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1.
J Immunol ; 198(2): 937-949, 2017 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-27974453

RESUMEN

Epigenetic mechanisms play a critical role during differentiation of T cells by contributing to the formation of stable and heritable transcriptional patterns. To better understand the mechanisms of memory maintenance in CD8+ T cells, we performed genome-wide analysis of DNA methylation, histone marking (acetylated lysine 9 in histone H3 and trimethylated lysine 9 in histone), and gene-expression profiles in naive, effector memory (EM), and terminally differentiated EM (TEMRA) cells. Our results indicate that DNA demethylation and histone acetylation are coordinated to generate the transcriptional program associated with memory cells. Conversely, EM and TEMRA cells share a very similar epigenetic landscape. Nonetheless, the TEMRA transcriptional program predicts an innate immunity phenotype associated with genes never reported in these cells, including several mediators of NK cell activation (VAV3 and LYN) and a large array of NK receptors (e.g., KIR2DL3, KIR2DL4, KIR2DL1, KIR3DL1, KIR2DS5). In addition, we identified up to 161 genes that encode transcriptional regulators, some of unknown function in CD8+ T cells, and that were differentially expressed in the course of differentiation. Overall, these results provide new insights into the regulatory networks involved in memory CD8+ T cell maintenance and T cell terminal differentiation.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Epigénesis Genética , Regulación de la Expresión Génica/inmunología , Memoria Inmunológica/genética , Western Blotting , Separación Celular , Inmunoprecipitación de Cromatina , Metilación de ADN , Citometría de Flujo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/genética , Humanos , Memoria Inmunológica/inmunología , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena en Tiempo Real de la Polimerasa , Transcripción Genética , Transcriptoma
2.
Oncoimmunology ; 10(1): 1897294, 2021 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-33796404

RESUMEN

B7-H6, a ligand for the NK activating receptor NKp30, has been identified as a biomarker of poor prognosis in several solid cancers. However, little is known about the role of B7-H6 and the mechanisms that control its expression in acute myeloid leukemia (AML). Epigenome modulation, including epigenomic reader dysregulation, is one of the hallmarks of AML. Bromodomain-containing protein 4 (BRD4), the best-known member of the BET family of epigenetic readers, is overexpressed in AML cells and regulates the transcription of genes involved in the pathogenesis of AML, as MYC oncogene. Here, we analyze the role of BRD4 in regulating B7-H6 in AML cells. Results demonstrated that the specific inhibition of BRD4 drastically reduces the expression of B7-H6 in AML cells. Histone acetylation mediated by CBP30/P300 facilitates the binding of BRD4 to the B7-H6 promoter, which recruits the P-TEFb elongation factor that phosphorylates RNA polymerase II, thereby activating B7-H6 transcription. BRD4 also co-bounded with JMJD6 at the distal enhancer of the B7-H6 gene. Metabolic modulation with metformin modifies the acetylation pattern in the B7-H6 promoter, impairing BRD4 binding, thereby inhibiting B7-H6 expression. B7-H6 knockdown induces the apoptosis in HEL-R cell line. Moreover, a high level of B7-H6 expression in AML patients is related to increased BRD4 levels, myelodysplastic-derived AML, and del5q, the two latter being associated with poor prognosis. Our data show that BRD4 is a positive regulator of the pro-tumorigenic molecule B7-H6 and that the blockage of the B7-H6 is a potential therapeutic target for the treatment of AML.


Asunto(s)
Antígenos B7 , Proteínas de Ciclo Celular , Leucemia Mieloide Aguda , Factores de Transcripción , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Epigénesis Genética/genética , Humanos , Histona Demetilasas con Dominio de Jumonji , Leucemia Mieloide Aguda/genética , Receptor 3 Gatillante de la Citotoxidad Natural/genética , Factores de Transcripción/genética
3.
Clin Epigenetics ; 13(1): 187, 2021 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-34635175

RESUMEN

BACKGROUND: SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1) receptors for entry into cells, and the serine protease TMPRSS2 for S protein priming. Inhibition of protease activity or the engagement with ACE2 and NRP1 receptors has been shown to be an effective strategy for blocking infectivity and viral spreading. Valproic acid (VPA; 2-propylpentanoic acid) is an epigenetic drug approved for clinical use. It produces potent antiviral and anti-inflammatory effects through its function as a histone deacetylase (HDAC) inhibitor. Here, we propose VPA as a potential candidate to tackle COVID-19, in which rapid viral spread and replication, and hyperinflammation are crucial elements. RESULTS: We used diverse cell lines (HK-2, Huh-7, HUVEC, Caco-2, and BEAS-2B) to analyze the effect of VPA and other HDAC inhibitors on the expression of the ACE-2 and NRP-1 receptors and their ability to inhibit infectivity, viral production, and the inflammatory response. Treatment with VPA significantly reduced expression of the ACE2 and NRP1 host proteins in all cell lines through a mechanism mediated by its HDAC inhibitory activity. The effect is maintained after SARS-CoV-2 infection. Consequently, the treatment of cells with VPA before infection impairs production of SARS-CoV-2 infectious viruses, but not that of other ACE2- and NRP1-independent viruses (VSV and HCoV-229E). Moreover, the addition of VPA 1 h post-infection with SARS-CoV-2 reduces the production of infectious viruses in a dose-dependent manner without significantly modifying the genomic and subgenomic messenger RNAs (gRNA and sg mRNAs) or protein levels of N protein. The production of inflammatory cytokines (TNF-α and IL-6) induced by TNF-α and SARS-CoV-2 infection is diminished in the presence of VPA. CONCLUSIONS: Our data showed that VPA blocks three essential processes determining the severity of COVID-19. It downregulates the expression of ACE2 and NRP1, reducing the infectivity of SARS-CoV-2; it decreases viral yields, probably because it affects virus budding or virions stability; and it dampens the triggered inflammatory response. Thus, administering VPA could be considered a safe treatment for COVID-19 patients until vaccines have been rolled out across the world.


