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1.
Nat Immunol ; 23(1): 122-134, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34937932

RESUMEN

T cell activation, a key early event in the adaptive immune response, is subject to elaborate transcriptional control. In the present study, we examined how the activities of eight major transcription factor (TF) families are integrated to shape the epigenome of naive and activated CD4 and CD8 T cells. By leveraging extensive polymorphisms in evolutionarily divergent mice, we identified the 'heavy lifters' positively influencing chromatin accessibility. Members of Ets, Runx and TCF/Lef TF families occupied the vast majority of accessible chromatin regions, acting as 'housekeepers', 'universal amplifiers' and 'placeholders', respectively, at sites that maintained or gained accessibility upon T cell activation. In addition, a small subset of strongly induced immune response genes displayed a noncanonical TF recruitment pattern. Our study provides a key resource and foundation for the understanding of transcriptional and epigenetic regulation in T cells and offers a new perspective on the hierarchical interactions between critical TFs.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Epigenoma/inmunología , Activación de Linfocitos/inmunología , Factores de Transcripción/inmunología , Inmunidad Adaptativa/inmunología , Animales , Cromatina/inmunología , Epigénesis Genética/inmunología , Regulación de la Expresión Génica/inmunología , Masculino , Ratones
2.
Immunity ; 55(8): 1354-1369.e8, 2022 08 09.
Artículo en Inglés | MEDLINE | ID: mdl-35926508

RESUMEN

FoxP3 is an essential transcription factor (TF) for immunologic homeostasis, but how it utilizes the common forkhead DNA-binding domain (DBD) to perform its unique function remains poorly understood. We here demonstrated that unlike other known forkhead TFs, FoxP3 formed a head-to-head dimer using a unique linker (Runx1-binding region [RBR]) preceding the forkhead domain. Head-to-head dimerization conferred distinct DNA-binding specificity and created a docking site for the cofactor Runx1. RBR was also important for proper folding of the forkhead domain, as truncation of RBR induced domain-swap dimerization of forkhead, which was previously considered the physiological form of FoxP3. Rather, swap-dimerization impaired FoxP3 function, as demonstrated with the disease-causing mutation R337Q, whereas a swap-suppressive mutation largely rescued R337Q-mediated functional impairment. Altogether, our findings suggest that FoxP3 can fold into two distinct dimerization states: head-to-head dimerization representing functional specialization of an ancient DBD and swap dimerization associated with impaired functions.


Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal , Linfocitos T Reguladores , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , ADN , Dimerización , Factores de Transcripción Forkhead/metabolismo , Homeostasis
3.
Cell ; 167(5): 1281-1295.e18, 2016 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-27863244

RESUMEN

Glioblastoma stem cells (GSCs) are implicated in tumor neovascularization, invasiveness, and therapeutic resistance. To illuminate mechanisms governing these hallmark features, we developed a de novo glioblastoma multiforme (GBM) model derived from immortalized human neural stem/progenitor cells (hNSCs) to enable precise system-level comparisons of pre-malignant and oncogene-induced malignant states of NSCs. Integrated transcriptomic and epigenomic analyses uncovered a PAX6/DLX5 transcriptional program driving WNT5A-mediated GSC differentiation into endothelial-like cells (GdECs). GdECs recruit existing endothelial cells to promote peritumoral satellite lesions, which serve as a niche supporting the growth of invasive glioma cells away from the primary tumor. Clinical data reveal higher WNT5A and GdECs expression in peritumoral and recurrent GBMs relative to matched intratumoral and primary GBMs, respectively, supporting WNT5A-mediated GSC differentiation and invasive growth in disease recurrence. Thus, the PAX6/DLX5-WNT5A axis governs the diffuse spread of glioma cells throughout the brain parenchyma, contributing to the lethality of GBM.


