Epigenetic silencing of TGFBI confers resistance to trastuzumab in human breast cancer

Background: acquired resistance to trastuzumab is a major clinical problem in the treatment of HER2-positive (HER2+) breast cancer patients. The selection of trastuzumab-resistant patients is a great challenge of precision oncology. The aim of this study was to identify novel epigenetic biomarkers associated to trastuzumab resistance in HER2+ BC patients. Methods: we performed a genome-wide DNA methylation (450K array) and a transcriptomic analysis (RNA-Seq) comparing trastuzumab-sensitive (SK) and trastuzumab-resistant (SKTR) HER2+ human breast cancer cell models. The methylation and expression levels of candidate genes were validated by bisulfite pyrosequencing and qRT-PCR, respectively. Functional assays were conducted in the SK and SKTR models by gene silencing and overexpression. Methylation analysis in 24 HER2+ human BC samples with complete response or non-response to trastuzumab-based treatment was conducted by bisulfite pyrosequencing. Results: epigenomic and transcriptomic analysis revealed the consistent hypermethylation and downregulation of TGFBI, CXCL2, and SLC38A1 genes in association with trastuzumab resistance. The DNA methylation and expression levels of these genes were validated in both sensitive and resistant models analyzed. Of the genes, TGFBI presented the highest hypermethylation-associated silencing both at the transcriptional and protein level. Ectopic expression of TGFBI in the SKTR model suggest an increased sensitivity to trastuzumab treatment. In primary tumors, TGFBI hypermethylation was significantly associated with trastuzumab resistance in HER2+ breast cancer patients. Conclusions: our results suggest for the first time an association between the epigenetic silencing of TGFBI by DNA methylation and trastuzumab resistance in HER2+ cell models. These results provide the basis for further clinical studies to validate the hypermethylation of TGFBI promoter as a biomarker of trastuzumab resistance in HER2+ breast cancer patients

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

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 RNA5 (mRNA5). 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

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

Altres ajuts: Funding for this research was provided by the Asociación Española Contra el Cáncer Scientific Foundation (Accelerator Award A26825); and the Olga Torres Foundation.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

Analysis of the circRNA and T-UCR populations identifies convergent pathways in mouse and human models of Rett syndrome

Noncoding RNAs play regulatory roles in physiopathology, but their involvement in neurodevelopmental diseases is poorly understood. Rett syndrome is a severe, progressive neurodevelopmental disorder linked to loss-of-function mutations of the MeCP2 gene for which no cure is yet available. Analysis of the noncoding RNA profile corresponding to the brain-abundant circular RNA (circRNA) and transcribed-ultraconserved region (T-UCR) populations in a mouse model of the disease reveals widespread dysregulation and enrichment in glutamatergic excitatory signaling and microtubule cytoskeleton pathways of the corresponding host genes. Proteomic analysis of hippocampal samples from affected individuals confirms abnormal levels of several cytoskeleton-related proteins together with key alterations in neurotransmission. Importantly, the glutamate receptor GRIA3 gene displays altered biogenesis in affected individuals and in vitro human cells and is influenced by expression of two ultraconserved RNAs. We also describe post-transcriptional regulation of SIRT2 by circRNAs, which modulates acetylation and total protein levels of GluR-1. As a consequence, both regulatory mechanisms converge on the biogenesis of AMPA receptors, with an effect on neuronal differentiation. In both cases, the noncoding RNAs antagonize MeCP2-directed regulation. Our findings indicate that noncoding transcripts may contribute to key alterations in Rett syndrome and are not only useful tools for revealing dysregulated processes but also molecules of biomarker value

Women in (Dis)placement: The Field of Studies on Migrations, Social Remittances, Care and Gender in Chile

This article presents current perspectives on the gender approach to the study of migration in Chile between 1990 and 2018, contextualizing it in light of international debates in the social sciences. We will discuss how the feminization and the growth of Latin American migrations have given rise to a prolific field of research, as exemplified by studies conducted in central and northern Chile. We will show how the concepts of social remittances and caregiving permeate the Chilean debate on migrant women. We conclude with reflections on topics and perspectives to be incorporated into the Chilean research agenda on gender and migration.Se presenta un estado del arte sobre el enfoque de género en los estudios de la migración en Chile entre 1990 y 2018, contextualizándolo a la luz de debates internacionales de las ciencias sociales. Abordaremos cómo la feminización y el incremento de las migraciones latinoamericanas inauguran un prolijo campo de investigaciones, articulado a través de estudios desarrollados en el centro y en el norte de Chile. Señalaremos cómo los conceptos de remesas sociales y cuidados permean el debate chileno sobre las mujeres migrantes. Finalizamos con reflexiones sobre temas y perspectivas a ser incorporados en la agenda chilena de investigaciones sobre género y migración.The authors would like to thank the Chilean National Commission for Scientific and Technological Research (CONICYT) for funding the study that led to this article through Fondecyt Regular Project number 1160683: “Ser Mujer Mayor en Santiago. Organización social de los cuidados, feminización del envejecimiento y desigualdades acumuladas” (“Being an older woman in Santiago. Social organization of care, feminization of ageing and accumulated inequalities”), led by Herminia Gonzálvez Torralbo and Fondecyt Regular Project number 1190056: “The Boundaries of Gender Violence: Migrant Women’s Experiences in South American Border Territories” led by Menara Lube Guizardi

