RESUMEN
Transforming growth factor ß (TGF-ß) is a key cytokine regulating the development, activation, proliferation, differentiation, and death of T cells. In CD4+ T cells, TGF-ß maintains the quiescence and controls the activation of naive T cells. While inhibiting the differentiation and function of Th1 and Th2 cells, TGF-ß promotes the differentiation of Th17 and Th9 cells. TGF-ß is required for the induction of Foxp3 in naive T cells and the development of regulatory T cells. TGF-ß is crucial in the differentiation of tissue-resident memory CD8+ T cells and their retention in the tissue, whereas it suppresses effector T cell function. In addition, TGF-ß also regulates the generation or function of natural killer T cells, γδ T cells, innate lymphoid cells, and gut intraepithelial lymphocytes. Here I highlight the major findings and recent advances in our understanding of TGF-ß regulation of T cells and provide a personal perspective of the field.
Asunto(s)
Linfocitos T CD8-positivos , Factor de Crecimiento Transformador beta1 , Animales , Humanos , Diferenciación Celular , Inmunidad Innata , Linfocitos/metabolismo , Linfocitos T Reguladores/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Gamete formation and subsequent offspring development often involve extended phases of suspended cellular development or even dormancy. How cells adapt to recover and resume growth remains poorly understood. Here, we visualized budding yeast cells undergoing meiosis by cryo-electron tomography (cryoET) and discovered elaborate filamentous assemblies decorating the nucleus, cytoplasm, and mitochondria. To determine filament composition, we developed a "filament identification" (FilamentID) workflow that combines multiscale cryoET/cryo-electron microscopy (cryoEM) analyses of partially lysed cells or organelles. FilamentID identified the mitochondrial filaments as being composed of the conserved aldehyde dehydrogenase Ald4ALDH2 and the nucleoplasmic/cytoplasmic filaments as consisting of acetyl-coenzyme A (CoA) synthetase Acs1ACSS2. Structural characterization further revealed the mechanism underlying polymerization and enabled us to genetically perturb filament formation. Acs1 polymerization facilitates the recovery of chronologically aged spores and, more generally, the cell cycle re-entry of starved cells. FilamentID is broadly applicable to characterize filaments of unknown identity in diverse cellular contexts.
Asunto(s)
Gametogénesis , Mitocondrias , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Aldehído Deshidrogenasa/metabolismo , Aldehído Deshidrogenasa/química , Núcleo Celular/metabolismo , Núcleo Celular/ultraestructura , Coenzima A Ligasas/metabolismo , Microscopía por Crioelectrón , Citoplasma/metabolismo , Tomografía con Microscopio Electrónico , Meiosis , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/ultraestructura , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Esporas Fúngicas/metabolismo , Modelos Moleculares , Estructura Cuaternaria de ProteínaRESUMEN
Cellular homeostasis requires the robust control of biomolecule concentrations, but how do millions of mRNAs coordinate their stoichiometries in the face of dynamic translational changes? Here, we identified a two-tiered mechanism controlling mRNA:mRNA and mRNA:protein stoichiometries where mRNAs super-assemble into condensates with buffering capacity and sorting selectivity through phase-transition mechanisms. Using C. elegans oogenesis arrest as a model, we investigated the transcriptome cytosolic reorganization through the sequencing of RNA super-assemblies coupled with single mRNA imaging. Tightly repressed mRNAs self-assembled into same-sequence nanoclusters that further co-assembled into multiphase condensates. mRNA self-sorting was concentration dependent, providing a self-buffering mechanism that is selective to sequence identity and controls mRNA:mRNA stoichiometries. The cooperative sharing of limiting translation repressors between clustered mRNAs prevented the disruption of mRNA:repressor stoichiometries in the cytosol. Robust control of mRNA:mRNA and mRNA:protein stoichiometries emerges from mRNA self-demixing and cooperative super-assembly into multiphase multiscale condensates with dynamic storage capacity.