Asunto(s)
Glioblastoma/genética , Glioblastoma/patología , Invasividad Neoplásica/genética , Proteína Wnt-5a/genética , Células Endoteliales/citología , Células Endoteliales/metabolismo , Epigenómica , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/metabolismo , Humanos , Células-Madre Neurales/metabolismo , Factor de Transcripción PAX6/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factores de Transcripción/metabolismo
4.
Nature ; 626(8000): 864-873, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38326607

RESUMEN

Macrophage activation is controlled by a balance between activating and inhibitory receptors1-7, which protect normal tissues from excessive damage during infection8,9 but promote tumour growth and metastasis in cancer7,10. Here we report that the Kupffer cell lineage-determining factor ID3 controls this balance and selectively endows Kupffer cells with the ability to phagocytose live tumour cells and orchestrate the recruitment, proliferation and activation of natural killer and CD8 T lymphoid effector cells in the liver to restrict the growth of a variety of tumours. ID3 shifts the macrophage inhibitory/activating receptor balance to promote the phagocytic and lymphoid response, at least in part by buffering the binding of the transcription factors ELK1 and E2A at the SIRPA locus. Furthermore, loss- and gain-of-function experiments demonstrate that ID3 is sufficient to confer this potent anti-tumour activity to mouse bone-marrow-derived macrophages and human induced pluripotent stem-cell-derived macrophages. Expression of ID3 is therefore necessary and sufficient to endow macrophages with the ability to form an efficient anti-tumour niche, which could be harnessed for cell therapy in cancer.


Asunto(s)
Proteínas Inhibidoras de la Diferenciación , Macrófagos del Hígado , Neoplasias , Animales , Humanos , Ratones , Células de la Médula Ósea/citología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Linaje de la Célula , Células Madre Pluripotentes Inducidas/citología , Proteínas Inhibidoras de la Diferenciación/deficiencia , Proteínas Inhibidoras de la Diferenciación/genética , Proteínas Inhibidoras de la Diferenciación/metabolismo , Células Asesinas Naturales/citología , Células Asesinas Naturales/inmunología , Macrófagos del Hígado/citología , Macrófagos del Hígado/inmunología , Macrófagos del Hígado/metabolismo , Hígado/inmunología , Hígado/patología , Activación de Macrófagos , Proteínas de Neoplasias , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/terapia , Fagocitosis
5.
Immunity ; 53(5): 971-984.e5, 2020 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-33176163

RESUMEN

Regulatory T (Treg) cell identity is defined by the lineage-specifying transcription factor (TF) Foxp3. Here we examined mechanisms of Foxp3 function by leveraging naturally occurring genetic variation in wild-derived inbred mice, which enables the identification of DNA sequence motifs driving epigenetic features. Chromatin accessibility, TF binding, and gene expression patterns in resting and activated subsets of Treg cells, conventional CD4 T cells, and cells expressing a Foxp3 reporter null allele revealed that the majority of Foxp3-dependent changes occurred at sites not bound by Foxp3. Chromatin accessibility of these indirect Foxp3 targets depended on the presence of DNA binding motifs for other TFs, including TCF1. Foxp3 expression correlated with decreased TCF1 and reduced accessibility of TCF1-bound chromatin regions. Deleting one copy of the Tcf7 gene recapitulated Foxp3-dependent negative regulation of chromatin accessibility. Thus, Foxp3 defines Treg cell identity in a largely indirect manner by fine-tuning the activity of other major chromatin remodeling TFs such as TCF1.


Asunto(s)
Factores de Transcripción Forkhead/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/patología , Autoinmunidad/genética , Sitios de Unión , Ensamble y Desensamble de Cromatina , Modelos Animales de Enfermedad , Epigénesis Genética , Femenino , Factores de Transcripción Forkhead/genética , Regulación de la Expresión Génica , Inmunohistoquímica , Masculino , Ratones , Motivos de Nucleótidos , Especificidad de Órganos/genética , Especificidad de Órganos/inmunología , Unión Proteica , Transactivadores/metabolismo
6.
Cell ; 158(1): 185-197, 2014 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-24954535

