Summary
The focus of our research is the study of the emerging roles of noncoding RNAs as key regulators of gene expression in physiological cellular programs and also at the onset or progression of human diseases, with a major interest in tumorigenesis. Research in the group combines a battery of biochemical, cellular, and global genomic approaches to dissect mechanisms of gene expression regulation with the participation of ncRNAs. Our recent publications have uncovered new RNA–RNA cross-talk and regulatory networks of relevance in cancer (Liz et al., Mol Cell 2014); the identification of new mechanisms for lncRNA-mediated gene expression regulation through the formation of R loops (Boque-Sastre et al, Proc. Natl. Acad. Sci USA 2015), the silencing of particular lncRNAs involved in the p53 pathway in human cancers (Diaz-Lagares et al, Proc. Natl. Acad. Sci USA 2016), or the aberrant reexpression of oncofetal lncRNAs in a variety of tumors (Oliveira-Mateos et al, Nat Comm 2019).
Research
The current research lines of the group can be grouped under the following projects:
1. New regulatory roles for LONG noncoding RNAs (lncRNAs): specifically, we study antisense transcripts and their mechanism of action as gene expression modulators, specially acting as epigenetic regulators at the chromatin level in both physiological and disease state. In many instances, these lncRNAs function by interacting and guiding chromatin remodelling complexes (including both DNA and histone modifiers) towards their target sites in the genome to exert gene activating or repressing roles. Their dysregulation is at the basis of a variety of pathologies, including cancer.
2. Oncofetal lncRNAs: we investigate the function of certain lncRNAs in maintaining undifferentiated, highly proliferative states during normal embryonic development and tissular differentiation and how their expression is reactivated in cancer to sustain cancer cell stemness. One major aim is to deepen in the translational character of our research through searching for potent biomarkers and/or therapeutic targets among the ncRNA species.
3. RNA-RNA interactions and their impact in fundamental cellular processes: we are specially interested in miRNA biogenesis: a variety of proteins can fine-tune the processing and maturation of specific miRNA sequences both in the cell nucleus and in the cytoplasm. We investigate how certain lncRNAs can also influence miRNA production through direct RNA-RNA interaction by enhancing or interfering with the Microprocessor machinery.
Molecular basis of Rett syndrome: we aim to profile the alterations in the noncoding transcriptome contributing to this severe neurodevelopmental disease. The brain is the tissue where the RNA-dependent regulatory mechanisms display their highest level of complexity. We use both murine and human models of the syndrome to investigate how changes in specific ncRNA species help define the physiopathology of the syndrome. We are currently focusing our efforts in circularRNAs and transcribed ultraconserved regions, 2 of the most poorly characterised RNA species.
Awards
Fellowships and awards received by the members of the group include:
- 1999-2002: Pre-doctoral “BEFI” Research Fellowship from the Instituto de Salud Carlos III, Ministerio de Eduación y Ciencia. Sònia Guil
- 2004-2006: Post-doctoral “EMBO” long-term Fellowship from the European Molecular Biology Organisation. Sònia Guil
- 2008-2013: “Ramón y Cajal” contract for Senior Researchers from the Ministerio de Educación y Ciencia. Sònia Guil
- 2014-2017: Pre-doctoral fellowship from the Basque Government. Cristina Oliveira
2016-2020: Pre-doctoral fellowship from the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, Brasil). Edilene Siqueira
Collaborations
Drs. Lourdes Farré and Alberto Villanueva, ICO/IDIBELL, L’Hospitalet.
Dr. Antonio Gentilella, IDIBELL, L’Hospitalet.
Dr. Oscar Martínez-Tirado, IDIBELL, L’Hospitalet
Dr. Artur Llobet, UB/IDIBELL, L’Hospitalet.
Dr. Jeroen Pasterkamp, UMC Utrecht, The Netherlands.
Dr. Daniela Palacios, HSantaLucia, Roma, Italy.
Dr. George Calin, MD Anderson Cancer Center, The University of Texas, USA.
Selected publications
Oliveira-Mateos C, Sánchez-Castillo A, Soler M, Obiols-Guardia A, Piñeyro D, Boque-Sastre R, Calleja-Cervantes ME, Castro de Moura M, Martínez-Cardús A, Rubio T, Pelletier J, Martínez-Iniesta M, Herrero-Martín D, Tirado OM, Gentilella A, Villanueva A, Esteller M, Farré L, Guil S
The transcribed pseudogene RPSAP52 enhances the oncofetal HMGA2-IGF2BP2-RAS axis through LIN28B-dependent and independent let-7 inhibition.
Nat Commun 4 Set 2019, 10 (1) 3979. Epub 4 Set 2019One largely unknown question in cell biology is the discrimination between inconsequential and functional transcriptional events with relevant regulatory functions. Here, we find that the oncofetal HMGA2 gene is aberrantly reexpressed in many tumor types together with its antisense transcribed pseudogene RPSAP52. RPSAP52 is abundantly present in the cytoplasm, where it interacts with the RNA binding protein IGF2BP2/IMP2, facilitating its binding to mRNA targets, promoting their translation by mediating their recruitment on polysomes and enhancing proliferative and self-renewal pathways. Notably, downregulation of RPSAP52 impairs the balance between the oncogene LIN28B and the tumor suppressor let-7 family of miRNAs, inhibits cellular proliferation and migration in vitro and slows down tumor growth in vivo. In addition, high levels of RPSAP52 in patient samples associate with a worse prognosis in sarcomas. Overall, we reveal the roles of a transcribed pseudogene that may display properties of an oncofetal master regulator in human cancers.
Més informacióBoque-Sastre R, Guil S
A lncRNA Decoy Predicts Sensitivity to Cisplatin.
Trends Mol Med Abr 2020, 26 (4) 352-354. Epub 18 Feb 2020In a recent iScience paper by Fan et al., the long noncoding (lnc)RNA CISAL is shown to form a DNA-RNA triplex and to directly regulate BRCA1 transcription, thereby increasing cisplatin sensitivity and serving as a treatment efficacy biomarker. This opens promising avenues of research from both mechanistic and translational perspectives.
Més informacióSiqueira E, Obiols-Guardia A, Jorge-Torres OC, Oliveira-Mateos C, Soler M, Ramesh-Kumar D, Setién F, van Rossum D, Pascual-Alonso A, Xiol C, Ivan C, Shimizu M, Armstrong J, Calin GA, Pasterkamp RJ, Esteller M, Guil S
Analysis of the circRNA and T-UCR populations identifies convergent pathways in mouse and human models of Rett syndrome.
Mol Ther Nucleic Acids 8 Mar 2022, 27 621-644. Epub 22 Des 2021Noncoding 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.
Més informacióCurrent projects
Pseudogenes como arn oncofetales largos no codificantes: caracterizacion funcional e implicaciones para la terapia contra el cancer
| Responsable: | Sonia Guil |
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| Codi: | PID2019-111658RB-I00 |
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| Financiadors: | |
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| Data d'inici: | 01/06/2020 |
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| Data de finalització: | 30/11/2023 |
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