Asunto(s)
Condensados Biomoleculares , Caenorhabditis elegans , ARN Mensajero , Animales , Caenorhabditis elegans/citología , Caenorhabditis elegans/metabolismo , Oogénesis , Biosíntesis de Proteínas , Transporte de ARN , ARN Mensajero/química , ARN Mensajero/metabolismo , Proteínas/química , Proteínas/metabolismo , Condensados Biomoleculares/química , Condensados Biomoleculares/metabolismoRESUMEN
Piloerection (goosebumps) requires concerted actions of the hair follicle, the arrector pili muscle (APM), and the sympathetic nerve, providing a model to study interactions across epithelium, mesenchyme, and nerves. Here, we show that APMs and sympathetic nerves form a dual-component niche to modulate hair follicle stem cell (HFSC) activity. Sympathetic nerves form synapse-like structures with HFSCs and regulate HFSCs through norepinephrine, whereas APMs maintain sympathetic innervation to HFSCs. Without norepinephrine signaling, HFSCs enter deep quiescence by down-regulating the cell cycle and metabolism while up-regulating quiescence regulators Foxp1 and Fgf18. During development, HFSC progeny secretes Sonic Hedgehog (SHH) to direct the formation of this APM-sympathetic nerve niche, which in turn controls hair follicle regeneration in adults. Our results reveal a reciprocal interdependence between a regenerative tissue and its niche at different stages and demonstrate sympathetic nerves can modulate stem cells through synapse-like connections and neurotransmitters to couple tissue production with demands.
Asunto(s)
Nervio Accesorio/fisiología , Folículo Piloso/citología , Cabello/crecimiento & desarrollo , Proteínas Hedgehog/metabolismo , Norepinefrina/metabolismo , Transducción de Señal/genética , Células Madre/metabolismo , Células Madre/fisiología , Nervio Accesorio/citología , Animales , Ciclo Celular/genética , Frío , Femenino , Factores de Crecimiento de Fibroblastos/metabolismo , Factores de Transcripción Forkhead/metabolismo , Perfilación de la Expresión Génica , Cabello/citología , Cabello/fisiología , Folículo Piloso/crecimiento & desarrollo , Folículo Piloso/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Piloerección , RNA-Seq , Receptores Adrenérgicos beta 2/deficiencia , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Proteínas Represoras/metabolismo , Transducción de Señal/efectos de los fármacos , Receptor Smoothened/genética , Receptor Smoothened/metabolismo , Nicho de Células Madre , Células Madre/citología , Sistema Nervioso Simpático/citología , Sistema Nervioso Simpático/fisiología , Sinapsis/fisiologíaRESUMEN
The function of somatic stem cells declines with age. Understanding the molecular underpinnings of this decline is key to counteract age-related disease. Here, we report a dramatic drop in the neural stem cells (NSCs) number in the aging murine brain. We find that this smaller stem cell reservoir is protected from full depletion by an increase in quiescence that makes old NSCs more resistant to regenerate the injured brain. Once activated, however, young and old NSCs show similar proliferation and differentiation capacity. Single-cell transcriptomics of NSCs indicate that aging changes NSCs minimally. In the aging brain, niche-derived inflammatory signals and the Wnt antagonist sFRP5 induce quiescence. Indeed, intervention to neutralize them increases activation of old NSCs during homeostasis and following injury. Our study identifies quiescence as a key feature of old NSCs imposed by the niche and uncovers ways to activate NSCs to repair the aging brain.