RESUMEN

Activating mutations in KRAS are among the most frequent events in diverse human carcinomas and are particularly prominent in human pancreatic ductal adenocarcinoma (PDAC). An inducible Kras(G12D)-driven mouse model of PDAC has established a critical role for sustained Kras(G12D) expression in tumor maintenance, providing a model to determine the potential for and the underlying mechanisms of Kras(G12D)-independent PDAC recurrence. Here, we show that some tumors undergo spontaneous relapse and are devoid of Kras(G12D) expression and downstream canonical MAPK signaling and instead acquire amplification and overexpression of the transcriptional coactivator Yap1. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving Kras(G12D)-independent tumor maintenance. The Yap1/Tead2 complex acts cooperatively with E2F transcription factors to activate a cell cycle and DNA replication program. Our studies, along with corroborating evidence from human PDAC models, portend a novel mechanism of escape from oncogenic Kras addiction in PDAC.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adenocarcinoma/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Neoplasias Pancreáticas/metabolismo , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Adenocarcinoma/patología , Animales , Carcinoma Ductal Pancreático/patología , Ciclo Celular , Proteínas de Ciclo Celular , Línea Celular Tumoral , Replicación del ADN , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Factores de Transcripción E2F/metabolismo , Humanos , Ratones , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas/metabolismo , Factores de Transcripción de Dominio TEA , Factores de Transcripción/metabolismo , Proteínas Señalizadoras YAP , Proteínas ras/metabolismo
8.
Nature ; 616(7957): 452-456, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36858074

RESUMEN

Some active asteroids have been proposed to be formed as a result of impact events1. Because active asteroids are generally discovered by chance only after their tails have fully formed, the process of how impact ejecta evolve into a tail has, to our knowledge, not been directly observed. The Double Asteroid Redirection Test (DART) mission of NASA2, in addition to having successfully changed the orbital period of Dimorphos3, demonstrated the activation process of an asteroid resulting from an impact under precisely known conditions. Here we report the observations of the DART impact ejecta with the Hubble Space Telescope from impact time T + 15 min to T + 18.5 days at spatial resolutions of around 2.1 km per pixel. Our observations reveal the complex evolution of the ejecta, which are first dominated by the gravitational interaction between the Didymos binary system and the ejected dust and subsequently by solar radiation pressure. The lowest-speed ejecta dispersed through a sustained tail that had a consistent morphology with previously observed asteroid tails thought to be produced by an impact4,5. The evolution of the ejecta after the controlled impact experiment of DART thus provides a framework for understanding the fundamental mechanisms that act on asteroids disrupted by a natural impact1,6.

9.
Mol Cell ; 81(11): 2477-2493.e10, 2021 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-33891860

RESUMEN

CD8 T cells play an essential role in defense against viral and bacterial infections and in tumor immunity. Deciphering T cell loss of functionality is complicated by the conspicuous heterogeneity of CD8 T cell states described across experimental and clinical settings. By carrying out a unified analysis of over 300 assay for transposase-accessible chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-seq) experiments from 12 studies of CD8 T cells in cancer and infection, we defined a shared differentiation trajectory toward dysfunction and its underlying transcriptional drivers and revealed a universal early bifurcation of functional and dysfunctional T cell states across models. Experimental dissection of acute and chronic viral infection using single-cell ATAC (scATAC)-seq and allele-specific single-cell RNA (scRNA)-seq identified state-specific drivers and captured the emergence of similar TCF1+ progenitor-like populations at an early branch point, at which functional and dysfunctional T cells diverge. Our atlas of CD8 T cell states will facilitate mechanistic studies of T cell immunity and translational efforts.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Epigénesis Genética/inmunología , Inmunidad Celular , Coriomeningitis Linfocítica/genética , Neoplasias/genética , Factores de Transcripción/genética , Enfermedad Aguda , Atlas como Asunto , Linfocitos T CD8-positivos/clasificación , Linfocitos T CD8-positivos/patología , Cromatina/química , Cromatina/inmunología , Enfermedad Crónica , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Activación de Linfocitos , Coriomeningitis Linfocítica/inmunología , Coriomeningitis Linfocítica/patología , Virus de la Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/patogenicidad , Neoplasias/inmunología , Neoplasias/patología , Análisis de Componente Principal , Análisis de la Célula Individual , Factores de Transcripción/clasificación , Factores de Transcripción/inmunología , Transcripción Genética , Transposasas/genética , Transposasas/metabolismo
10.
Immunity ; 50(5): 1202-1217.e7, 2019 05 21.
Artículo en Inglés | MEDLINE | ID: mdl-31027997

