Centro Andaluz de Biología Molecular y Medicina Regenerativa

Epigenetics and gene expression

Research projects

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).

 

Figure 1. CHD8 binds transcriptionally active promoters. Distribution of CHD8, RNA polymerase II and the epigenetic mark H3K4me3 by ChIP-seq.

 

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).

 

Figure 2. A. Co-expression network of breast tissue. B. Co-expression matrix of chromosome 19 (left) y correlation matrix from Hi-C chromatin contact data obtained through Hi-C (right) (PMID:19815776).


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.

 

Figure 3. Epithelial to mesenchymal transition in NMuMG cell induced by TGF-beta. E-Cadherin (Cdh1) (green); ZO-1 (red); Vimentin (Vim) (green) DAPI (blue).

Reviews:

F. Prado, S. Jimeno-Gonzalez and J.C. Reyes. 2017. Histone availability as a strategy to control gene expression. RNA Biology. 14(3):281-286.

S. Jimeno-Gonzalez and J.C. Reyes. 2016. Chromatin structure and RNA-processing go together. Transcription. 7(3):63-68. doi: 10.1080/21541264.2016.1168507.

A. Subtil-Rodríguez and J. C. Reyes . 2011. To cross, or not to cross the nucleosome, that is the elongation question. RNA Biology. 8: 389 – 393

M. García-Domínguez and J. C. Reyes . 2009. SUMO association with repressor complexes, emerging routes for transcriptional control. Biochimica et Biophysica Acta, 1789:451-459.

R. March-Díaz and J. C. Reyes . 2009. The beauty of being a variant: H2A.Z and the SWR1 complex in plants. Molecular Plant, 2:565-577.

J.C. Reyes . 2006. Chromatin remodelers that control plant development. Current Opinion in Plant Biology. 9:21-27.

 

Selected articles:

J.A. Guerrero-Martínez and J.C. Reyes. 2018. High expression of SMARCA4 or SMARCA2 is frequently associated with an opposite prognosis in cancer. Scientific Report. 8(1):2043

M. Guijo, M. Ceballos-Chávez, E. Gómez-Marín, L. Basurto-Cayuela and J.C. Reyes. 2017. Expression of TDRD9 in a subset of lung carcinomas by CpG island hypomethylation protects from DNA damage. Oncotarget. Doi: 10.18632/oncotarget.22709.

M.E. Soler-Oliva, J.A. Guerrero-Martínez, V. Bachetti and J.C. Reyes. 2017. Analysis of the relationship between co-expression domains and chromatin 3D organization. PLoS Computational Biology. 13(9):e1005708

S. Jimeno-Gonzalez, M. Ceballos‐Chávez, J.C. Reyes. 2015. A positioned +1 nucleosome enhances RNA polymerase II promoter proximal pausing in human cells. Nucleic Acids Research. 43(6):3068-78. doi: 10.1093/nar/gkv149.

A. Subtil-Rodríguez, M. Ceballos‐Chávez, E. G. Giannopoulou, D. Soronellas, O. Elemento, M. Beato and J. C. Reyes. 2015. The chromatin remodeler CHD8 is required for activation of progesterone receptor-dependent enhancers. PLoS Genetics. 11(4):e1005174. doi: 10.1371/journal.pgen.1005174.

S. Rivero, M. Ceballos-Chávez, S.S. Bhattacharya and J.C. Reyes. 2015. HMG20A is required for SNAI1-mediated Epithelial to Mesenchymal Transition. Oncogene. doi: 10.1038/onc.2014.446.

A. Subtil-Rodríguez, E. Vázquez-Chávez, M. Ceballos‐Chávez, M. Rodríguez-Paredes, J. I. Martín-Subero, M. Esteller and J. C. Reyes. 2014. The chromatin remodeler CHD8 is required for E2F-dependent transcription activation of S phase genes. Nucleic Acids Research. 42:2185-96.

T. Alfonso‐Pérez, M. S. Domínguez-Sánchez, M. García-Domínguez and J. C. Reyes. 2014. Cytoplasmic interaction of the tumor suppressor protein hSNF5 with Dynamin-2 controls endocytosis. Oncogene. doi: 10.1038/onc.2013.276.

M. Ceballos-Chávez, S. Rivero, P. García-Gutiérrez, M. Rodríguez-Paredes, M. García-Domínguez, S. S. Bhattacharya, and J. C. Reyes. 2012. Control of neuronal differentiation by sumoylation BRAF35, a subunit of the LSD1-CoREST histone demethylase complex. Proceedings of the National Academy of Sciences USA 109(21):8085-90

A. Subtil-Rodríguez and J. C. Reyes . 2010. BRG1 helps RNA polymerase II to overcome a nucleosomal barrier during elongation, in vivo. EMBO Report . 11:751-757

E. Aichinger, C.B. Villar, S. Farrona, J.C. Reyes, L. Hennig and C. Köhler . 2009. CHD3 proteins and Polycomb group proteins antagonistically determine cell identity in Arabidopsis. PLoS Genetics , 5(8):e1000605.

Rodríguez-Paredes, M. Ceballos-Chávez, M. Esteller, M. García-Domínguez and J.C. Reyes . 2009. The chromatin remodeling factor CHD8 interacts with elongating RNA polymerase II and controls expression of the cyclin E2 gene. Nucleic Acids Research , 37:2449-2460.

R. March-Díaz, M. García-Domínguez J. Lozano-Juste, J. León, F.J. Florencio and J.C. Reyes . 2008. Histone h2a.z and homologs of components of the SWR1 complex control immunity in Arabidopsis. Plant Journal . 53:475-487.

S. Farrona, L. Hurtado, J. Bowman and J.C. Reyes . 2004. The Arabidopsis thaliana SNF2 homolog AtBRM controls shoot development and flowering. Development . 131:4965-4975.

J.C. Reyes, J. Barra, C. Muchardt, A. Camus, C. Babinet and M. Yaniv . 1998. Altered control of cellular proliferation in the absence of mammaliam brahma (SNF2alpha). EMBO Journal . 17: 6979-6991.

Group leader:
  • Dr. José C. Reyes
Postdoctorals:
  • Dr. Maria Ceballos-Chávez
PhD students:
  • Laura Basurto Cayuela
  • Elena Gomez Marin
  • Jose Antonio Guerrero Martínez