Asunto(s)
Encéfalo/fisiología , Factores de Edad , Animales , Encéfalo/citología , Diferenciación Celular/fisiología , División Celular/fisiología , Proliferación Celular/fisiología , Senescencia Celular/fisiología , Homeostasis , Masculino , Ratones , Ratones Endogámicos C57BL , Regeneración Nerviosa , Células-Madre Neurales/citología , Células-Madre Neurales/fisiología , Neurogénesis , Nicho de Células MadreRESUMEN
Central to the classical hematopoietic stem cell (HSC) paradigm is the concept that the maintenance of blood cell numbers is exclusively executed by a discrete physical entity: the transplantable HSC. The HSC paradigm has served as a stereotypic template in stem cell biology, yet the search for rare, hardwired professional stem cells has remained futile in most other tissues. In a more open approach, the focus on the search for stem cells as a physical entity may need to be replaced by the search for stem cell function, operationally defined as the ability of an organ to replace lost cells. The nature of such a cell may be different under steady state conditions and during tissue repair. We discuss emerging examples including the renewal strategies of the skin, gut epithelium, liver, lung, and mammary gland in comparison with those of the hematopoietic system. While certain key housekeeping and developmental signaling pathways are shared between different stem cell systems, there may be no general, deeper principles underlying the renewal mechanisms of the various individual tissues.
Asunto(s)
Células Madre Adultas/citología , Células Madre Adultas/fisiología , Animales , Diferenciación Celular , Linaje de la Célula , Proliferación Celular , Autorrenovación de las Células , Femenino , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/fisiología , Humanos , Masculino , Modelos Biológicos , Fenotipo , Transducción de SeñalRESUMEN
Most cells live in environments that are permissive for proliferation only a small fraction of the time. Entering quiescence enables cells to survive long periods of nondivision and reenter the cell cycle when signaled to do so. Here, we describe what is known about the molecular basis for quiescence in Saccharomyces cerevisiae, with emphasis on the progress made in the last decade. Quiescence is triggered by depletion of an essential nutrient. It begins well before nutrient exhaustion, and there is extensive crosstalk between signaling pathways to ensure that all proliferation-specific activities are stopped when any one essential nutrient is limiting. Every aspect of gene expression is modified to redirect and conserve resources. Chromatin structure and composition change on a global scale, from histone modifications to three-dimensional chromatin structure. Thousands of proteins and RNAs aggregate, forming unique structures with unique fates, and the cytoplasm transitions to a glass-like state.
Asunto(s)
Procesamiento Proteico-Postraduccional , Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Ciclo Celular/genética , Citoplasma , Cromatina/genéticaRESUMEN
Cellular quiescence-reversible exit from the cell cycle-is an important feature of many cell types important for organismal health. Quiescent cells activate protective mechanisms that allow their persistence in the absence of growth and division for long periods of time. Aging and cellular dysfunction compromise the survival and re-activation of quiescent cells over time. Counteracting this decline are two interconnected organelles that lie at opposite ends of the secretory pathway: the endoplasmic reticulum and lysosomes. In this review, we highlight recent studies exploring the roles of these two organelles in quiescent cells from diverse contexts and speculate on potential other roles they may play, such as through organelle contact sites. Finally, we discuss emerging models of cellular quiescence, utilizing new cell culture systems and model organisms, that are suited to the mechanistic investigation of the functions of these organelles in quiescent cells.
Asunto(s)
Retículo Endoplásmico , Lisosomas , Ciclo Celular , División Celular , Retículo Endoplásmico/metabolismo , Homeostasis , Lisosomas/metabolismoRESUMEN
The DREAM complex orchestrates cell quiescence and the cell cycle. However, how the DREAM complex is deregulated in cancer remains elusive. Here, we report that PAF (PCLAF/KIAA0101) drives cell quiescence exit to promote lung tumorigenesis by remodeling the DREAM complex. PAF is highly expressed in lung adenocarcinoma (LUAD) and is associated with poor prognosis. Importantly, Paf knockout markedly suppressed LUAD development in mouse models. PAF depletion induced LUAD cell quiescence and growth arrest. PAF is required for the global expression of cell-cycle genes controlled by the repressive DREAM complex. Mechanistically, PAF inhibits DREAM complex formation by binding to RBBP4, a core DREAM subunit, leading to transactivation of DREAM target genes. Furthermore, pharmacological mimicking of PAF-depleted transcriptomes inhibited LUAD tumor growth. Our results unveil how the PAF-remodeled DREAM complex bypasses cell quiescence to promote lung tumorigenesis and suggest that the PAF-DREAM axis may be a therapeutic vulnerability in lung cancer.
