Genome-wide profiling of p53-regulated enhancer RNAs uncovers a subset of enhancers controlled by a lncRNA

p53 binds enhancers to regulate key target genes. Here, we globally mapped p53-regulated enhancers by looking at enhancer RNA (eRNA) production. Intriguingly, while many p53-induced enhancers contained p53-binding sites, most did not. As long non-coding RNAs(lncRNAs) are prominent regulators of chromatin dynamics, we hypothesized that p53-induced lncRNAs contribute to the activation of enhancers by p53. Among p53-induced lncRNAs, we identified LED and demonstrate that its suppression attenuates p53 function. Chromatin-binding and eRNA expression analyses show that LED associates with and activates strong enhancers. One prominent target of LED was located at an enhancer region within CDKN1A gene, a potent p53-responsive cell cycle inhibitor. LED knockdown reduces CDKN1A enhancer induction and activity, and cell cycle arrest following p53 activation. Finally, promoter-associated hypermethylation analysis shows silencing of LED in human tumours. Thus, our study identifies a new layer of complexity in the p53 pathway and suggests its dysregulation in cancer

N-BLR, a primate-specific non-coding transcript leads to colorectal cancer invasion and migration

Background: non-coding RNAs have been drawing increasing attention in recent years as functional data suggest that they play important roles in key cellular processes. N-BLR is a primate-specific long non-coding RNA that modulates the epithelial-to-mesenchymal transition, facilitates cell migration, and increases colorectal cancer invasion. Results: we performed multivariate analyses of data from two independent cohorts of colorectal cancer patients and show that the abundance of N-BLR is associated with tumor stage, invasion potential, and overall patient survival. Through in vitro and in vivo experiments we found that N-BLR facilitates migration primarily via crosstalk with E-cadherin and ZEB1. We showed that this crosstalk is mediated by a pyknon, a short ~20 nucleotide-long DNA motif contained in the N-BLR transcript and is targeted by members of the miR-200 family. In light of these findings, we used a microarray to investigate the expression patterns of other pyknon-containing genomic loci. We found multiple such loci that are differentially transcribed between healthy and diseased tissues in colorectal cancer and chronic lymphocytic leukemia. Moreover, we identified several new loci whose expression correlates with the colorectal cancer patients' overall survival. Conclusions: the primate-specific N-BLR is a novel molecular contributor to the complex mechanisms that underlie metastasis in colorectal cancer and a potential novel biomarker for this disease. The presence of a functional pyknon within N-BLR and the related finding that many more pyknon-containing genomic loci in the human genome exhibit tissue-specific and disease-specific expression suggests the possibility of an alternative class of biomarkers and therapeutic targets that are primate-specific

The dynamic DNA methylomes of double-stranded DNA viruses associated with human cancer

The natural history of cancers associated with virus exposure is intriguing, since only a minority of human tissues infected with these viruses inevitably progress to cancer. However, the molecular reasons why the infection is controlled or instead progresses to subsequent stages of tumorigenesis are largely unknown. In this article, we provide the first complete DNA methylomes of double-stranded DNA viruses associated with human cancer that might provide important clues to help us understand the described process. Using bisulfite genomic sequencing of multiple clones, we have obtained the DNA methylation status of every CpG dinucleotide in the genome of the Human Papilloma Viruses 16 and 18 and Human Hepatitis B Virus, and in all the transcription start sites of the Epstein-Barr Virus. These viruses are associated with infectious diseases (such as hepatitis B and infectious mononucleosis) and the development of human tumors (cervical, hepatic, and nasopharyngeal cancers, and lymphoma), and are responsible for 1 million deaths worldwide every year. The DNA methylomes presented provide evidence of the dynamic nature of the epigenome in contrast to the genome. We observed that the DNA methylome of these viruses evolves from an unmethylated to a highly methylated genome in association with the progression of the disease, from asymptomatic healthy carriers, through chronically infected tissues and pre-malignant lesions, to the full-blown invasive tumor. The observed DNA methylation changes have a major functional impact on the biological behavior of the viruses

Des-Dobra: re-visão e tradução. A construção da poetisa em Adília Lopes = Des-Pliegue: re-visión y traducción. La construcción de la poetisa en Adília Lopes

