Long noncoding RNA and gene regulation in cancer
CIMA, University of Navarra
One of the most remarkable discoveries of the last decade came about thanks to the sequencing of the entire human transcriptome. It is now obvious that the majority of the cellular transcripts are produced from “non conventional” genes that do not code for proteins, and a very significant fraction of them are long noncoding RNAs (lncRNAs). Our group and others have shown that lncRNAs, despite not coding for proteins, regulate genome functions and gene expression, and that alterations in lncRNAs are inherent to human disease. For instance, we have found that lncRNAs have critical functions associated with tumor suppressors or oncogenes, such as p53 or MYC, playing key roles in cell transformation. However, our understanding of lncRNA activities and the underlying molecular mechanism are still extremely poor.
Our laboratory focuses our efforts on investigating how lncRNAs influence the regulation, propagation and expression of the genome, and how these functions are altered in cancer, which is key for the development of improved diagnostics and therapies. To that end, we combine the implementation of genomics, functional screenings with CRISPR methodologies, molecular biology as well as the analysis of patient samples. Our lines of work are:
- Role of chromatin-associated lncRNAs in the induction of cellular senescence and their impact in cancer cells.
We are investigating how lncRNAs interact differentially with the chromatin SWI/SNF complexes in proliferating and senescent cells, being required for promoter-enhancer regulation and the coordinated activation of sets of pro-oncogenic genes.
- Role of lncRNAs in the replication of human chromatin.
We aim to understand how lncRNAs, as players in chromatin dynamics- or by other means- influence genome replication and consequently have an impact in cell division and genome integrity.
In this context, we are also investigating lncRNAs functionally connected to replication stress, and assess their role in this cancer hallmark as well as their therapeutic potential.
- Interplay between lncRNA and the RNA regulatory proteins, including the proteins involved in RNA modifications. This is a poorly explored aspect of lncRNA biology that is determinant to understand the function and molecular mechanisms of lncRNAs. We are currently investigating these interactions in the context on cancer cells.
- Grossi E, Raimondi I, Goñi E, González J, Marchese FP, Chapaprieta V, Martín-Subero JI, Guo S, Huarte M. Nat Commun. 2020. A lncRNA-SWI/SNF complex crosstalk controls transcriptional activation at specific promoter regions. Feb 18;11(1):936. doi: 10.1038/s41467-020-14623-3.
- Marchese FP, Raimondi I, Huarte M.(2017) The multidimensional mechanisms of long noncoding RNA function. Genome Biol. 2017 Oct 31;18(1):206
- Marín-Béjar O, Mas AM, González J, Martinez D, Athie A, Morales X, Galduroz M, Raimondi I, Grossi E, Guo S, Rouzaut A, Ulitsky I, Huarte M. (2017) The human lncRNA LINC-PINT inhibits tumor cell invasion through a highly conserved sequence element. Genome Biol. Oct 27;18(1):202
- Marchese FP, Grossi E, Marín-Béjar O, Bharti SK, Raimondi I, González J, Martínez-Herrera DJ, Athie A, Amadoz A, Brosh RM and Huarte M (2016). A lncRNA regulates sister chromatid cohesion. Mol Cell. Aug 4;63(3):397-407.
- Huarte M (2015) The emerging roles of lncRNAs in cancer. Nat Med. 2015 Nov;21(11):1253-61
- Sánchez Y, Segura V, Marín-Béjar O, Athie A, Marchese FP, González J, Bujanda L, Guo S, Matheu A and Huarte M (2014). Genome-wide analysis of the human p53 transcriptional network unveils a lncRNA tumor suppressor signature. Nature Communications, 5:5812.
- Marin-Bejar O, Marchese FP, Athie A, Sanchez Y, Gonzalez J, Segura V, Huang L, Moreno I, Navarro A, Monzo M, Garcia-Foncillas J, Rinn JL, Guo S, Huarte M(2013). Pint lincRNA connects the p53 pathway with epigenetic silencing by the Polycomb repressive complex 2. Genome Biol 14, R104.
- Huarte, M*, Guttman, M., Feldser, D., Garber, M., Khalil, A.M., Zuk, O., Amit, I., Regev, A., Lander, E.S., Jacks, T., Rinn, J.L*. (2010). A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell 142, 409-419.