Asunto(s)
Carcinogénesis/genética , Proteínas de Unión al ADN/genética , Proteínas de Interacción con los Canales Kv/genética , Neoplasias Pulmonares/genética , Pulmón/patología , Proteínas Represoras/genética , Células A549 , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Animales , Carcinogénesis/patología , División Celular/genética , Línea Celular , Línea Celular Tumoral , Proliferación Celular/genética , Femenino , Humanos , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ratones Desnudos , Células 3T3 NIH , Activación Transcripcional/genética , Transcriptoma/genéticaRESUMEN
There is increasing evidence demonstrating that adult neural stem cells (NSCs) are a cell of origin of glioblastoma. Here we analyzed the interaction between transformed and wild-type NSCs isolated from the adult mouse subventricular zone niche. We found that transformed NSCs are refractory to quiescence-inducing signals. Unexpectedly, we also demonstrated that these cells induce quiescence in surrounding wild-type NSCs in a cell-cell contact and Notch signaling-dependent manner. Our findings therefore suggest that oncogenic mutations are propagated in the stem cell niche not just through cell-intrinsic advantages, but also by outcompeting neighboring stem cells through repression of their proliferation.
Asunto(s)
Glioblastoma/fisiopatología , Células Madre Neoplásicas/fisiología , Células-Madre Neurales/citología , Receptores Notch/genética , Transducción de Señal/fisiología , Animales , Comunicación Celular/fisiología , Proliferación Celular/fisiología , Células Cultivadas , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Glioblastoma/genética , Ventrículos Laterales/citología , Ratones , Células Madre Neoplásicas/citología , Células-Madre Neurales/fisiologíaRESUMEN
Through recurrent bouts synchronous with the hair cycle, quiescent melanocyte stem cells (McSCs) become activated to generate proliferative progeny that differentiate into pigment-producing melanocytes. The signaling factors orchestrating these events remain incompletely understood. Here, we use single-cell RNA sequencing with comparative gene expression analysis to elucidate the transcriptional dynamics of McSCs through quiescence, activation, and melanocyte maturation. Unearthing converging signs of increased WNT and BMP signaling along this progression, we endeavored to understand how these pathways are integrated. Employing conditional lineage-specific genetic ablation studies in mice, we found that loss of BMP signaling in the lineage leads to hair graying due to a block in melanocyte maturation. We show that interestingly, BMP signaling functions downstream from activated McSCs and maintains WNT effector, transcription factor LEF1. Employing pseudotime analysis, genetics, and chromatin landscaping, we show that following WNT-mediated activation of McSCs, BMP and WNT pathways collaborate to trigger the commitment of proliferative progeny by fueling LEF1- and MITF-dependent differentiation. Our findings shed light upon the signaling interplay and timing of cues that orchestrate melanocyte lineage progression in the hair follicle and underscore a key role for BMP signaling in driving complete differentiation.
