Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program

Altres ajuts: This work was supported by the Obra Social "La Caixa" (to M. Esteller).Tumors have aberrant proteomes that often do not match their corresponding transcriptome profiles. One possible cause of this discrepancy is the existence of aberrant RNA modification landscapes in the so-called epitranscriptome. Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RNA methyltransferase for 5-methylcytosine. In this setting, NSUN5 exhibits tumor-suppressor characteristics in vivo glioma models. We also found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA that drives an overall depletion of protein synthesis, and leads to the emergence of an adaptive translational program for survival under conditions of cellular stress. Interestingly, NSUN5 epigenetic inactivation also renders these gliomas sensitive to bioactivatable substrates of the stress-related enzyme NQO1. Most importantly, NSUN5 epigenetic inactivation is a hallmark of glioma patients with long-term survival for this otherwise devastating disease

Hypoxia Negatively Regulates Antimetastatic PEDF in Melanoma Cells by a Hypoxia Inducible Factor-Independent, Autophagy Dependent Mechanism

Pigment epithelium-derived factor (PEDF), a member of the serine protease inhibitor (SERPIN) superfamily, displays a potent antiangiogenic and antimetastatic activity in a broad range of tumor types. Melanocytes and low aggressive melanoma cells secrete high levels of PEDF, while its expression is lost in highly aggressive melanomas. PEDF efficiently abrogates a number of functional properties critical for the acquisition of metastatic ability by melanoma cells, such as neovascularization, proliferation, migration, invasiveness and extravasation. In this study, we identify hypoxia as a relevant negative regulator of PEDF in melanocytes and low aggressive melanoma cells. PEDF was regulated at the protein level. Importantly, although downregulation of PEDF was induced by inhibition of 2-oxoglutarate-dependent dioxygenases, it was independent of the hypoxia inducible factor (HIF), a key mediator of the adaptation to hypoxia. Decreased PEDF protein was not mediated by inhibition of translation through untranslated regions (UTRs) in melanoma cells. Degradation by metalloproteinases, implicated on PEDF degradation in retinal pigment epithelial cells, or by the proteasome, was also excluded as regulatory mechanism in melanoma cells. Instead, we found that degradation by autophagy was critical for PEDF downregulation under hypoxia in human melanoma cells. Our findings show that hypoxic conditions encountered during primary melanoma growth downregulate antiangiogenic and antimetastasic PEDF by a posttranslational mechanism involving degradation by autophagy and could therefore contribute to the acquisition of highly metastatic potential characteristic of aggressive melanoma cells

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Enteric methane mitigation strategies for ruminant livestock systems in the Latin America and Caribbean region: a meta-analysis.

Latin America and Caribbean (LAC) is a developing region characterized for its importance for global food security, producing 23 and 11% of the global beef and milk production, respectively. The region?s ruminant livestock sector however, is under scrutiny on environmental grounds due to its large contribution to enteric methane (CH4) emissions and influence on global climate change. Thus, the identification of effective CH4 mitigation strategies which do not compromise animal performance is urgently needed, especially in context of the Sustainable Development Goals (SDG) defined in the Paris Agreement of the United Nations. Therefore, the objectives of the current study were to: 1) collate a database of individual sheep, beef and dairy cattle records from enteric CH4 emission studies conducted in the LAC region, and 2) perform a meta-analysis to identify feasible enteric CH4 mitigation strategies, which do not compromise animal performance. After outlier?s removal, 2745 animal records (65% of the original data) from 103 studies were retained (from 2011 to 2021) in the LAC database. Potential mitigation strategies were classified into three main categories (i.e., animal breeding, dietary, and rumen manipulation) and up to three subcategories, totaling 34 evaluated strategies. A random effects model weighted by inverse variance was used (Comprehensive Meta-Analysis V3.3.070). Six strategies decreased at least one enteric CH4 metric and simultaneously increased milk yield (MY; dairy cattle) or average daily gain (ADG; beef cattle and sheep). The breed composition F1 Holstein × Gyr decreased CH4 emission per MY (CH4IMilk) while increasing MY by 99%. Adequate strategies of grazing management under continuous and rotational stocking decreased CH4 emission per ADG (CH4IGain) by 22 and 35%, while increasing ADG by 22 and 71%, respectively. Increased dietary protein concentration, and increased concentrate level through cottonseed meal inclusion, decreased CH4IMilk and CH4IGain by 10 and 20% and increased MY and ADG by 12 and 31%, respectively. Lastly, increased feeding level decreased CH4IGain by 37%, while increasing ADG by 171%. The identified effective mitigation strategies can be adopted by livestock producers according to their specific needs and aid LAC countries in achieving SDG as defined in the Paris Agreement