BCN, 3 June 2021.- All the cells of an organism share the same DNA sequence, but their functions, shapes or even lifespans vary greatly. This happens because each cell “reads” different chapters of the genome, thus producing alternative sets of proteins and embarking on different paths. Epigenetic regulation—DNA methylation is one of the most common mechanisms—is responsible for the activation or inactivation of a given gene in a specific cell, defining a secondary cell-specific genetic code.

Researchers led by Modesto Orozco, head of the Molecular Modelling and Bioinformatics lab at IRB Barcelona, have described how methylation has a protein-independent regulatory role by increasing the stiffness of DNA, which affects the 3D structure of the genome, thus impacting gene activation. Present work reveals a cryptic mechanism connecting epigenetic footprinting and gene programming, which can help us to better understand development, ageing and cancer. This work has been carried out in collaboration with Ivo Gut, Simon Heath, Marta Gut, Julie Blanc and Anna Esteve-Codina from the CNAG-CRG.

“The new model organism and the theoretical analysis framework that we have developed and published are really innovative and we hope they will facilitate research projects undertaken by many laboratories around the world studying DNA methylation and its impact on gene expression,” explains Modesto Orozco, also an ICREA Academia Fellow and Professor of the University of Barcelona (UB).

3D structure and gene expression

The DNA inside the cell is folded and structured in a 3D manner to maintain its correct organisation and preservation. When a gene has to be “read”, DNA unfolds in this region, allowing access to the cellular machinery. Therefore, the 3D structure increases or decreases accessibility to a gene, conditioning whether that gene will produce the protein it encodes for, or not. For this study, the Molecular Modelling and Bioinformatics group used next-generation sequencing methods and molecular simulations to model the whole genome structure.

“Using these techniques, we observed that we could recapitulate the characteristic distribution of DNA methylation seen in mammalian genomes, and we confirmed our earlier in vitro result on the relationship between 3D structure, DNA flexibility, and methylation, showing that this also occurs in vivo,” explains Isabelle Brun Heath, director of the Experimental Bioinformatics Laboratory and codirector the study.

According to Ivo Gut, leader of the Biomedical Genomics Group at the CNAG-CRG, "this study gives insight into the fundamental regulation of genomes and demonstrates how the application of advanced genome technologies helps us to better understand how connections between genomic components might lead to disease."

This work was supported by the Spanish Ministry of Science, the Catalan SGR, the Instituto Nacional de Bioinformática, the European Research Council (ERC_SimDNA) and the BioExcel and MuG VRE H2000 projects. This work also received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie actions, and from the Spanish Ministry of Science, the ISCIII /MINECO, and the ERDF.

Image caption: DNA methylation has an intrinsic effect on 3D genome structure (IRB)

Work of reference: Impact of DNA methylation on 3D genome structure

Source: IRB Barcelona