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1.
Immunity ; 48(3): 570-583.e8, 2018 03 20.
Artículo en Inglés | MEDLINE | ID: mdl-29562203

RESUMEN

Polymorphisms in NFKB1 that diminish its expression have been linked to human inflammatory diseases and increased risk for epithelial cancers. The underlying mechanisms are unknown, and the link is perplexing given that NF-κB signaling reportedly typically exerts pro-tumorigenic activity. Here we have shown that NF-κB1 deficiency, even loss of a single allele, resulted in spontaneous invasive gastric cancer (GC) in mice that mirrored the histopathological progression of human intestinal-type gastric adenocarcinoma. Bone marrow chimeras revealed that NF-κB1 exerted tumor suppressive functions in both epithelial and hematopoietic cells. RNA-seq analysis showed that NF-κB1 deficiency resulted in aberrant JAK-STAT signaling, which dysregulated expression of effectors of inflammation, antigen presentation, and immune checkpoints. Concomitant loss of STAT1 prevented these immune abnormalities and GC development. These findings provide mechanistic insight into how polymorphisms that attenuate NFKB1 expression predispose humans to epithelial cancers, highlighting the pro-tumorigenic activity of STAT1 and identifying targetable vulnerabilities in GC.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Inflamación/genética , Inflamación/metabolismo , FN-kappa B/deficiencia , Factor de Transcripción STAT1/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Animales , Presentación de Antígeno/inmunología , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Modelos Animales de Enfermedad , Células Epiteliales/metabolismo , Células Epiteliales/patología , Redes Reguladoras de Genes , Humanos , Inflamación/patología , Ratones , Ratones Noqueados , Factor de Transcripción STAT1/deficiencia , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/patología
2.
Blood ; 143(19): 1937-1952, 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38446574

RESUMEN

ABSTRACT: In physiological conditions, few circulating hematopoietic stem/progenitor cells (cHSPCs) are present in the peripheral blood, but their contribution to human hematopoiesis remain unsolved. By integrating advanced immunophenotyping, single-cell transcriptional and functional profiling, and integration site (IS) clonal tracking, we unveiled the biological properties and the transcriptional features of human cHSPC subpopulations in relationship to their bone marrow (BM) counterpart. We found that cHSPCs reduced in cell count over aging and are enriched for primitive, lymphoid, and erythroid subpopulations, showing preactivated transcriptional and functional state. Moreover, cHSPCs have low expression of multiple BM-retention molecules but maintain their homing potential after xenotransplantation. By generating a comprehensive human organ-resident HSPC data set based on single-cell RNA sequencing data, we detected organ-specific seeding properties of the distinct trafficking HSPC subpopulations. Notably, circulating multi-lymphoid progenitors are primed for seeding the thymus and actively contribute to T-cell production. Human clonal tracking data from patients receiving gene therapy (GT) also showed that cHSPCs connect distant BM niches and participate in steady-state hematopoietic production, with primitive cHSPCs having the highest recirculation capability to travel in and out of the BM. Finally, in case of hematopoietic impairment, cHSPCs composition reflects the BM-HSPC content and might represent a biomarker of the BM state for clinical and research purposes. Overall, our comprehensive work unveiled fundamental insights into the in vivo dynamics of human HSPC trafficking and its role in sustaining hematopoietic homeostasis. GT patients' clinical trials were registered at ClinicalTrials.gov (NCT01515462 and NCT03837483) and EudraCT (2009-017346-32 and 2018-003842-18).


Asunto(s)
Hematopoyesis , Células Madre Hematopoyéticas , Homeostasis , Animales , Humanos , Ratones , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Análisis de la Célula Individual
3.
Nature ; 560(7717): 253-257, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-30069049