RESUMEN

Stable changes in chromatin states and gene expression in cells of the immune system form the basis for memory of infections and other challenges. Here, we used naturally occurring cis-regulatory variation in wild-derived inbred mouse strains to explore the mechanisms underlying long-lasting versus transient gene regulation in CD8 T cells responding to acute viral infection. Stably responsive DNA elements were characterized by dramatic and congruent chromatin remodeling events affecting multiple neighboring sites and required distinct transcription factor (TF) binding motifs for their accessibility. Specifically, we found that cooperative recruitment of T-box and Runx family transcription factors to shared targets mediated stable chromatin remodeling upon T cell activation. Our observations provide insights into the molecular mechanisms driving virus-specific CD8 T cell responses and suggest a general mechanism for the formation of transcriptional and epigenetic memory applicable to other immune and non-immune cells.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Ensamble y Desensamble de Cromatina/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Regulación de la Expresión Génica/genética , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Proteínas de Dominio T Box/genética , Animales , Linfocitos T CD8-positivos/virología , Línea Celular , Cromatina/genética , Epigénesis Genética/genética , Femenino , Expresión Génica/genética , Regulación de la Expresión Génica/inmunología , Variación Genética , Memoria Inmunológica/genética , Memoria Inmunológica/inmunología , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Coriomeningitis Linfocítica/virología , Masculino , Ratones , Ratones Endogámicos C57BL , Transcripción Genética/genética
11.
Nat Immunol ; 16(8): 838-849, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26147685

RESUMEN

Interferon-γ (IFN-γ) primes macrophages for enhanced microbial killing and inflammatory activation by Toll-like receptors (TLRs), but little is known about the regulation of cell metabolism or mRNA translation during this priming. We found that IFN-γ regulated the metabolism and mRNA translation of human macrophages by targeting the kinases mTORC1 and MNK, both of which converge on the selective regulator of translation initiation eIF4E. Physiological downregulation of mTORC1 by IFN-γ was associated with autophagy and translational suppression of repressors of inflammation such as HES1. Genome-wide ribosome profiling in TLR2-stimulated macrophages showed that IFN-γ selectively modulated the macrophage translatome to promote inflammation, further reprogram metabolic pathways and modulate protein synthesis. These results show that IFN-γ-mediated metabolic reprogramming and translational regulation are key components of classical inflammatory macrophage activation.


Asunto(s)
Interferón gamma/inmunología , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Biosíntesis de Proteínas/inmunología , ARN Mensajero/inmunología , Secuencia de Bases , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/inmunología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Western Blotting , Células Cultivadas , Factor 4E Eucariótico de Iniciación/genética , Factor 4E Eucariótico de Iniciación/inmunología , Factor 4E Eucariótico de Iniciación/metabolismo , Perfilación de la Expresión Génica , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/inmunología , Proteínas de Homeodominio/metabolismo , Humanos , Interferón gamma/farmacología , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/inmunología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Activación de Macrófagos/efectos de los fármacos , Activación de Macrófagos/genética , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina , MicroARNs/genética , Microscopía Fluorescente , Complejos Multiproteicos/genética , Complejos Multiproteicos/inmunología , Complejos Multiproteicos/metabolismo , Biosíntesis de Proteínas/efectos de los fármacos , Biosíntesis de Proteínas/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/inmunología , Proteínas Serina-Treonina Quinasas/metabolismo , Interferencia de ARN , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transducción de Señal/inmunología , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/inmunología , Serina-Treonina Quinasas TOR/metabolismo , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/inmunología , Receptor Toll-Like 2/metabolismo , Factor de Transcripción HES-1
12.
Nature ; 581(7807): 204-208, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32405000

