Publicaciones científicas

Se han encontrado 8 publicaciones con los criterios indicados.
Garcia-Prieto CA, Álvarez-Errico D, Musulen E, Bueno-Costa A, N Vazquez B, Vaquero A, Esteller M

Validation of a DNA methylation microarray for 285,000 CpG sites in the mouse genome.

Epigenetics 17 Mar 2022, . Epub 17 Mar 2022
The mouse has been extensively used as the model organism in many studies to characterize biological pathways, drug effects and to mimic human diseases. The similar DNA sequences between both species facilitates these type of experiments. However, much less is known about the mouse epigenome, particularly for DNA methylation. Progress in delivering mouse DNA methylomes has been slow due to the currently available time-consuming and expensive methodologies. Following the great acceptance of the human DNA methylation microarrays, we have herein validated a newly developed DNA methylation microarray (Infinium Mouse Methylation BeadChip) that interrogates 280,754 unique CpG sites within the mouse genome. The CpGs included in the platform cover CpG islands, shores, shelfs and open sea sequences; and loci surrounding transcription start sites and gene bodies. From the functional standpoint, mouse ENCODE representative DNase hypersensitivity sites (rDHSs) and candidate cis-Regulatory Elements (cCREs) are also included. Herein, we show that the profiled mouse DNA methylation microarray provides reliable values among technical replicates; matched results from fresh frozen versus formalin-fixed samples; detects hemimethylated X-chromosome and imprinted CpG sites; and is able to determine CpG methylation changes in mouse cell lines treated with a DNA demethylating agent or upon genetic disruption of a DNA methyltransferase. Most important, using unsupervised hierarchical clustering and t-SNE approaches, the platform is able to classify all types of normal mouse tissues and organs. These data underscore the great features of the assessed microarray to obtain comprehensive DNA methylation profiles of the mouse genome.
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Martínez-Gutiérrez A, Fernández-Duran I, Marazuela-Duque A, Simonet NG, Yousef I, Martínez-Rovira I, Martínez-Hoyos J, Vaquero A

Shikimic acid protects skin cells from UV-induced senescence through activation of the NAD+-dependent deacetylase SIRT1.

Aging (Albany NY) 26 Abr 2021, 13 .
UV radiation is one of the main contributors to skin photoaging by promoting the accumulation of cellular senescence, which in turn induces a proinflammatory and tissue-degrading state that favors skin aging. The members of the sirtuin family of NAD+-dependent enzymes play an anti-senescence role and their activation suggests a promising approach for preventing UV-induced senescence in the treatment of skin aging. A two-step screening designed to identify compounds able to protect cells from UV-induced senescence through sirtuin activation identified shikimic acid (SA), a metabolic intermediate in many organisms, as a bona-fide candidate. The protective effects of SA against senescence were dependent on specific activation of SIRT1 as the effect was abrogated by the SIRT1 inhibitor EX-527. Upon UV irradiation SA induced S-phase accumulation and a decrease in p16INK4A expression but did not protect against DNA damage or increased polyploidies. In contrast, SA reverted misfolded protein accumulation upon senescence, an effect that was abrogated by EX-527. Consistently, SA induced an increase in the levels of the chaperone BiP, resulting in a downregulation of unfolded protein response (UPR) signaling and UPR-dependent autophagy, avoiding their abnormal hyperactivation during senescence. SA did not directly activate SIRT1 in vitro, suggesting that SIRT1 is a downstream effector of SA signaling specifically in the response to cellular senescence. Our study not only uncovers a shikimic acid/SIRT1 signaling pathway that prevents cellular senescence, but also reinforces the role of sirtuins as key regulators of cell proteostasis.
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Laporte-Amargos J, Gudiol C, Arnan M, Puerta-Alcalde P, Carmona-Torre F, Huguet M, Albasanz-Puig A, Parody R, Garcia-Vidal C, Del Pozo JL, Batlle M, Tebé C, Rigo-Bonnin R, Muñoz C, Padullés A, Tubau F, Videla S, Sureda A, Carratalà J

Efficacy of extended infusion of β-lactam antibiotics for the treatment of febrile neutropenia in haematologic patients: protocol for a randomised, multicentre, open-label, superiority clinical trial (BEATLE).

