Incorporating multiscale effects into models of gene expression

Positively charged protein residues, called histones, bind like spools around DNA into tightly packed fibers known as chromatin. These proteins play an important role in gene regulation. But any modification to a histone — such as methylation, the addition of a methyl group to arginine or lysine residues — can impact its functionality and, in turn, gene expression.

Li et al. developed a multiscale model to investigate how methylation affects chromatin structure and gene regulation.

Their model incorporates short-range effects on histones’ local structures, nucleosome stacking and protein binding, and long-range interactions using machine learning on experimental datasets. In tests of two different histone methylations, the researchers found their model not only successfully mimics existing biological observations, but also highlights their distinct roles and interaction pathways.

“By applying this model to cancer, neurodegenerative diseases, and developmental disorders, we can investigate how abnormal histone modifications contribute to disease progression,” said author Tamar Schlick.

Though the group emphasizes that their method and associated studies underscore the power of multiscale modeling in epigenetics, recreating more realistic conditions will require additional work. Currently, the technique can study two specific types of chromatin interactions independently, but these modifications do not happen one at a time in vivo. Future studies will include incorporating interactions concurrently to study any additional impacts, as well as expanding the genomic datasets and cell types in their models.

“While the model successfully captures key aspects of methylation-driven chromatin folding, future improvements will focus on enhancing applicability by incorporating more complex chromatin modifications and interactions,” Schlick said. “By bridging computational modeling and experimental epigenetics, we hope to contribute to a deeper understanding of gene regulation and chromatin architecture, and their role in human disease.”

Source: “Incorporating multiscale methylation effects into nucleosome-resolution chromatin models for simulating mesoscale fibers,” by Zilong Li, Stephanie Portillo-Ledesma, Moshe Janani, and Tamar Schlick, Journal of Chemical Physics (2025). The article can be accessed at https://doi.org/10.1063/5.0242199 .

This paper is part of the Chromatin Structure and Dynamics: Recent Advancements Collection, learn more here .