We conducted stratified analyses by race and neighborhood deprivation score to investigate whether the association varied according to social determinants of health. RESULTS: The analytic sample included 1365 Black and 1555 White participants with a mean±SD age of 50.1±3.6 years. Among Black participants, shorter distance to a river and greater green space cover were associated with lower odds of CAC (per interquartile range decrease [1.45 km] to the river: odds ratio [OR], 0.90 [95% CI, 0.84-0.96]; per 10 percentage-point increase of green space cover: OR, 0.85 [95% CI, 0.75-0.95]). Among participants in deprived neighborhoods, greater green space cover was associated with lower odds of CAC (per a 10 percentage-point increase: OR, 0.89 [95% CI, 0.80-0.99]), whereas shorter distance to the park was associated with higher odds of CAC (per an interquartile range decrease [5.3 km]: OR, 1.07 [95% CI, 1.00-1.15]). Black participants in deprived neighborhoods had lower odds of CAC with shorter distance to a river (per an interquartile range decrease: OR, 0.90 [95% CI, 0.82-0.98]) and greater green space cover (per a 10 percentage-point increase: OR, 0.85 [95% CI, 0.75-0.97]). There was no statistical interaction between the blue and green spaces and race or neighborhood characteristics in association with CAC. CONCLUSIONS: Longitudinally, shorter distance to a river and greater green space cover were associated with less CAC among Black participants and those in deprived neighborhoods. Shorter distance to a park was associated with increased odds of CAC among participants in deprived neighborhoods. Black participants residing in more deprived neighborhoods showed lower odds of CAC in association with greater exposure to river and green space cover.
Asunto(s)
Negro o Afroamericano , Enfermedad de la Arteria Coronaria , Calcificación Vascular , Humanos , Masculino , Femenino , Persona de Mediana Edad , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/etnología , Enfermedad de la Arteria Coronaria/epidemiología , Adulto , Calcificación Vascular/diagnóstico por imagen , Calcificación Vascular/etnología , Calcificación Vascular/epidemiología , Población Blanca , Factores de Riesgo , Características del Vecindario , Características de la Residencia , Estudios Longitudinales , Población Urbana , Poblaciones Vulnerables , Parques RecreativosRESUMEN
Recent advances in high-throughput chromatin conformation capture (Hi-C) technologies at the single-cell level enable the identification of cell type-specific chromatin loops directly from complex tissues. This may help to interpret noncoding variants identified by genome-wide association studies (GWAS) in disease-relevant cell types. We briefly review current experimental and computational strategies for mapping chromatin loops in single cells.
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Cromatina , Estudio de Asociación del Genoma Completo , Cromatina/genética , Mapeo Cromosómico , Cromosomas , Conformación MolecularRESUMEN
Single-cell high-throughput chromatin conformation capture technologies (scHi-C) has been used to map chromatin spatial organization in complex tissues. However, computational tools to detect differential chromatin contacts (DCCs) from scHi-C datasets in development and through disease pathogenesis are still lacking. Here, we present SnapHiC-D, a computational pipeline to identify DCCs between two scHi-C datasets. Compared to methods designed for bulk Hi-C data, SnapHiC-D detects DCCs with high sensitivity and accuracy. We used SnapHiC-D to identify cell-type-specific chromatin contacts at 10 Kb resolution in mouse hippocampal and human prefrontal cortical tissues, demonstrating that DCCs detected in the hippocampal and cortical cell types are generally associated with cell-type-specific gene expression patterns and epigenomic features. SnapHiC-D is freely available at https://github.com/HuMingLab/SnapHiC-D.
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Cromatina , Epigenómica , Humanos , Animales , Ratones , Cromatina/genética , HipocampoRESUMEN
Variants at the SLC30A8 locus are associated with type 2 diabetes (T2D) risk. The lead variant, rs13266634, encodes an amino acid change, Arg325Trp (R325W), at the C-terminus of the secretory granule-enriched zinc transporter, ZnT8. Although this protein-coding variant was previously thought to be the sole driver of T2D risk at this locus, recent studies have provided evidence for lowered expression of SLC30A8 mRNA in protective allele carriers. In the present study, we examined multiple variants that influence SLC30A8 allele-specific expression. Epigenomic mapping has previously identified an islet-selective enhancer cluster at the SLC30A8 locus, hosting multiple T2D risk and cASE associations, which is spatially associated with the SLC30A8 promoter and additional neighboring genes. Here, we show that deletion of variant-bearing enhancer regions using CRISPR-Cas9 in human-derived EndoC-ßH3 cells lowers the expression of SLC30A8 and several neighboring genes and improves glucose-stimulated insulin secretion. While downregulation of SLC30A8 had no effect on beta cell survival, loss of UTP23, RAD21, or MED30 markedly reduced cell viability. Although eQTL or cASE analyses in human islets did not support the association between these additional genes and diabetes risk, the transcriptional regulator JQ1 lowered the expression of multiple genes at the SLC30A8 locus and enhanced stimulated insulin secretion.
