Reference

junio15Proc Natl Acad Sci U S A. 2015 May 5;112(18):5785-90. doi: 10.1073/pnas.1421197112. Epub 2015 Apr 22.

Authors

Raquel Boque-Sastre, Marta Soler, Cristina Oliveira-Mateos, Anna Portela, Catia Moutinho, Sergi Sayols, Alberto Villanueva, Manel Esteller, and Sonia Guil

Abstract

The mechanisms used by antisense transcripts to regulate their corresponding sense mRNAs are not fully understood. Herein, we have addressed this issue for the vimentin (VIM) gene, a member of the intermediate filament family involved in cell and tissue integrity that is deregulated in different types of cancer. VIM mRNA levels are positively correlated with the expression of a previously uncharacterized head-to-head antisense transcript, both transcripts being silenced in colon primary tumors concomitant with promoter hypermethylation. Furthermore, antisense transcription promotes formation of an R-loop structure that can be disfavored in vitro and in vivo by ribonuclease H1 overexpression, resulting in VIM down-regulation. Antisense knockdown and R-loop destabilization both result in chromatin compaction around the VIM promoter and a reduction in the binding of transcriptional activators of the NF-κB pathway. These results are the first examples to our knowledge of R-loop–mediated enhancement of gene expression involving head-to-head antisense transcription at a cancer-related locus.

Description

En los últimos años la visión del RNA no codificante de proteínas ha cambiado radicalmente, de llamarlo “genoma basura” a apreciar la variedad de funciones independientemente de la capacidad codificante de estos RNAs. Los transcritos naturales antisense (NATs, RNAs endógenos que se solapan total o parcialmente con transcritos originados en la cadena contraria) son el tipo más abundante de RNAs no codificantes largos (lncRNAs). Se estima que un 50-70% de los transcritos tienen su correspondiente antisense. Aún así, se sabe muy poco del mecanismo que utilizan los transcritos antisense para regular al RNA mensajero de la cadena contraria (el transcrito sense). En nuestro grupo hemos descrito el primer caso de activación transcripcional que involucraría la formación de un híbrido RNA:DNA (o R loop) con participación del transcrito antisense no codificante cerca del inicio de transcripción del gen vimentina (VIM), el cual es muy importante en la progresión tumoral de distintos tipos de cánceres. Esta estructura favorece la descondensación local de la cromatina y la unión de factores de transcripción. Esta investigación confiere a los R loops formados por un transcrito antisense un papel regulador positivo hasta ahora desconocido, lo que abre las puertas a estudiar este mecanismo en más genes relacionados con cáncer.

pnas boque sastrefotogrupo

REFERENCIA DEL GRUPO INVESTIGADOR

El grupo de Epigenética del Cáncer del Instituto de Investigación Biomédica de Bellvitge (IDIBELL) dirigido por el Dr. Manel Esteller tiene como objetivo la investigación de las alteraciones de la metilación del DNA, las modificaciones de histonas y el RNA no codificante de proteínas (ncRNAs), para encontrar la relación de estos fenómenos con el desarrollo del cáncer en humanos. En concreto la investigadora Sònia Guil se centra en el estudio de funciones reguladoras por parte de ncRNAs que actúen a nivel transcripcional o post-transcripcional y que puedan tener un impacto en la expresión génica de genes de especial interés en cáncer.

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