Asunto(s)
Proteínas Morfogenéticas Óseas/fisiología , Diferenciación Celular/genética , Melanocitos/citología , Transducción de Señal/genética , Células Madre/citología , Animales , Linaje de la Célula/genética , Perfilación de la Expresión Génica , Factor de Unión 1 al Potenciador Linfoide/metabolismo , Ratones , Factor de Transcripción Asociado a Microftalmía/metabolismo , Análisis de la Célula IndividualRESUMEN
Most adult hippocampal neural stem cells (NSCs) remain quiescent, with only a minor portion undergoing active proliferation and neurogenesis. The molecular mechanisms that trigger the transition from quiescence to activation are still poorly understood. Here, we found the activity of the transcriptional co-activator Yap1 to be enriched in active NSCs. Genetic deletion of Yap1 led to a significant reduction in the relative proportion of active NSCs, supporting a physiological role of Yap1 in regulating the transition from quiescence to activation. Overexpression of wild-type Yap1 in adult NSCs did not induce NSC activation, suggesting tight upstream control mechanisms, but overexpression of a gain-of-function mutant (Yap1-5SA) elicited cell cycle entry in NSCs and hilar astrocytes. Consistent with a role of Yap1 in NSC activation, single cell RNA sequencing revealed a partial induction of an activated NSC gene expression program. Furthermore, Yap1-5SA expression also induced expression of Taz and other key components of the Yap/Taz regulon that were previously identified in glioblastoma stem cell-like cells. Consequently, dysregulated Yap1 activity led to repression of hippocampal neurogenesis, aberrant cell differentiation, and partial acquisition of a glioblastoma stem cell-like signature.
Asunto(s)
Glioblastoma , Células-Madre Neurales , Adulto , Humanos , Glioblastoma/metabolismo , Diferenciación Celular/fisiología , Hipocampo/metabolismo , Neurogénesis/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Células-Madre Neurales/metabolismoRESUMEN
Eukaryotic cells decide in late G1 phase of the cell cycle whether to commit to another round of division. This point of cell cycle commitment is termed "Restriction Point" in mammals and "Start" in the budding yeast Saccharomyces cerevisiae. At Start, yeast cells integrate multiple signals such as pheromones and nutrients, and will not pass Start if nutrients are lacking. However, how cells respond to nutrient depletion after the Start decision remains poorly understood. Here, we analyze how post-Start cells respond to nutrient depletion, by monitoring Whi5, the cell cycle inhibitor whose export from the nucleus determines Start. Surprisingly, we find that cells that have passed Start can re-import Whi5 into the nucleus. In these cells, the positive feedback loop activating G1/S transcription is interrupted, and the Whi5 repressor re-binds DNA. Cells which re-import Whi5 become again sensitive to mating pheromone, like pre-Start cells, and CDK activation can occur a second time upon replenishment of nutrients. These results demonstrate that upon starvation, the commitment decision at Start can be reversed. We therefore propose that cell cycle commitment in yeast is a multi-step process, similar to what has been suggested for mammalian cells.
Asunto(s)
Proteínas de Saccharomyces cerevisiae , Saccharomycetales , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Ciclo Celular , División Celular , Fase G1 , Saccharomycetales/metabolismoRESUMEN
Adhesion between stem cells and their niche provides stable anchorage and signaling cues to sustain properties such as quiescence. Skeletal muscle stem cells (MuSCs) adhere to an adjacent myofiber via cadherin-catenin complexes. Previous studies on N- and M-cadherin in MuSCs revealed that although N-cadherin is required for quiescence, they are collectively dispensable for MuSC niche localization and regenerative activity. Although additional cadherins are expressed at low levels, these findings raise the possibility that cadherins are unnecessary for MuSC anchorage to the niche. To address this question, we conditionally removed from MuSCs ß- and γ-catenin, and, separately, αE- and αT-catenin, factors that are essential for cadherin-dependent adhesion. Catenin-deficient MuSCs break quiescence similarly to N-/M-cadherin-deficient MuSCs, but exit the niche and are depleted. Combined in vivo, ex vivo and single cell RNA-sequencing approaches reveal that MuSC attrition occurs via precocious differentiation, re-entry to the niche and fusion to myofibers. These findings indicate that cadherin-catenin-dependent adhesion is required for anchorage of MuSCs to their niche and for preservation of the stem cell compartment. Furthermore, separable cadherin-regulated functions govern niche localization, quiescence and MuSC maintenance.
