The main goal of my group is to understand how chromatin of regulatory elements and gene bodies change during transcription, how these changes are regulated and inherited through epigenetic mechanisms and what protein factors are responsible for them. We specially investigate how alteration of these chromatin mechanisms are implicated in human disease, particularly in cancer.
- Chromatin Remodeling and Gene expression
- Relationship between 3D chromatin structure and gene expression
- Metastasis epigenetics: Epigenetic changes during epithelial to mesenchymal transition and its reversion.
Chromatin Remodeling and Gene expression.
Chromatin is the network where the metabolism of DNA occurs, including transcription, replication, repair and recombination. All the enzymatic machineries that have to reach the DNA for these processes require the previous concourse of chromatin remodelling complexes that open the chromatin. Some of these remodelers alter histone-DNA interactions using the energy of ATP hydrolysis. Alterations of these machineries often result in congenital malformations and cancer. Currently we are studying the role in transcriptional regulation of one of these proteins called CHD8. CHD8 binds the promoter of transcriptionally active genes (Figure 1) and controls its expression (Rodríguez-Paredes et al., 2009; Subtil-Rodríguez et al., 2014). We have recently uncovered that CHD8 is also required to activate progesterone dependent enhancers (Subtil-Rodríguez et al., 2015). We also study the role of the chromatin remodeling SWI/SNF complex in cancer (Alfonso-Perez et al., 2014).
Relationship between 3D chromatin structure and gene expression
We also study the relationship between 3D chromatin contacts and gene expression through computational methods. The study of co-transcriptional networks (Figure 2A) evidenced that coexpressed genes tend to be grouped in the genome. We call these group of collinear genes co-expression domains (CODs). Analysis of the relationship between CODs and chromatin 3D organization using Hi-C contact data, demonstrated that genes inside CODs present similar patterns of chromatin contacts (Figure 2B) (Soler-Oliva et al., 2017).
Metastasis epigenetics: Epigenetic changes during epithelial to mesenchymal transition and its reversion.
Epithelial and mesenchymal cellular phenotypes are the edges of a spectrum of states that can be transitory (also called metastable) or stable. The epithelial to mesenchymal transition (EMT) (Figure 3) and its reversion (MET) are common processes during embryonic development and have attracted considerable interest due to the fact that they seem to be related to tumor cells dissemination and migration, generation of tumor circulating cells, cancer stem cells, chemoresistance and metastasis formation. A large reorganization of transcription patterns and epigenetic information, that we are only starting to understand, occurs during EMT and MET. In our group we investigate epigenetic changes that occurs during EMT and MET and the chromatin factors implicated. We have shown that the protein HMG20A, associated to the LSD1/CoREST histone demethylase complex, is involved in repression of epithelial genes during this process (Rivero et al., 2015). We are studying the role of HMG20A, and other factors identified in a genetic screen, in EMT, cancer and metastasis.