RESUMEN

It has been speculated that brain activities might directly control adaptive immune responses in lymphoid organs, although there is little evidence for this. Here we show that splenic denervation in mice specifically compromises the formation of plasma cells during a T cell-dependent but not T cell-independent immune response. Splenic nerve activity enhances plasma cell production in a manner that requires B-cell responsiveness to acetylcholine mediated by the α9 nicotinic receptor, and T cells that express choline acetyl transferase1,2 probably act as a relay between the noradrenergic nerve and acetylcholine-responding B cells. We show that neurons in the central nucleus of the amygdala (CeA) and the paraventricular nucleus (PVN) that express corticotropin-releasing hormone (CRH) are connected to the splenic nerve; ablation or pharmacogenetic inhibition of these neurons reduces plasma cell formation, whereas pharmacogenetic activation of these neurons increases plasma cell abundance after immunization. In a newly developed behaviour regimen, mice are made to stand on an elevated platform, leading to activation of CeA and PVN CRH neurons and increased plasma cell formation. In immunized mice, the elevated platform regimen induces an increase in antigen-specific IgG antibodies in a manner that depends on CRH neurons in the CeA and PVN, an intact splenic nerve, and B cell expression of the α9 acetylcholine receptor. By identifying a specific brain-spleen neural connection that autonomically enhances humoral responses and demonstrating immune stimulation by a bodily behaviour, our study reveals brain control of adaptive immunity and suggests the possibility to enhance immunocompetency by behavioural intervention.


Asunto(s)
Conducta Animal/fisiología , Encéfalo/fisiología , Inmunidad Humoral/inmunología , Bazo/inmunología , Bazo/inervación , Acetilcolina/metabolismo , Acetilcolina/farmacología , Neuronas Adrenérgicas/metabolismo , Amígdala del Cerebelo/citología , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Animales , Encéfalo/citología , Encéfalo/efectos de los fármacos , Colina O-Acetiltransferasa/metabolismo , Hormona Liberadora de Corticotropina/metabolismo , Hemocianinas/inmunología , Inmunoglobulina G/inmunología , Activación de Linfocitos , Masculino , Ratones , Núcleo Hipotalámico Paraventricular/citología , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/metabolismo , Células Plasmáticas/citología , Células Plasmáticas/efectos de los fármacos , Células Plasmáticas/inmunología , Receptores Nicotínicos/deficiencia , Receptores Nicotínicos/metabolismo , Bazo/citología , Bazo/efectos de los fármacos , Estrés Psicológico/inmunología , Estrés Psicológico/metabolismo , Linfocitos T/inmunología
13.
Nature ; 588(7839): 642-647, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33177713

RESUMEN

Gene-expression programs define shared and species-specific phenotypes, but their evolution remains largely uncharacterized beyond the transcriptome layer1. Here we report an analysis of the co-evolution of translatomes and transcriptomes using ribosome-profiling and matched RNA-sequencing data for three organs (brain, liver and testis) in five mammals (human, macaque, mouse, opossum and platypus) and a bird (chicken). Our within-species analyses reveal that translational regulation is widespread in the different organs, in particular across the spermatogenic cell types of the testis. The between-species divergence in gene expression is around 20% lower at the translatome layer than at the transcriptome layer owing to extensive buffering between the expression layers, which especially preserved old, essential and housekeeping genes. Translational upregulation specifically counterbalanced global dosage reductions during the evolution of sex chromosomes and the effects of meiotic sex-chromosome inactivation during spermatogenesis. Despite the overall prevalence of buffering, some genes evolved faster at the translatome layer-potentially indicating adaptive changes in expression; testis tissue shows the highest fraction of such genes. Further analyses incorporating mass spectrometry proteomics data establish that the co-evolution of transcriptomes and translatomes is reflected at the proteome layer. Together, our work uncovers co-evolutionary patterns and associated selective forces across the expression layers, and provides a resource for understanding their interplay in mammalian organs.


