Study describes the impact of DNA methylation on the 3D structure of genome

Although all cells in an organism share the same DNA sequence, their shapes, roles, and even lifespans differ drastically. This occurs because each cell “reads” distinct chapters of the genome, creating various sets of proteins and following distinct pathways.

DNA methylation has an intrinsic effect on 3D genome structure. Image Credit: Institute for Research in Biomedicine (IRB Barcelona).

Epigenetic regulation—one of the most frequent ways is DNA methylation—is responsible for the inactivation or activation of a single gene in a certain cell, establishing a secondary cell-specific genetic code.

Researchers led by Dr. Modesto Orozco, head of IRB Barcelona’s Molecular Modelling and Bioinformatics lab, have defined how methylation has a protein-independent regulatory function by raising the stiffness of DNA, which impacts the 3D structure of the genome and thus influences gene activation.

The current study discloses a cryptic process that links gene programming and epigenetic footprinting, which can help gain better insights into aging, development, and cancer.

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.”

Dr Modesto Orozco, ICREA Academia Fellow and Professor, University of Barcelona

3D structure and gene expression

To preserve proper organization and preservation, the DNA inside the cell is folded and organized in 3D. When a gene must be “read,” DNA in this region unfolds, enabling access to the cellular machinery.

As a result, the 3D structure enhances or lowers accessibility to a gene, influencing whether or not that gene produces the protein it encodes for. The Molecular Modelling and Bioinformatics group employed next-generation sequencing techniques and molecular simulations to model the whole genome structure for this work.

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.”

Dr Isabelle Brun Heath, Study Co-Director and Director, Experimental Bioinformatics Laboratory, IRB Barcelona