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Diabetes Mellitus Tipo 2 , Elementos de Facilitación Genéticos , Células Secretoras de Insulina , Transportador 8 de Zinc , Humanos , Transportador 8 de Zinc/genética , Transportador 8 de Zinc/metabolismo , Células Secretoras de Insulina/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Supervivencia Celular/genética , Variación Genética , Insulina/metabolismo , Línea CelularRESUMEN
During viral infection, sensing of cytosolic DNA by the cyclic GMP-AMP synthase (cGAS) activates the adaptor protein STING and triggers an antiviral response. Little is known about the mechanisms that determine the kinetics of activation and deactivation of the cGAS-STING pathway, ensuring effective but controlled innate antiviral responses. Here we found that the ubiquitin ligase Trim38 targets cGas for sumoylation in uninfected cells and during the early phase of viral infection. Sumoylation of cGas prevented its polyubiquitination and degradation. Trim38 also sumoylated Sting during the early phase of viral infection, promoting both Sting activation and protein stability. In the late phase of infection, cGas and Sting were desumoylated by Senp2 and subsequently degraded via proteasomal and chaperone-mediated autophagy pathways, respectively. Our findings reveal an essential role for Trim38 in the innate immune response to DNA virus and provide insight into the mechanisms that ensure optimal activation and deactivation of the cGAS-STING pathway.
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Virus ADN/inmunología , ADN/metabolismo , Nucleótidos Cíclicos/metabolismo , Nucleotidiltransferasas/metabolismo , Sumoilación/fisiología , Virosis/metabolismo , Animales , Proteínas Portadoras/metabolismo , Cisteína Endopeptidasas/metabolismo , Inmunidad Innata/inmunología , Cinética , Proteínas de la Membrana/metabolismo , Ratones , Complejo de la Endopetidasa Proteasomal/metabolismo , Transducción de Señal/inmunología , Transducción de Señal/fisiología , Sumoilación/inmunología , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína Ligasas , Ubiquitinación/inmunología , Ubiquitinación/fisiologíaRESUMEN
The building sector, including building operations and materials, was responsible for the emission of â¼11.9 gigatons of global energy-related CO2 in 2020, accounting for 37% of the total CO2 emissions, the largest share among different sectors. Lowering the carbon footprint of buildings requires the development of carbon-storage materials as well as novel designs that could enable multifunctional components to achieve widespread applications. Wood is one of the most abundant biomaterials on Earth and has been used for construction historically. Recent research breakthroughs on advanced engineered wood products epitomize this material's tremendous yet largely untapped potential for addressing global sustainability challenges. In this review, we explore recent developments in chemically modified wood that will produce a new generation of engineered wood products for building applications. Traditionally, engineered wood products have primarily had a structural purpose, but this review broadens the classification to encompass more aspects of building performance. We begin by providing multiscale design principles of wood products from a computational point of view, followed by discussion of the chemical modifications and structural engineering methods used to modify wood in terms of its mechanical, thermal, optical, and energy-related performance. Additionally, we explore life cycle assessment and techno-economic analysis tools for guiding future research toward environmentally friendly and economically feasible directions for engineered wood products. Finally, this review highlights the current challenges and perspectives on future directions in this research field. By leveraging these new wood-based technologies and analysis tools for the fabrication of carbon-storage materials, it is possible to design sustainable and carbon-negative buildings, which could have a significant impact on mitigating climate change.
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Neuronal-activity-dependent transcription couples sensory experience to adaptive responses of the brain including learning and memory. Mechanisms of activity-dependent gene expression including alterations of the epigenome have been characterized1-8. However, the fundamental question of whether sensory experience remodels chromatin architecture in the adult brain in vivo to induce neural code transformations and learning and memory remains to be addressed. Here we use in vivo calcium imaging, optogenetics and pharmacological approaches to show that granule neuron activation in the anterior dorsal cerebellar vermis has a crucial role in a delay tactile startle learning paradigm in mice. Of note, using large-scale transcriptome and chromatin profiling, we show that activation of the motor-learning-linked granule neuron circuit reorganizes neuronal chromatin including through long-distance enhancer-promoter and transcriptionally active compartment interactions to orchestrate distinct granule neuron gene expression modules. Conditional CRISPR knockout of the chromatin architecture regulator cohesin in anterior dorsal cerebellar vermis granule neurons in adult mice disrupts enhancer-promoter interactions, activity-dependent transcription and motor learning. These findings define how sensory experience patterns chromatin architecture and neural circuit coding in the brain to drive motor learning.
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Retroalimentación Sensorial , Genoma , Aprendizaje/fisiología , Destreza Motora/fisiología , Vías Nerviosas , Plasticidad Neuronal/genética , Animales , Proteínas de Ciclo Celular/metabolismo , Vermis Cerebeloso/citología , Vermis Cerebeloso/metabolismo , Ensamble y Desensamble de Cromatina , Proteínas de Unión al ADN/metabolismo , Elementos de Facilitación Genéticos/genética , Epigénesis Genética , Femenino , Masculino , Ratones , Fibras Musgosas del Hipocampo , Regiones Promotoras Genéticas/genética , Células de Purkinje , Reflejo de SobresaltoRESUMEN
In this Letter, '≥' should be '≤' in the sentence: "Intra-chromosomal reads were further split into short-range reads (≥1 kb) and long-range reads (>1 kb)". This error has been corrected online.An amendment to this paper has been published and can be accessed via a link at the top of the paper.