Asunto(s)
Evolución Molecular , Mamíferos/genética , Biosíntesis de Proteínas , Transcriptoma/genética , Animales , Encéfalo/metabolismo , Pollos/genética , Femenino , Genes Ligados a X/genética , Humanos , Hígado/metabolismo , Macaca/genética , Masculino , Ratones , Zarigüeyas/genética , Especificidad de Órganos/genética , Ornitorrinco/genética , Biosíntesis de Proteínas/genética , RNA-Seq , Ribosomas/metabolismo , Cromosomas Sexuales/genética , Especificidad de la Especie , Espermatogénesis/genética , Testículo/metabolismo , Regulación hacia Arriba
14.
Cell ; 140(4): 579-89, 2010 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-20178749

RESUMEN

Initially acquired memory dissipates rapidly if not consolidated. Such memory decay is thought to result either from the inherently labile nature of newly acquired memories or from interference by subsequently attained information. Here we report that a small G protein Rac-dependent forgetting mechanism contributes to both passive memory decay and interference-induced forgetting in Drosophila. Inhibition of Rac activity leads to slower decay of early memory, extending it from a few hours to more than one day, and to blockade of interference-induced forgetting. Conversely, elevated Rac activity in mushroom body neurons accelerates memory decay. This forgetting mechanism does not affect memory acquisition and is independent of Rutabaga adenylyl cyclase-mediated memory formation mechanisms. Endogenous Rac activation is evoked on different time scales during gradual memory loss in passive decay and during acute memory removal in reversal learning. We suggest that Rac's role in actin cytoskeleton remodeling may contribute to memory erasure.


Asunto(s)
Proteínas de Drosophila/fisiología , Drosophila/fisiología , Proteínas de Unión al GTP rac/fisiología , Factores Despolimerizantes de la Actina/genética , Animales , Memoria/fisiología , Trastornos de la Memoria , Cuerpos Pedunculados
15.
Exp Cell Res ; 436(1): 113956, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38341081

RESUMEN

Patients with hepatocellular carcinoma (HCC) are vulnerable to drug resistance. Although drug resistance has been taken much attention to HCC therapy, little is known of regorafenib and regorafenib resistance (RR). This study aimed to determine the drug resistance pattern and the role of RhoA in RR. Two regorafenib-resistant cell lines were constructed based on Huh7 and Hep3B cell lines. In vitro and in vivo assays were conducted to study RhoA expression, the activity of Hippo signaling pathway and cancer stem cell (CSC) traits. The data showed that RhoA was highly expressed, Hippo signaling was hypoactivated and CSC traits were more prominent in RR cells. Inhibiting RhoA could reverse RR, and the alliance of RhoA inhibition and regorafenib synergistically attenuated CSC phenotype. Furthermore, inhibiting LARG/RhoA increased Kibra/NF2 complex formation, prevented YAP from shuttling into the nucleus and repressed CD44 mRNA expression. Clinically, the high expression of RhoA correlated with poor prognosis. LARG, RhoA, YAP1 and CD44 show positive correlation with each other. Thus, inhibition of RhoGEF/RhoA has the potential to reverse RR and repress CSC phenotype in HCC.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Piridinas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Vía de Señalización Hippo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Compuestos de Fenilurea/farmacología
16.
Cereb Cortex ; 34(6)2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38869374

RESUMEN

The central sulcus divides the primary motor and somatosensory cortices in many anthropoid primate brains. Differences exist in the surface area and depth of the central sulcus along the dorso-ventral plane in great apes and humans compared to other primate species. Within hominid species, there are variations in the depth and aspect of their hand motor area, or knob, within the precentral gyrus. In this study, we used post-image analyses on magnetic resonance images to characterize the central sulcus shape of humans, chimpanzees (Pan troglodytes), gorillas (Gorilla gorilla), and orangutans (Pongo pygmaeus and Pongo abelii). Using these data, we examined the morphological variability of central sulcus in hominids, focusing on the hand region, a significant change in human evolution. We show that the central sulcus shape differs between great ape species, but all show similar variations in the location of their hand knob. However, the prevalence of the knob location along the dorso-ventral plane and lateralization differs between species and the presence of a second ventral motor knob seems to be unique to humans. Humans and orangutans exhibit the most similar and complex central sulcus shapes. However, their similarities may reflect divergent evolutionary processes related to selection for different positional and habitual locomotor functions.