Asunto(s)
Cadherinas , Nicho de Células Madre , Nicho de Células Madre/genética , Cadherinas/genética , Cadherinas/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Transducción de Señal , Cateninas/genética , Cateninas/metabolismo , Músculo Esquelético/metabolismo , Adhesión Celular/genéticaRESUMEN
Many animals share a lifelong capacity to adapt their growth rates and body sizes to changing environmental food supplies. However, the cellular and molecular basis underlying this plasticity remains only poorly understood. We therefore studied how the sea anemones Nematostella vectensis and Aiptasia (Exaiptasia pallida) respond to feeding and starvation. Combining quantifications of body size and cell numbers with mathematical modelling, we observed that growth and shrinkage rates in Nematostella are exponential, stereotypic and accompanied by dramatic changes in cell numbers. Notably, shrinkage rates, but not growth rates, are independent of body size. In the facultatively symbiotic Aiptasia, we show that growth and cell proliferation rates are dependent on the symbiotic state. On a cellular level, we found that >7% of all cells in Nematostella juveniles reversibly shift between S/G2/M and G1/G0 cell cycle phases when fed or starved, respectively. Furthermore, we demonstrate that polyp growth and cell proliferation are dependent on TOR signalling during feeding. Altogether, we provide a benchmark and resource for further investigating the nutritional regulation of body plasticity on multiple scales using the genetic toolkit available for Nematostella.
Asunto(s)
Tamaño Corporal , Proliferación Celular , Anémonas de Mar , Animales , Anémonas de Mar/citología , Anémonas de Mar/fisiología , Ciclo Celular/fisiología , Conducta Alimentaria/fisiología , Transducción de Señal , Simbiosis , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
A growing wealth of data suggest that reactive oxygen species (ROS) signalling might be crucial in conferring embryonic or adult stem cells their specific properties. However, how stem cells control ROS production and scavenging, and how ROS in turn contribute to stemness, remain poorly understood. Using the Xenopus retina as a model system, we first investigated the redox status of retinal stem cells (RSCs). We discovered that they exhibit higher ROS levels compared with progenitors and retinal neurons, and express a set of specific redox genes. We next addressed the question of ROS functional involvement in these cells. Using pharmacological or genetic tools, we demonstrate that inhibition of NADPH oxidase-dependent ROS production increases the proportion of quiescent RSCs. Surprisingly, this is accompanied by an apparent acceleration of the mean division speed within the remaining proliferating pool. Our data further unveil that such impact on RSC cell cycling is achieved by modulation of the Wnt/Hedgehog signalling balance. Altogether, we highlight that RSCs exhibit distinctive redox characteristics and exploit NADPH oxidase signalling to limit quiescence and fine-tune their proliferation rate.
Asunto(s)
Células Madre Adultas , Células-Madre Neurales , Animales , Xenopus laevis/metabolismo , Especies Reactivas de Oxígeno , Proliferación Celular , Proteínas Hedgehog , Retina/metabolismo , Células Madre Adultas/metabolismo , NADPH Oxidasas/genética , Vía de Señalización WntRESUMEN
Stem cells are critical for the maintenance of many tissues, but whether their integrity is maintained in the face of immunity is unclear. Here we found that cycling epithelial stem cells, including Lgr5+ intestinal stem cells, as well as ovary and mammary stem cells, were eliminated by activated T cells, but quiescent stem cells in the hair follicle and muscle were resistant to T cell killing. Immune evasion was an intrinsic property of the quiescent stem cells resulting from systemic downregulation of the antigen presentation machinery, including MHC class I and TAP proteins, and is mediated by the transactivator NLRC5. This process was reversed upon stem cell entry into the cell cycle. These studies identify a link between stem cell quiescence, antigen presentation, and immune evasion. As cancer-initiating cells can derive from stem cells, these findings may help explain how the earliest cancer cells evade immune surveillance.