Trials 18 May 2020, 21 (1) 412. Epub 18 May 2020
Febrile neutropaenia (FN) is a very common complication in patients with haematological malignancies and is associated with considerable morbidity and mortality. Broad-spectrum antipseudomonal β-lactam antibiotics (BLA) are routinely used for the treatment of cancer patients with FN. However, the clinical efficacy of BLA may be diminished in these patients because they present with pathophysiological variations that compromise the pharmacokinetic (PK) parameters of these antibiotics. Optimised administration of BLA in prolonged infusions has demonstrated better clinical outcomes in critically ill patients. However, there is a paucity of data on the usefulness of this strategy in patients with FN. The aim of this study is to test the hypothesis that the administration of BLA would be clinically more effective by extended infusion (EI) than by intermittent infusion (II) in haematological patients with FN.
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Wössner N, Alhalabi Z, González J, Swyter S, Gan J, Schmidtkunz K, Zhang L, Vaquero A, Ovaa H, Einsle O, Sippl W, Jung M

Sirtuin 1 Inhibiting Thiocyanates (S1th)-A New Class of Isotype Selective Inhibitors of NAD

Front Oncol 2020, 10 657. Epub 30 Abr 2020
Sirtuin 1 (Sirt1) is a NAD
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SirT7 auto-ADPribosylation regulates glucose starvation response through macroH2A1

Sci.Adv. 6(30): eaaz2590 , .
Sirtuins are key players of metabolic stress response. Originally described as deacetylases, some sirtuins also exhibit poorly understood mono-adenosine 5'-diphosphate (ADP)-ribosyltransferase (mADPRT) activity. We report that the deacetylase SirT7 is a dual sirtuin, as it also features auto-mADPRT activity. SirT7 mADPRT occurs at a previously undefined active site, and its abrogation alters SirT7 chromatin distribution. We identify an epigenetic pathway by which ADP-ribosyl-SirT7 is recognized by the ADP-ribose reader mH2A1.1 under glucose starvation, inducing SirT7 relocalization to intergenic regions. SirT7 promotes mH2A1 enrichment in a subset of nearby genes, many of them involved in second messenger signaling, resulting in their specific up- or down-regulation. The expression profile of these genes under calorie restriction is consistently abrogated in SirT7-deficient mice, resulting in impaired activation of autophagy. Our work provides a novel perspective on sirtuin duality and suggests a role for SirT7/mH2A1.1 axis in glucose homeostasis and aging.
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Vazquez, B.N, Thackray, J.K., Simonet, N., Chahar, S., Kane-Goldsmith, N., An, W., Xing, J.C., Verzi, M.P., Vaquero A, Tischfield, J.A., Serrano, L

SIRT7 mediates L1 elements transcriptional repression and their association with the nuclear lamina

