Buitrago, DianaLabrador, MireiaArcon, Juan PabloLema, RafaelFlores, OscarEsteve-Codina, AnnaBlanc, JulieVillegas, NúriaBellido, DavidGut, MartaDans, Pablo D.Heath, SimonGut, Ivo GlynneBrun-Heath, IsabelleOrozco, Modesto2021-11-262021-11-262021Buitrago D, Labrador M, Arcon JP, Lema R, Flores O, Esteve-Codina A, Blanc J, Villegas N, Bellido D, Gut M, Dans PD, Heath SC, Gut IG, Brun Heath I, Orozco M. Impact of DNA methylation on 3D genome structure. Nat Commun. 2021;12(1):3243. DOI: 10.1038/s41467-021-23142-82041-1723http://hdl.handle.net/10230/49064Determining the effect of DNA methylation on chromatin structure and function in higher organisms is challenging due to the extreme complexity of epigenetic regulation. We studied a simpler model system, budding yeast, that lacks DNA methylation machinery making it a perfect model system to study the intrinsic role of DNA methylation in chromatin structure and function. We expressed the murine DNA methyltransferases in Saccharomyces cerevisiae and analyzed the correlation between DNA methylation, nucleosome positioning, gene expression and 3D genome organization. Despite lacking the machinery for positioning and reading methylation marks, induced DNA methylation follows a conserved pattern with low methylation levels at the 5' end of the gene increasing gradually toward the 3' end, with 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, mimicking the patterns seen in mammals. We also see that DNA methylation increases chromatin condensation in peri-centromeric regions, decreases overall DNA flexibility, and favors the heterochromatin state. Taken together, these results demonstrate that methylation intrinsically modulates chromatin structure and function even in the absence of cellular machinery evolved to recognize and process the methylation signal.application/pdfeng© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-021-23142-8Chromatin remodellingComputational modelsDNA methylationNuclear organizationinfo:eu-repo/semantics/openAccess