Asunto(s)
Folículo Piloso/citología , Evasión Inmune , Vigilancia Inmunológica , Células Madre/inmunología , Animales , Presentación de Antígeno , Péptidos y Proteínas de Señalización Intracelular/fisiología , Células Asesinas Naturales/inmunología , Ratones , Ratones Endogámicos C57BL , Músculos/citología , Receptores Acoplados a Proteínas G/fisiología , Escape del TumorRESUMEN
It is unclear how quiescence is enforced in naive T cells, but activation by foreign antigens and self-antigens is allowed, despite the presence of inhibitory signals. We showed that active transforming growth factor ß (TGF-ß) signaling was present in naive T cells, and T cell receptor (TCR) engagement reduced TGF-ß signaling during T cell activation by downregulating TGF-ß type 1 receptor (TßRI) through activation of caspase recruitment domain-containing protein 11 (CARD11) and nuclear factor κB (NF-κB). TGF-ß prevented TCR-mediated TßRI downregulation, but this was abrogated by interleukin-6 (IL-6). Mitigation of TCR-mediated TßRI downregulation through overexpression of TßRI in naive and activated T cells rendered T cells less responsive and suppressed autoimmunity. Naive T cells in autoimmune patients exhibited reduced TßRI expression and increased TCR-driven proliferation compared to healthy subjects. Thus, TCR-mediated regulation of TßRI-TGF-ß signaling acts as a crucial criterion to determine T cell quiescence and activation.
Asunto(s)
Proteínas Adaptadoras de Señalización CARD/metabolismo , Linfocitos T CD4-Positivos/inmunología , Guanilato Ciclasa/metabolismo , Activación de Linfocitos/inmunología , Receptor Tipo I de Factor de Crecimiento Transformador beta/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Autoinmunidad/inmunología , Proteínas Adaptadoras de Señalización CARD/genética , Línea Celular , Proliferación Celular , Colitis/inmunología , Colitis/patología , Modelos Animales de Enfermedad , Regulación hacia Abajo/inmunología , Guanilato Ciclasa/genética , Células HEK293 , Humanos , Interleucina-6/inmunología , Lupus Eritematoso Sistémico/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta/biosíntesis , Transducción de Señal/inmunología , Factor de Crecimiento Transformador beta1/biosíntesisRESUMEN
Quiescence is a stress-resistant state in which cells reversibly exit the cell cycle and suspend most processes. Quiescence is essential for stem cell maintenance, and its misregulation is implicated in tumor formation. One of the hallmarks of quiescent cells is highly condensed chromatin. Because condensed chromatin often correlates with transcriptional silencing, it has been hypothesized that chromatin compaction represses transcription during quiescence. However, the technology to test this model by determining chromatin structure within cells at gene resolution has not previously been available. Here, we use Micro-C XL to map chromatin contacts at single-nucleosome resolution genome-wide in quiescent Saccharomyces cerevisiae cells. We describe chromatin domains on the order of 10-60 kilobases that, only in quiescent cells, are formed by condensin-mediated loops. Condensin depletion prevents the compaction of chromatin within domains and leads to widespread transcriptional de-repression. Finally, we demonstrate that condensin-dependent chromatin compaction is conserved in quiescent human fibroblasts.
Asunto(s)
Adenosina Trifosfatasas/metabolismo , Senescencia Celular , Ensamble y Desensamble de Cromatina , Cromatina/genética , Proteínas de Unión al ADN/metabolismo , Fibroblastos/enzimología , Complejos Multiproteicos/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/enzimología , Transcripción Genética , Adenosina Trifosfatasas/genética , Sitios de Unión , Proliferación Celular , Células Cultivadas , Cromatina/metabolismo , Proteínas de Unión al ADN/genética , Regulación Fúngica de la Expresión Génica , Humanos , Complejos Multiproteicos/genética , Unión Proteica , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crecimiento & desarrollo , Proteínas de Saccharomyces cerevisiae/genética , Factores de TiempoRESUMEN
Alternative histone acylations integrate gene expression with cellular metabolic states. Recent measurements of cellular acyl-coenzyme A (acyl-CoA) pools highlight the potential that histone post-translational modifications (PTMs) contribute directly to the regulation of metabolite pools. A metabolite-centric view throws new light onto roles and evolution of histone PTMs.