RESUMEN

Acetylation of histones by lysine acetyltransferases (KATs) is essential for chromatin organization and function1. Among the genes coding for the MYST family of KATs (KAT5-KAT8) are the oncogenes KAT6A (also known as MOZ) and KAT6B (also known as MORF and QKF)2,3. KAT6A has essential roles in normal haematopoietic stem cells4-6 and is the target of recurrent chromosomal translocations, causing acute myeloid leukaemia7,8. Similarly, chromosomal translocations in KAT6B have been identified in diverse cancers8. KAT6A suppresses cellular senescence through the regulation of suppressors of the CDKN2A locus9,10, a function that requires its KAT activity10. Loss of one allele of KAT6A extends the median survival of mice with MYC-induced lymphoma from 105 to 413 days11. These findings suggest that inhibition of KAT6A and KAT6B may provide a therapeutic benefit in cancer. Here we present highly potent, selective inhibitors of KAT6A and KAT6B, denoted WM-8014 and WM-1119. Biochemical and structural studies demonstrate that these compounds are reversible competitors of acetyl coenzyme A and inhibit MYST-catalysed histone acetylation. WM-8014 and WM-1119 induce cell cycle exit and cellular senescence without causing DNA damage. Senescence is INK4A/ARF-dependent and is accompanied by changes in gene expression that are typical of loss of KAT6A function. WM-8014 potentiates oncogene-induced senescence in vitro and in a zebrafish model of hepatocellular carcinoma. WM-1119, which has increased bioavailability, arrests the progression of lymphoma in mice. We anticipate that this class of inhibitors will help to accelerate the development of therapeutics that target gene transcription regulated by histone acetylation.


Asunto(s)
Bencenosulfonatos/farmacología , Senescencia Celular/efectos de los fármacos , Histona Acetiltransferasas/antagonistas & inhibidores , Hidrazinas/farmacología , Linfoma/tratamiento farmacológico , Linfoma/patología , Sulfonamidas/farmacología , Acetilación/efectos de los fármacos , Animales , Bencenosulfonatos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Desarrollo de Medicamentos , Fibroblastos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Histona Acetiltransferasas/deficiencia , Histona Acetiltransferasas/genética , Histonas/química , Histonas/metabolismo , Hidrazinas/uso terapéutico , Linfoma/enzimología , Linfoma/genética , Lisina/química , Lisina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Sulfonamidas/uso terapéutico
4.
Circulation ; 138(23): 2648-2661, 2018 12 04.
Artículo en Inglés | MEDLINE | ID: mdl-30571257

RESUMEN

BACKGROUND: Acute rheumatic fever (ARF) and rheumatic heart disease are autoimmune consequences of group A streptococcus infection and remain major causes of cardiovascular morbidity and mortality around the world. Improved treatment has been stymied by gaps in understanding key steps in the immunopathogenesis of ARF and rheumatic heart disease. This study aimed to identify (1) effector T cell cytokine(s) that might be dysregulated in the autoimmune response of patients with ARF by group A streptococcus, and (2) an immunomodulatory agent that suppresses this response and could be clinically translatable to high-risk patients with ARF. METHODS: The immune response to group A streptococcus was analyzed in peripheral blood mononuclear cells from an Australian Aboriginal ARF cohort by a combination of multiplex cytokine array, flow cytometric analysis, and global gene expression analysis by RNA sequencing. The immunomodulatory drug hydroxychloroquine was tested for effects on this response. RESULTS: We found a dysregulated interleukin-1ß-granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine axis in ARF peripheral blood mononuclear cells exposed to group A streptococcus in vitro, whereby persistent interleukin-1ß production is coupled to overproduction of GM-CSF and selective expansion of CXCR3+CCR4-CCR6- CD4 T cells. CXCR3+CCR4-CCR6- CD4 T cells are the major source of GM-CSF in human CD4 T cells and CXCL10, a CXCR3 ligand and potent T helper 1 chemoattractant, was elevated in sera from patients with ARF. GM-CSF has recently emerged as a key T cell-derived effector cytokine in numerous autoimmune diseases, including myocarditis, and the production of CXCL10 may explain selective trafficking of these cells to the heart. We provide evidence that interleukin-1ß amplifies the expansion of GM-CSF-expressing CD4 T cells, which is effectively suppressed by hydroxychloroquine. RNA sequencing showed shifts in gene expression profiles and differentially expressed genes in peripheral blood mononuclear cells derived from patients at different clinical stages of ARF. CONCLUSIONS: Given the safety profile of hydroxychloroquine and its clinical pedigree in treating autoimmune diseases such as rheumatoid arthritis, where GM-CSF plays a pivotal role, we propose that hydroxychloroquine could be repurposed to reduce the risk of rheumatic heart disease after ARF.


