Publicació científica

S'han trobat 1441 publicacions amb els criteris indicats.
Rosselló-Tortella M, Llinàs-Arias P, Sakaguchi Y, Miyauchi K, Davalos V, Setien F, Calleja-Cervantes ME, Piñeyro D, Martínez-Gómez J, Guil S, Joshi R, Villanueva A, Suzuki T, Esteller M

Epigenetic loss of the transfer RNA-modifying enzyme TYW2 induces ribosome frameshifts in colon cancer

Proc Natl Acad Sci U S A. 2020 Aug 25 1 Ago 2020, 117(34):20785-20793 .
Transfer RNA (tRNA) activity is tightly regulated to provide a physiological protein translation, and tRNA chemical modifications control its function in a complex with ribosomes and messenger RNAs (mRNAs). In this regard, the correct hypermodification of position G37 of phenylalanine-tRNA, adjacent to the anticodon, is critical to prevent ribosome frameshifting events. Here we report that the tRNA-yW Synthesizing Protein 2 (TYW2) undergoes promoter hypermethylation-associated transcriptional silencing in human cancer, particularly in colorectal tumors. The epigenetic loss of TYW2 induces guanosine hypomodification in phenylalanine-tRNA, an increase in -1 ribosome frameshift events, and down-regulation of transcripts by mRNA decay, such as of the key cancer gene ROBO1. Importantly, TYW2 epigenetic inactivation is linked to poor overall survival in patients with early-stage colorectal cancer, a finding that could be related to the observed acquisition of enhanced migration properties and epithelial-to-mesenchymal features in the colon cancer cells that harbor TYW2 DNA methylation-associated loss. These findings provide an illustrative example of how epigenetic changes can modify the epitranscriptome and further support a role for tRNA modifications in cancer biology
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SirT7 auto-ADP-ribosylation regulates glucose starvation response through mH2A1

Science Advances 24 Jul 2020, 6 .
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.

The Contribution of Epigenetics to Cancer Immunotherapy

Trends in Immunology 1 Jul 2020, .
Effective anticancer immunotherapy treatments constitute a qualitative leap in cancer management. Nonetheless, not all patients benefit from such therapies because they fail to achieve complete responses, suffer frequent relapses, or develop potentially life-threatening toxicities. Epigenomic signatures in immune and cancer cells appear to be accurate and promising predictors of patient outcomes with immunotherapy. In addition, combined treatments with epigenetic drugs can exploit the dynamic nature of epigenetic changes to potentially modulate responses to immunotherapy. Candidate epigenetic biomarkers may provide a rationale for patient stratification and precision medicine, thus maximizing the chances of treatment success while minimizing unwanted effects. We present a comprehensive up-to-date view of potential epigenetic biomarkers in immunotherapy and discuss their advantages over other indicators.
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Esteller, M, Ferrer, G, Rosselló, M

Epitranscriptomics in Hematopoiesis and Hematologic Malignancies.

Blood Cancer Discovery 22 Jun 2020, .
Since the 1960s, a large number of chemical modifications have been identified in RNA molecules, establishing the RNA epigenetics field named “epitranscriptomics.” These chemical marks participate in several RNA metabolic processes; however, the biological relevance of many of these modifications and the many enzymes involved in their function is not completely understood. Emerging knowledge of the epitranscriptome (pseudouridine, N6-methyladenosine, and A-to-I editing) in hematopoiesis and hematologic malignancies reveals the requirement of these modifications in normal development and their alteration in disorders, leading to the development of new molecules and strategies to target the epitranscriptome as a novel therapeutic approach. RNA modifications are required for the correct development of hematopoietic cells, and their alteration can promote the development of malignancies or the transition from a low-grade to an aggressive disease. While we are expanding our understanding of the epitranscriptome of normal and malignant hematopoiesis, the number of potential new therapeutic interventions is rising.
Comes M, Batlle M, Ribera JM

Treatment adapted to pregnancy in a patient with Burkitt lymphoma.

Med Clin (Barc) 12 Jun 2020, 154 (11) 470-471. Epub 20 Jul 2019Més informació
Blecua P, Martinez-Verbo L, Esteller M

The DNA methylation landscape of hematological malignancies: an update.