Asunto(s)
Evolución Biológica , Gorilla gorilla , Hominidae , Imagen por Resonancia Magnética , Corteza Motora , Pan troglodytes , Filogenia , Animales , Humanos , Masculino , Pan troglodytes/anatomía & histología , Pan troglodytes/fisiología , Gorilla gorilla/anatomía & histología , Gorilla gorilla/fisiología , Femenino , Corteza Motora/anatomía & histología , Corteza Motora/fisiología , Corteza Motora/diagnóstico por imagen , Hominidae/anatomía & histología , Hominidae/fisiología , Adulto , Mano/fisiología , Mano/anatomía & histología , Adulto Joven , Pongo pygmaeus/anatomía & histología , Pongo pygmaeus/fisiología , Especificidad de la Especie , Pongo abelii/anatomía & histología , Pongo abelii/fisiología
17.
Proc Natl Acad Sci U S A ; 119(15): e2116844119, 2022 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-35377811

RESUMEN

In pathological or artificial conditions, memory can be formed as silenced engrams that are unavailable for retrieval by presenting conditioned stimuli but can be artificially switched into the latent state so that natural recall is allowed. However, it remains unclear whether such different states of engrams bear any physiological significance and can be switched through physiological mechanisms. Here, we show that an acute social reward experience switches the silent memory engram into the latent state. Conversely, an acute social stress causes transient forgetting via turning a latent memory engram into a silent state. Such emotion-driven bidirectional switching between latent and silent states of engrams is mediated through regulation of Rac1 activity­dependent reversible forgetting in the hippocampus, as stress-activated Rac1 suppresses retrieval, while reward recovers silenced memory under amnesia by inhibiting Rac1. Thus, data presented reveal hippocampal Rac1 activity as the basis for emotion-mediated switching between latent and silent engrams to achieve emotion-driven behavioral flexibility.


Asunto(s)
Región CA1 Hipocampal , Recuerdo Mental , Conducta Social , Proteína de Unión al GTP rac1 , Animales , Región CA1 Hipocampal/enzimología , Señales (Psicología) , Recuerdo Mental/fisiología , Ratones , Neuronas/enzimología , Recompensa , Proteína de Unión al GTP rac1/metabolismo
18.
Proc Natl Acad Sci U S A ; 119(50): e2122494119, 2022 12 13.
Artículo en Inglés | MEDLINE | ID: mdl-36469777

RESUMEN

Physical interfaces widely exist in nature and engineering. Although the formation of passive interfaces is well elucidated, the physical principles governing active interfaces remain largely unknown. Here, we combine simulation, theory, and cell-based experiment to investigate the evolution of an active-active interface. We adopt a biphasic framework of active nematic liquid crystals. We find that long-lived topological defects mechanically energized by activity display unanticipated dynamics nearby the interface, where defects perform "U-turns" to keep away from the interface, push the interface to develop local fingers, or penetrate the interface to enter the opposite phase, driving interfacial morphogenesis and cross-interface defect transport. We identify that the emergent interfacial morphodynamics stems from the instability of the interface and is further driven by the activity-dependent defect-interface interactions. Experiments of interacting multicellular monolayers with extensile and contractile differences in cell activity have confirmed our predictions. These findings reveal a crucial role of topological defects in active-active interfaces during, for example, boundary formation and tissue competition that underlie organogenesis and clinically relevant disorders.