Asunto(s)
Regulación de la Expresión Génica/efectos de los fármacos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Hidroxicloroquina/farmacología , Interleucina-1beta/metabolismo , Fiebre Reumática/patología , Adolescente , Adulto , Proteína C-Reactiva/análisis , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Diferenciación Celular , Niño , Citocinas/análisis , Citocinas/genética , Citocinas/metabolismo , Femenino , Humanos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Masculino , ARN/química , ARN/aislamiento & purificación , ARN/metabolismo , Fiebre Reumática/metabolismo , Streptococcus pyogenes/inmunología , Células TH1/citología , Células TH1/inmunología , Células TH1/metabolismo , Adulto Joven
5.
Nat Cell Biol ; 25(11): 1704-1715, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37932452

RESUMEN

X-chromosome inactivation (XCI) balances gene expression between the sexes in female mammals. Shortly after fertilization, upregulation of Xist RNA from one X chromosome initiates XCI, leading to chromosome-wide gene silencing. XCI is maintained in all cell types, except the germ line and the pluripotent state where XCI is reversed. The mechanisms triggering Xist upregulation have remained elusive. Here we identify GATA transcription factors as potent activators of Xist. Through a pooled CRISPR activation screen in murine embryonic stem cells, we demonstrate that GATA1, as well as other GATA transcription factors can drive ectopic Xist expression. Moreover, we describe GATA-responsive regulatory elements in the Xist locus bound by different GATA factors. Finally, we show that GATA factors are essential for XCI induction in mouse preimplantation embryos. Deletion of GATA1/4/6 or GATA-responsive Xist enhancers in mouse zygotes effectively prevents Xist upregulation. We propose that the activity or complete absence of various GATA family members controls initial Xist upregulation, XCI maintenance in extra-embryonic lineages and XCI reversal in the epiblast.


Asunto(s)
Factores de Transcripción GATA , ARN Largo no Codificante , Animales , Femenino , Ratones , Fertilización/genética , Factores de Transcripción GATA/genética , Mamíferos , ARN Largo no Codificante/genética , Regulación hacia Arriba , Cromosoma X , Inactivación del Cromosoma X/genética
6.
Nat Commun ; 12(1): 3638, 2021 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-34131144

RESUMEN

To ensure dosage compensation between the sexes, one randomly chosen X chromosome is silenced in each female cell in the process of X-chromosome inactivation (XCI). XCI is initiated during early development through upregulation of the long non-coding RNA Xist, which mediates chromosome-wide gene silencing. Cell differentiation, Xist upregulation and gene silencing are thought to be coupled at multiple levels to ensure inactivation of exactly one out of two X chromosomes. Here we perform an integrated analysis of all three processes through allele-specific single-cell RNA-sequencing. Specifically, we assess the onset of random XCI in differentiating mouse embryonic stem cells, and develop dedicated analysis approaches. By exploiting the inter-cellular heterogeneity of XCI onset, we identify putative Xist regulators. Moreover, we show that transient Xist upregulation from both X chromosomes results in biallelic gene silencing right before transitioning to the monoallelic state, confirming a prediction of the stochastic model of XCI. Finally, we show that genetic variation modulates the XCI process at multiple levels, providing a potential explanation for the long-known X-controlling element (Xce) effect, which leads to preferential inactivation of a specific X chromosome in inter-strain crosses. We thus draw a detailed picture of the different levels of regulation that govern the initiation of XCI. The experimental and computational strategies we have developed here will allow us to profile random XCI in more physiological contexts, including primary human cells in vivo.


Asunto(s)
ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Regulación hacia Arriba , Inactivación del Cromosoma X , Alelos , Animales , Compensación de Dosificación (Genética) , Femenino , Silenciador del Gen , Ratones , Ratones Endogámicos C57BL , Células Madre Embrionarias de Ratones , Análisis de Secuencia de ARN , Cromosoma X , Inactivación del Cromosoma X/genética , Inactivación del Cromosoma X/fisiología
7.
Oncoimmunology ; 7(7): e1440929, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29900045

RESUMEN

Erdheim-Chester disease (ECD) is a rare histiocytosis, characterized by xanthogranulomatous tissue infiltration by foamy histiocytes. Fibrosis, a histologic hallmark of ECD, is responsible for lesion growth and clinical manifestations. Unraveling molecular fibrotic pathway in ECD would allow the identification of new pharmacologic targets. In this study, we evaluated serum and tissue samples from a large cohort of ECD patients focusing on two major pro-fibrotic mediators, TGF-ß1 and chemokine ligand 18 (CCL18). We found a marked increase in CCL18 but not TGF-ß1 levels in serum and lesions of ECD patients (p < 0.001), independently of treatment status and consistently over time. Using a linear mathematical model, we also found that elevated CCL18 serum levels correlate with both number and severity of disease localizations. These findings suggest the involvement of CCL18-induced fibrosis in ECD pathogenesis, providing a rationale for exploring CCL18 inhibition as a treatment for progressive fibrosis in ECD.

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