Nucleic Acids Res. 47(15):7870-7885 (2019). , .
Long interspersed elements-1 (LINE-1, L1) are retrotransposons that hold the capacity of self-propagation in the genome with potential mutagenic outcomes. How somatic cells restrict L1 activity and how this process becomes dysfunctional during aging and in cancer cells is poorly understood. L1s are enriched at lamin-associated domains, heterochromatic regions of the nuclear periphery. Whether this association is necessary for their repression has been elusive. Here we show that the sirtuin family member SIRT7 participates in the epigenetic transcriptional repression of L1 genome-wide in both mouse and human cells. SIRT7 depletion leads to increased L1 expression and retrotransposition. Mechanistically, we identify a novel interplay between SIRT7 and Lamin A/C in L1 repression. Our results demonstrate that SIRT7-mediated H3K18 deacetylation regulates L1 expression and promotes L1 association with elements of the nuclear lamina. The failure of such activity might contribute to the observed genome instability and compromised viability in SIRT7 knockout mice. Overall, our results reveal a novel function of SIRT7 on chromatin organization by mediating the anchoring of L1 to the nuclear envelope, and a new functional link of the nuclear lamina with transcriptional repression.
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Urdinguio, R.G., Lopez, V., Bayón, G.F., Sierra, M., García-Toraño,E., Fernandez, R., García, M., Carella, A., Cueto, P., Prieto, P., Dmitrieva, M., Santamarina, P., Mangas, C., Diaconou, E., Ferrero, C., Tejedor, J.R., Bravo, C., Bueno, C., Sanjuán, A., Rodríguez, R.M., Suarez, B., López-Larrea, C., Bernal, T., Colado, E., Balbín, M., García-Suarez, O., Chiara, M.D., Sáenz-de-Santa-María, I., Rodríguez, F., Pando-Sandoval, A., Rodrigo, L., Santos, L., Salas, A., Vallejo, J., Carrera, A.C., Rico, D., Hernández-López, I., Vayá, A., Ricart, J.M., Seto, A., Vaquero A, Sima, N., Pisano, D., Graña, O., Thomas, T., Voss, A.K., Villar-Garea, A., Deutzmann, R., Fernandez, A.F., Fraga, M.F, Menéndez P

Chromatin regulation by Histone H4 acetylation at Lysine 16 during cell death and differentiation in the myeloid compartment

Nucleic Acids Res. 47(10):5016-5037 (2019). , .
Histone H4 acetylation at Lysine 16 (H4K16ac) is a key epigenetic mark involved in gene regulation, DNA repair and chromatin remodeling, and though it is known to be essential for embryonic development, its role during adult life is still poorly understood. Here we show that this lysine is massively hyperacetylated in peripheral neutrophils. Genome-wide mapping of H4K16ac in terminally differentiated blood cells, along with functional experiments, supported a role for this histone post-translational modification in the regulation of cell differentiation and apoptosis in the hematopoietic system. Furthermore, in neutrophils, H4K16ac was enriched at specific DNA repeats. These DNA regions presented an accessible chromatin conformation and were associated with the cleavage sites that generate the 50 kb DNA fragments during the first stages of programmed cell death. Our results thus suggest that H4K16ac plays a dual role in myeloid cells as it not only regulates differentiation and apoptosis, but it also exhibits a non-canonical structural role in poising chromatin for cleavage at an early stage of neutrophil cell death.
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Li, T., Garcia-Gomez, A., Morante-Palacios, O., Ciudad, L., Özkaramehmet, S., Van Dijck, E., Rodríguez-Ubreva, J., Vaquero, A. and, Ballestar E

SIRT1/2 orchestrate acquisition of DNA methylation and loss of histone H3 activating marks to prevent premature activation of inflammatory genes in macrophage

Nucleic Acids Research 48, 665–681 , .
Sirtuins 1 and 2 (SIRT1/2) are two NAD-dependent deacetylases with major roles in inflammation. In addition to deacetylating histones and other proteins, SIRT1/2-mediated regulation is coupled with other epigenetic enzymes. Here, we investigate the links between SIRT1/2 activity and DNA methylation in macrophage differentiation due to their relevance in myeloid cells. SIRT1/2 display drastic upregulation during macrophage differentiation and their inhibition impacts the expression of many inflammation-related genes. In this context, SIRT1/2 inhibition abrogates DNA methylation gains, but does not affect demethylation. Inhibition of hypermethylation occurs at many inflammatory loci, which results in more drastic upregulation of their expression upon macrophage polarization following bacterial lipopolysaccharide (LPS) challenge. SIRT1/2-mediated gains of methylation concur with decreases in activating histone marks, and their inhibition revert these histone marks to resemble an open chromatin. Remarkably, specific inhibition of DNA methyltransferases is sufficient to upregulate inflammatory genes that are maintained in a silent state by SIRT1/2. Both SIRT1 and SIRT2 directly interact with DNMT3B, and their binding to proinflammatory genes is lost upon exposure to LPS or through pharmacological inhibition of their activity. In all, we describe a novel role for SIRT1/2 to restrict premature activation of proinflammatory genes.
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