The Epigenetics Group is a consolidated group at IMIBIC. It comprises 7 people (2 researchers, 3 post-docs, 1 pre-doc and 1 technical staff) and performs basic and applied research at the interface between Epigenetics, DNA Repair and human disease.
Our primary research area is focused on developing molecular tools for epigenetic editing in human cells. Abnormal gene silencing through deposition of epigenetic marks such as DNA methylation is a hallmark of human diseases such as cancer. We are combining CRISPR technology with enzymes that initiate active DNA demethylation through DNA repair-like mechanisms for targeted reactivation of aberrantly methylated genes in cancer cells. We have shown that overexpression of a heterologous DNA demethylase in human cancer cells partially reverts their aberrant methylome to normal levels, causing reduced tumorigenesis in vivo. Additionally, we have recently achieved targeted DNA demethylation in human cells by fusion of a DNA demethylase to an RNA-guided dCAS9 protein. Results derived from our research may provide useful tools to epigenetically reprogram tumor cells in vitro and in vivo.
A second research area of our group is focused in understanding the interconnection between Epigenetics and DNA Repair pathways. Accumulating evidence points towards important but poorly understood mechanistic links between DNA demethylation and Base Excision Repair processes, both in humans and other organisms. Using as a model organism the plant Arabidopsis thaliana, we have shown that DNA repair and demethylating factors cooperate in genome maintenance and epigenome modification processes. We are now making use of the knowledge gained in plants to decipher similar mechanisms operating in human cells. Since pharmacological inhibition of DNA repair and Epigenetic processes in tumor cells is a promising approach in therapy, results in this research area may contribute to design improved cancer treatments.
The long term goal of our group is to translate mechanistic findings gained through basic research in humans and other organisms into the implementation of useful diagnostic and therapeutic tools.
Our group collaborates with other IMIBIC´s groups, such as GC06 (New Therapies in Cancer) and GC03 (Infectious Diseases).
We have also successful collaborative links with the Biotech Company CANVAX.
Lines of Research
Patterns of DNA methylation, an important epigenetic modification involved in gene silencing and development, are disrupted in cancer cells. Understanding the functional significance of aberrant methylation in tumors remains challenging, due in part to the lack of suitable tools to actively modify methylation patterns. DNA demethylation caused by mammalian DNA methyltransferase inhibitors is transient and replication-dependent, whereas that induced by TET enzymes involves oxidized 5-meC derivatives that perform poorly understood regulatory functions. Unlike animals, plants possess enzymes that directly excise unoxidized 5-meC from DNA, allowing restoration of unmethylated C through Base Excision Repair. The CRISPR/Cas9 technology can be repurposed for transcriptional regulation. We are using a catalytically inactive Cas9 (dCas9) in combination with sgRNAs for targeted delivery of plant DNA demethylases to specific loci in human cancer cells.
Recent research in both animal and plant cells strongly suggest that Base Excision Repair and active DNA demethylation are closely intertwined processes. However, the mechanisms involved are poorly understood. Knowledge gained through organisms amenable to genetic and biochemical may help to advance in this area. Using Arabidopsis as a model system we have recently demonstrated that the DNA repair factor DDB2 controls the DNA demethylation pathway and that, conversely, components of the DNA demethylation process pathway are involved in repair of DNA damage induced by alkylating agents. We are now using such knowledge to decipher similar mechanistic links operating in human cells.
Networks
CA18111 - COST Action - Genome editing in plants - a technology with transformative potential (PlantEd)
Key Words
- epigenetics
- DNA repair
- cancer
- DNA methylation
- DNA demethylation
- DNA glycosylases
- base excision repair
Información Adicional
Link to Group´s Web Page: EPIREP
Recent publications
Parrilla-Doblas JT, Roldán-Arjona T, Ariza RR, Córdoba-Cañero D. (2019) Active DNA Demethylation in Plants. Int J Mol Sci. 21;20(19). pii: E4683. doi: 10.3390/ijms20194683.
Roldán-Arjona T, Ariza RR, Córdoba-Cañero D. DNA Base Excision Repair in Plants: An Unfolding Story With Familiar and Novel Characters (2019) Front Plant Sci. 10:1055. doi: 10.3389/fpls.2019.01055.
Cabral Medeiros NM, Córdoba-Cañero D, García-Gil CB, Ariza RR, Roldán-Arjona T, Scortecci K. (2019) Characterization of an AP endonuclease from sugarcane - ScARP1. Biochem Biophys Res Commun. Jun 30;514(3):926-932.
Morales-Ruiz T, Romero-Valenzuela ÁC, Vázquez-Grande VM, Roldán-Arjona T, Ariza RR, Córdoba-Cañero D. (2018) Monitoring base excision repair in Chlamydomonas reinhardtii cell extracts. DNA Repair (Amst). May;65:34-41.
Martínez-Losada C, Serrano-López J, Serrano-López J, Noguera NI, Garza E, Piredda L, Lavorgna S, Consalvo MAI, Ottone T, Alfonso V, Peinado JR, Garcia-Ortiz MV, Morales-Ruiz T, Jérez A, Hurtado AM, Montesinos P, Cervera J, Such E, Ibañez M, Sempere A, Sanz MÁ, Lo-Coco F, Sánchez-García J. (2018) Clonal genetic evolution at relapse of favorable-risk acute myeloid leukemia with NPM1 mutation is associated with phenotypic changes and worse outcomes. Haematologica. 2018 Sep;103(9):e400-e403. doi: 10.3324/haematol.2018.188433.
Barbado, C., Córdoba-Cañero, D., Ariza, R.R., and Roldán-Arjona, T. (2018). Nonenzymatic release of N7-methylguanine channels repair of abasic sites into an AP endonuclease-independent pathway in Arabidopsis. Proc Natl Acad Sci U S A. Jan 30;115(5):E916-E924
Morales-Ruiz, T., Garcia-Ortiz, M.V., Devesa-Guerra, I., Raya-Ruiz, L., Tejedor, J.R., Bayon, G.F., Sierra, M.I., Fraga, M.F., Ariza, R.R., and Roldán-Arjona, T. (2018). DNA methylation reprogramming of human cancer cells by expression of a plant 5-methylcytosine DNA glycosylase. Epigenetics ;13(1):95-107.
Parrilla-Doblas, J.T., Ariza, R.R., and Roldán-Arjona, T. (2017). Targeted DNA demethylation in human cells by fusion of a plant 5-methylcytosine DNA glycosylase to a sequence-specific DNA binding domain. Epigenetics 12, 296-303.
Córdoba-Cañero, D., Cognat, V., Ariza, R.R., Roldán Arjona, T., and Molinier, J. (2017). Dual control of ROS1-mediated active DNA demethylation by DNA damage-binding protein 2 (DDB2). Plant J 92, 1170-1181.
Awards
First Prize to the best oral presentation at the III Congress of Young Researchers in Biomedicine to Macarena Dorado León (2019)
Fundación Torres Gutierrez award to the best research paper published in 2018 to Casimiro Barbado Garcia-Gil.
University of Córdoba Young Investigators Research Prize Jacobo Cárdenas (2015 edition) awarded to Dr. Jara Teresa Parrilla Doblas.