The transcribed ultraconserved region uc.160+ enhances processing and A-to-I editing of the miR-376 cluster : hypermethylation improves glioma prognosis

Altres ajuts:We thank the CERCA program (Generalitat de Catalunya) and the Josep Carreras Foundation for institutional support. This work was supported by the Ministerio de Ciencia e Innovación (MCI)-Agencia Estatal de Investigación (AEI) and the Instituto de Salud Carlos III (ISCIII), cofinanced by the European Development Regional Fund, 'A way to achieve Europe' ERDF, under grant numbers PID2019-111658RB-I00 (SG), RTI2018-094049-B-I00 'EPIRNA' (ME), and the Health and Science Departments of the Catalan Government (Generalitat de Catalunya).Transcribed ultraconserved regions (T-UCRs) are noncoding RNAs derived from DNA sequences that are entirely conserved across species. Their expression is altered in many tumor types, and, although a role for T-UCRs as regulators of gene expression has been proposed, their functions remain largely unknown. Herein, we describe the epigenetic silencing of the uc.160+ T-UCR in gliomas and mechanistically define a novel RNA-RNA regulatory network in which uc.160+ modulates the biogenesis of several members of the miR-376 cluster. This includes the positive regulation of primary microRNA (pri-miRNA) cleavage and an enhanced A-to-I editing on its mature sequence. As a consequence, the expression of uc.160+ affects the downstream, miR-376-regulated genes, including the transcriptional coregulators RING1 and YY1-binding protein (RYBP) and forkhead box P2 (FOXP2). Finally, we elucidate the clinical impact of our findings, showing that hypermethylation of the uc.160+ CpG island is an independent prognostic factor associated with better overall survival in lower-grade gliomas, highlighting the importance of T-UCRs in cancer pathophysiology

Estudio del transporte madre-hijo de anticuerpos antiestreptoquinasa

Se estudió cómo se comporta el transporte de anticuerpos anti-estreptoquinasa entre la madre y el recién nacido y cuáles son los factores que influyen en este. Se colectaron 125 muestras sanguíneas de puérperas, por la vena antecubital y de sus respectivos hijos a partir del cordón umbilical. Se confeccionaron encuestas para la recolección de datos a partir de las historias clínicas de las madres y los recién nacidos. Se empleó un método inmunoenzimático, heterogéneo, cualitativo, tipo sandwich de doble antígeno para la detección de anticuerpos anti-estreptoquinasa. A partir de los resultados obtenidos se concluyó que existe un transporte activo de los anticuerpos anti-estreptoquinasa de la madre al feto y que este transporte se ve influenciado por la edad cronológica de la madre, la edad gestacional, el estado nutricional de la madre y el peso del recién nacido.The behavior of the transport of streptokinase antibodies from the mother to the newborn infant, as well as the factors influencing on it, were studied here. 125 blood samples were obtained from the antecubital vein of the puerperas and from the umbilical cord of their children. Surveys were done to collect data from the medical histories of the mothers and the newborn infants. An immunoenzimatic, heterogenous and qualitatitve sandwich doble antigen method was used to detect anti-streptokinase antibodies. According to the results, it was concluded that there is an active transport of anti-streptokinase antibodies from the mother to the fetus and that this transport is influenced by the chronological age of the mother, the gestational age, the mother’s nutritional status and the birth weight

Switch to ocrelizumab in MS patients treated with natalizumab in extended interval dosing at high risk of PML: A 96-week follow-up pilot study

We aimed to assess the long-term safety and effectiveness of ocrelizumab in a cohort of patients with multiple sclerosis (MS) at high risk of progressive multifocal leukoencephalopathy (PML), previously treated with natalizumab in extending interval dosing (EID), who switched to ocrelizumab and to compare them with patients who continued EID-natalizumab. Thirty MS patients previously treated with natalizumab in EID (every 8 weeks) were included in this observational retrospective cohort study. Among them, 17 patients were switched to ocrelizumab and 13 continued with EID-natalizumab. Except for the John Cunningham virus (JCV) index, no significant differences were detected between both groups. Main outcome measures included: annualized relapse rate (ARR), radiological activity, disability progression, and the NEDA-3 index. Patients were followed for 96 weeks. The median washout period in ocrelizumab-switchers was 6 weeks. Among them, AAR and radiological activity during follow-up were 0.03, without significant differences in comparison with the previous period on natalizumab-EID. The comparison between ocrelizumab-switchers and patients continuing on EID-natalizumab showed no significant differences in AAR, radiological activity, or disability progression. However, the proportion of patients maintaining a NEDA-3 status in week 96 was slightly superior among ocrelizumab-switchers (94 vs 69%). No serious adverse events were observed in any group. In conclusion, switching from EID-natalizumab to ocrelizumab can be considered as a therapeutic option, particularly in patients with MS at high risk of PML, to mitigate the risks of both PML and disease reactivationFunding: This study received funding from IDIVAL (CSI 19/51 and CSI21/73). The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publicatio

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

Altres ajuts: Funding for this research was provided by the Asociación Española Contra el Cáncer Scientific Foundation (Accelerator Award A26825); and the Olga Torres Foundation.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