Asunto(s)
Enzima Convertidora de Angiotensina 2/genética , COVID-19/prevención & control , Epigénesis Genética/fisiología , Neuropilina-1/genética , Receptores Virales/efectos de los fármacos , Ácido Valproico/farmacología , Enzima Convertidora de Angiotensina 2/efectos de los fármacos , Antivirales/farmacología , Células Cultivadas , Inhibidores Enzimáticos/farmacología , Epigénesis Genética/genética , Humanos , Neuropilina-1/efectos de los fármacos , SARS-CoV-2
4.
Oncoimmunology ; 8(2): e1539617, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30713800

RESUMEN

Acute myeloid leukemia (AML) is a heterogeneous disease whose therapies currently show elevated toxicity and a high rate of relapse. Recently, the burgeoning of new anti-tumor therapeutic strategies aimed at enhancing the immune response has pushed natural killer cells (NKs) into the spotlight. These cells are powerful warriors that can bring about the lysis of tumor cells through their cytotoxic ability. However, tumor cells have developed strategies to evade recognition mediated by NKs. Here, we review the mechanisms triggered by AML cells and discuss the emerging immunotherapeutic strategies that potentiate the anti-tumor functions of NKs.

6.
Oncoimmunology ; 3: e28497, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25050215

RESUMEN

Natural Killer Group 2 member D (NKG2D) activating receptor, present on the surface of various immune cells, plays an important role in activating the anticancer immune response by their interaction with stress-inducible NKG2D ligands (NKG2DL) on transformed cells. However, cancer cells have developed numerous mechanisms to evade the immune system via the downregulation of NKG2DL from the cell surface, including the release of NKG2DL from the cell surface in a soluble form. Here, we review the mechanisms involved in the production of soluble NKG2DL (sNKG2DL) and the potential therapeutic strategies aiming to block the release of these immunosuppressive ligands. Therapeutically enabling the NKG2D-NKG2DL interaction would promote immunorecognition of malignant cells, thus abrogating disease progression.

7.
Epigenetics ; 8(7): 694-702, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23803720

RESUMEN

Great efforts in the field of solid organ transplantation are being devoted to identifying biomarkers that allow a transplanted patient's immune status to be established. Recently, it has been well documented that epigenetic mechanisms like DNA methylation and histone modifications regulate the expression of immune system-related genes, modifying the development of the innate and adaptive immune responses. An in-depth knowledge of these epigenetic mechanisms could modulate the immune response after transplantation and to develop new therapeutic strategies. Epigenetic modifiers, such as histone deacetylase (HDAC) inhibitors have considerable potential as anti-inflammatory and immunosuppressive agents, but their effect on transplantation has not hitherto been known. Moreover, the detection of epigenetic marks in key immune genes could be useful as biomarkers of rejection and progression among transplanted patients. Here, we describe recent discoveries concerning the epigenetic regulation of the immune system, and how this knowledge could be translated to the field of transplantation.


Asunto(s)
Epigénesis Genética , Tolerancia Inmunológica/genética , Inmunidad/genética , Animales , Biomarcadores/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Células Dendríticas/metabolismo , Humanos
8.
Epigenetics ; 8(1): 66-78, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23235109

RESUMEN

The human activating receptor NKG2D is mainly expressed by NK, NKT, γδ T and CD8(+) T cells and, under certain conditions, by CD4(+) T cells. This receptor recognizes a diverse family of ligands (MICA, MICB and ULBPs 1-6) leading to the activation of effector cells and triggering the lysis of target cells. The NKG2D receptor-ligand system plays an important role in the immune response to infections, tumors, transplanted graft and autoantigens. Elucidation of the regulatory mechanisms of NKG2D is therefore essential for therapeutic purposes. In this study, we speculate whether epigenetic mechanisms, such as DNA methylation and histone acetylation, participate in NKG2D gene regulation in T lymphocytes and NK cells. DNA methylation in the NKG2D gene was observed in CD4(+) T lymphocytes and T cell lines (Jurkat and HUT78), while this gene was unmethylated in NKG2D-positive cells (CD8(+) T lymphocytes, NK cells and NKL cell line) and associated with high levels of histone H3 lysine 9 acetylation (H3K9Ac). Treatment with the histone acetyltransferase (HAT) inhibitor curcumin reduces H3K9Ac levels in the NKG2D gene, downregulates NKG2D transcription and leads to a marked reduction in the lytic capacity of NKG2D-mediated NKL cells. These findings suggest that differential NKG2D expression in the different cell subsets is regulated by epigenetic mechanisms and that its modulation by epigenetic treatments might provide a new strategy for treating several pathologies.


Asunto(s)
Linfocitos T CD8-positivos/metabolismo , Metilación de ADN/genética , Histonas/metabolismo , Células Asesinas Naturales/metabolismo , Lisina/metabolismo , Subfamilia K de Receptores Similares a Lectina de Células NK/genética , Transcripción Genética , Acetilación/efectos de los fármacos , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/fisiología , Degranulación de la Célula/efectos de los fármacos , Degranulación de la Célula/genética , Curcumina/farmacología , Citotoxicidad Inmunológica/efectos de los fármacos , Citotoxicidad Inmunológica/genética , Metilación de ADN/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Interferón gamma/biosíntesis , Células Jurkat , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/fisiología , Subgrupos Linfocitarios/efectos de los fármacos , Subgrupos Linfocitarios/metabolismo , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Transcripción Genética/efectos de los fármacos
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