Impact of DNA methylation on the 3D structure of the genome
All cells within an organism share the same DNA sequence, but their functions, shape or even life expectancy changes. This is the result of different regions of the genome being read by each particular cell and, therefore, different sets of proteins being expressed. Epigenetic regulation is a process of gene activation/deactivation without altering DNA sequence, and its malfunction is related to several diseases such as immunodeficiency, ataxia, and acute myeloid leukemia, among others. In particular, DNA methylation is one of the most important epigenetic marks which introduces major changes in cellular function.
Research at NBD
Our co-founder Prof. Modesto Orozco has led a study that demonstrates that DNA methylations intrinsically modulate genome structure and function by increasing its overall rigidity. Moreover, they’ve demonstrated that this regulation process is independent from the protein machinery evolved to recognize and process methylation signals.
Impact on the genome structure
DNA methyltransferases were expressed in Saccharomyces cerevisiae, an organism lacking intrinsic methylation machinery. The correlation between DNA methylation, nucleosome positioning, gene expression and 3D genome organization was then analyzed. Despite lacking the machinery for positioning and reading methylation marks, induced DNA methylation followed conserved patterns, where low methylation levels at the 5’ end of the gene increase gradually toward the 3’ end, along with the concentration of methylated DNA in linkers and nucleosome free regions, and with actively expressed genes showing low and high levels of methylation at transcription start and terminating sites, respectively, mirroring the patterns seen in mammals. The authors also showed that DNA methylation increases chromatin condensation in peri-centromeric regions, decreases overall DNA flexibility, and favors the heterochromatin state.
Impact of DNA methylation on 3D genome structure