Mol Oncol 11 Jun 2020, . Epub 11 Jun 2020
The rapid advances in high-throughput sequencing technologies have made it more evident that epigenetic modifications orchestrate a plethora of complex biological processes. During the last decade, we have gained significant knowledge about a wide range of epigenetic changes that crucially contribute to some of the most aggressive forms of leukemia, lymphoma and myelodysplastic syndromes. DNA methylation is a key epigenetic player in the abnormal initiation, development and progression of these malignancies, often acting in synergy with other epigenetic alterations. It also contributes to the acquisition of drug resistance. In this review, we summarize the role of DNA methylation in hematological malignancies described in the current literature. We discuss in detail the dual role of DNA methylation in normal and aberrant hematopoiesis, as well as the involvement of this type of epigenetic change in other aspects of the disease. Finally, we present a comprehensive overview of the main clinical implications, including a discussion of the therapeutic strategies that regulate or reverse aberrant DNA methylation patterns in hematological malignancies, including their combination with (chemo-) immunotherapy.
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Stik G, Vidal E, Barrero M, Cuartero S, Vila-Casadesús M, Mendieta-Esteban J, Tian TV, Choi J, Berenguer C, Abad A, Borsari B, le Dily F, Cramer P, Marti-Renom MA, Stadhouders R, Graf T

CTCF is dispensable for immune cell transdifferentiation but facilitates an acute inflammatory response.

Nat. Genet. 8 Jun 2020, . Epub 8 Jun 2020
Three-dimensional organization of the genome is important for transcriptional regulation
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Casas E, Vavouri T

Mechanisms of epigenetic inheritance of variable traits through the germline.

Reproduction Jun 2020, 159 (6) R251-R263. Epub 22 Abr 2020
During the past half century, evidence for inheritance of variable traits has accumulated from experiments in plants and animals and epidemiological studies in humans. Here, we summarize some of the reported cases of epigenetic inheritance and the proposed mechanisms involved in the transmission of non-genetic information between generations in plants, nematodes, flies and mammals. It has long been accepted that information is epigenetically inherited in plants. Although many questions regarding the underlying mechanisms remain to be answered, it is now evident that epigenetic mechanisms are also responsible for the transmission of phenotypes in animals. We highlight similarities and differences between models and species.
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Blasco M, Martínez-Roca A, Rodríguez-Lobato LG, Garcia-Herrera A, Rosiñol L, Castro P, Fernández S, Quintana LF, Cibeira MT, Bladé J, Fernández de Larrea C, Tovar N, Jimenez R, Poch E, Guillen E, Campistol JM, Carreras E, Diaz-Ricart M, Palomo M

Complement as the enabler of carfilzomib-induced thrombotic microangiopathy.

Br. J. Haematol. 29 Mai 2020, . Epub 29 Mai 2020
Carfilzomib has been associated with the development of thrombotic microangiopathy (TMA) in relapsed/refractory multiple myeloma patients, a severe disease with no currently available aetiological treatment. We evaluated the potential role of terminal complement pathway in four patients with carfilzomib-induced TMA. Membrane attack complex (C5b-9) deposition on endothelial cells in culture exposed to plasma from patients during the acute phase of the disease suggests complement overactivation as a mechanism of potential endothelial damage in three out of four patients. If confirmed in larger cohorts, C5b-9 evaluation will allow early identification of patients who could benefit from complement blockade and treatment monitoring.
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Cossío FP, Esteller M, Berdasco M

Towards a more precise therapy in cancer: Exploring epigenetic complexity.

Curr Opin Chem Biol 29 Mai 2020, 57 41-49. Epub 29 Mai 2020
A plethora of preclinical evidences suggests that pharmacological targeting of epigenetic dysregulation is a potent strategy to combat human diseases. Nevertheless, the implementation of epidrugs in clinical practice is very scarce and mainly limited to haematological malignancies. In this review, we discuss cutting-edge strategies to foster the chemical design, the biological rationale and the clinical trial development of epidrugs. Specifically, we focus on the development of dual hybrids to exploit multitargeting of key epigenetic molecules deregulated in cancer; the study of epigenetic-synthetic lethality interactions as a mechanism to address loss-of-function mutations, and the combination of epidrugs with other therapies such as immunotherapy to avoid acquired chemoresistance and increase therapy sensitivity. By exploring these challenges, among others, the field of epigenetic chemical biology will increase its potential for clinical benefit, and more effective strategies targeting the aberrant epigenome in cancer are likely to be developed both in haematological and solid tumours.
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