Asunto(s)
Cristales Líquidos , Cristales Líquidos/química , Simulación por Computador
19.
Proc Natl Acad Sci U S A ; 119(6)2022 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-35101976

RESUMEN

Blood-brain barrier (BBB) breakdown and inflammation occurring at the BBB have a key, mainly a deleterious role in the pathophysiology of ischemic stroke. Neddylation is a ubiquitylation-like pathway that is critical in various cellular functions by conjugating neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) to target proteins. However, the roles of neddylation pathway in ischemic stroke remain elusive. Here, we report that NEDD8 conjugation increased during acute phase after ischemic stroke and was present in intravascular and intraparenchymal neutrophils. Inhibition of neddylation by MLN4924, also known as pevonedistat, inactivated cullin-RING E3 ligase (CRL), and reduced brain infarction and improved functional outcomes. MLN4924 treatment induced the accumulation of the CRL substrate neurofibromatosis 1 (NF1). By using virus-mediated NF1 silencing, we show that NF1 knockdown abolished MLN4924-dependent inhibition of neutrophil trafficking. These effects were mediated through activation of endothelial P-selectin and intercellular adhesion molecule-1 (ICAM-1), and blocking antibodies against P-selectin or anti-ICAM-1 antibodies reversed NF1 silencing-induced increase in neutrophil infiltration in MLN4924-treated mice. Furthermore, we found that NF1 silencing blocked MLN4924-afforded BBB protection and neuroprotection through activation of protein kinase C δ (PKCδ), myristoylated alanine-rich C-kinase substrate (MARCKS), and myosin light chain (MLC) in cerebral microvessels after ischemic stroke, and treatment of mice with the PKCδ inhibitor rottlerin reduced this increased BBB permeability. Our study demonstrated that increased neddylation promoted neutrophil trafficking and thus exacerbated injury of the BBB and stroke outcomes. We suggest that the neddylation inhibition may be beneficial in ischemic stroke.


Asunto(s)
Lesiones Encefálicas , Isquemia Encefálica , Ciclopentanos/farmacología , Proteína NEDD8/metabolismo , Proteínas del Tejido Nervioso , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Pirimidinas/farmacología , Ubiquitina-Proteína Ligasas , Animales , Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/enzimología , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/enzimología , Masculino , Ratones , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/metabolismo , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Ubiquitina-Proteína Ligasas/metabolismo
20.
J Infect Dis ; 230(1): 5-14, 2024 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-39052699

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes a variety of clinical manifestations, many of which originate from altered immune responses, either locally or systemically. Immune cell cross-talk occurs mainly in lymphoid organs. However, systemic cell interaction specific to coronavirus disease 2019 has not been well characterized. Here, by employing single-cell RNA sequencing and imaging flow cytometry analysis, we unraveled, in peripheral blood, a heterogeneous group of cell complexes formed by the adherence of CD14+ monocytes to different cytotoxic lymphocytes, including SARS-CoV-2-specific CD8+ T cells, γδ T cells, and natural killer T cells. These lymphocytes attached to CD14+ monocytes that showed enhanced inflammasome activation and pyroptosis-induced cell death in progression stage; in contrast, in the convalescent phase, CD14+ monocytes with elevated antigen presentation potential were targeted by cytotoxic lymphocytes, thereby restricting the excessive immune activation. Collectively, our study reports previously unrecognized cell-cell interplay in the SARS-CoV-2-specific immune response, providing new insight into the intricacy of dynamic immune cell interaction representing antiviral defense.


Asunto(s)
COVID-19 , Monocitos , SARS-CoV-2 , Linfocitos T Citotóxicos , Humanos , COVID-19/inmunología , COVID-19/virología , Monocitos/inmunología , SARS-CoV-2/inmunología , Linfocitos T Citotóxicos/inmunología , Linfocitos T CD8-positivos/inmunología , Receptores de Lipopolisacáridos/metabolismo , Inflamasomas/inmunología , Piroptosis/inmunología , Células T Asesinas Naturales/inmunología , Masculino , Comunicación Celular/inmunología , Análisis de la Célula Individual
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