[por] É nosso propósito, neste trabalho doutoral, ler a obra da poetisa portuguesa contemporânea Adília Lopes (Lisboa, 1960), a partir de uma perspetiva ginocrítica, suportada pelos Estudos de Género, e mais particularmente Feministas, refletindo, simultânea e consequentemente, sobre as questões levantadas pela escrita de mulheres, assim como apresentar uma leitura inserida num quadro de transcriação tradutológica. O projeto literário Adília Lopes raramente surge associado a um pensamento feminista ou politicamente interventivo. O presente estudo tem por objetivo principal sublinhar, precisamente, as relações entre a componente intervencionista e de luta do feminismo e o empenho da artista/cidadã na construção uma sociedade igualitária. Aceitando a perspetiva ginocrítica -na esteira de Elaine Showalter, Hélène Cixous ou Anna Klobucka- como modelo interpretativo que tem por objeto a mulher enquanto produtora de significado textual e, simultaneamente, como paradigma científico e académico, a primeira parte do nosso trabalho atenta na construção da autora de poesia, a poetisa, através do uso da pseudonímia feminina e da figura da autobiografia, concluindo da sua eficácia enquanto ato de resistência e denúncia dos jogos de autoridade e poder, baseados na dicotomia feminino / masculino. Neste situar do sujeito escritora em contexto, abordam-se as representações do corpo na idade pós-moderna na qual inscrevemos a nossa autora. Desta forma, destacamos o modo como se entrelaça, de forma complexa, a urdidura do pensamento feminista e pós-feminista com a conceção pós-modernista da história, da sociedade e do homem. Considerando a escrita adiliana um produto do seu tempo, estabelecemos as ligações da poesia de Lopes ao marco tipológico representado pelo pós-modernismo. Contudo, antes de procedermos à ilustração e à análise da forma como as coordenadas deste movimento se consubstanciam na obra adiliana, examinamos as grandes etapas do percurso histórico deste conceito periodológico. Neste sentido, damos especial destaque à sua perigosa ligação com os feminismos que entendemos plurais e diversos. Num segundo momento do nosso estudo, atentamos nas linhas de força da escrita de Adília Lopes, reveladas pela ferramenta intertextual e pelo seu diálogo incessante e peculiar com o mundo. Inscrevemos as histórias de Adília e Maria José nas narrativas feministas, destacando a politização da sua escrita, oriunda de uma personalização identitária que age como uma âncora que a localiza no seu corpo, na sua rua, na cidade, no país, no mundo. Vemos, por fim, de que forma a excessiva pessoalização do sujeito poético adiliano torna a sua escrita impessoal, no sentido dado por Roberto Esposito, a partir da reflexão da filósofa Simone Weil. A terceira pessoa, o terceiro corpo que emerge desta desagregação pessoal, celebra a comunhão cristã e redentora de Adília Lopes com o mundo dos homens. Na última parte deste trabalho académico, e propondo uma outra forma de leitura, apresentamos a tradução para castelhano do Clube da Poetisa Morta, publicado em 1997. Na perspetiva hermenêutico-tradutológica adotada, a tradução do texto literário apresenta-se sempre como uma re-visão criativa do texto original e um desvelamento ou uma instauração de novos horizontes de sentido. A tradutora assentará o seu plano de tradução no conceito de “projeto menorizante”, segundo o formato proposto por Lawrence Venuti, e privilegiará o “écart” (desvio) em detrimento da diferença textual, comungando assim com a reflexão filosófica de François Jullien a propósito do desvio e da diferença. O livro selecionado anuncia, desde o título, várias linhas de leitura presentes na obra adiliana, sejam a ironia iconoclasta, a temática da morte (figurada e literal), a miséria humana, motivo fundamental na poesia impessoal da autora, passando pelas referências à cultura popular, à religião católica e a culturemas específicos que fazem deste conjunto poemático um exemplo da escrita distintiva da poetisa portuguesa.[eng] This dissertation aims to read the poetry of the Portuguese author Adília Lopes (Lisbon, 1960) from a gynocritical perspective rooted in Gender Studies and more precisely Women’s Studies. It analyzes questions raised by women’s writing and, as a different form of reading, offering a recreation based on translation. At her début, Adília Lopes was only published by marginal editors and was labeled as an eccentric author whose writing could not be thought as poetry. In spite of the belated interest, the author is now recognized by scholars and renown editors, such as Assírio & Alvim. Nevertheless, the literary project named Adília Lopes was not often associated with a feminist or even political thought. For this reason, this study intends to reveal that Lopes’ poetry postulates a third way, a third body personified in writing and which resists the classifications and the impositions of a cruel, unequal, and profoundly individualistic society. Through her impersonal stylistic mode, the author’s poetry inscribes itself within both the necessary revision of past models and a new textual perspective. Reading the Adilian canon in the light of a gynocritical paradigm which fixes woman as a subject, rather than as a mere object, we find the foundations and processes that construct the feminine and the masculine in the poetic tissue, as they are represented in Lopes’ poetry, in the author’s ironic handling of stereotypes and clichés. Considering the close relation between this theoretical framework and new approaches to the postmodern lyric subject, this thesis also investigates the fabrication of a textual identity for a lyrical self, understood as the construction of the woman who writes poetry, that is, the composition of the poetess. The final part of the thesis proposes another reading practice promotted by the exercise in translating Adília Lopes’ book Clube da Poetisa Morta (“Dead poetess society”) into Spanish. With this purpose, the study reflects on translation as an intercultural, interpersonal and “inter-authorial” act. It focuses, thus, on some generic aspects about translation and, specifically, the translation of poetry. The woman translator that consciously undertakes the role of translator privileges a “minoritizing project” as defined by Venuti and centers on the notion of “écart” (deviation) to the detriment of the textual difference

Correction for Melo et al., Small molecule enoxacin is a cancer-specific growth inhibitor that acts by enhancing TAR RNA-binding protein 2-mediated microRNA processing

Medical sciences: correction for "Small molecule enoxacin is a cancer-specific growth inhibitor that acts by enhancing TAR RNA-binding protein 2-mediated microRNA processing," by SoniaMelo, Alberto Villanueva, Catia Moutinho, Veronica Davalos, Riccardo Spizzo, Cristina Ivan, Simona Rossi, Fernando Setien, Oriol Casanovas, Laia Simo-Riudalbas, Javier Carmona, Jordi Carrere, August Vidal, Alvaro Aytes, Sara Puertas, Santiago Ropero, Raghu Kalluri, Carlo M. Croce, George A. Calin, and Manel Esteller, which appeared in issue 11, March 15, 2011, of Proc Natl Acad Sci USA (108:4394-4399; first published February 28, 2011; 10.1073/pnas.1014720108)