Modeling the regulation of chromatin dynamics by redox modifications – CHROM

In our cells, gene activity is tightly controlled by reversible chemical modifications called epigenetic marks. These are of various types and modulate gene accessibility without affecting the DNA sequence. The modification of the histone proteins, responsible for DNA compaction in the nucleus, is one of them. Understanding how these changes impact DNA compaction (from nucleosome to chromatin structures) and genome functioning is a timely area of research, yet several aspects suffer from a critical lack of data and remain elusive to experimental tools. Indeed, despite increasing amounts of evidence show that oxidative-type modifications of histones play a role in gene expression regulation, there is a complete absence of structural data at the atomistic level to understand the molecular mechanisms behind their regulatory action.
The CHROM project aims at elucidating the impact of these oxidative modifications of histone proteins on chromatin dynamics, by computational means. It is focus on one modification, S-glutathionylation (SSG), which is known to favor chromatin opening. Owing to an ambitious multi-scale methodology featuring all-atom molecular dynamics simulations and hybrid QM/MM approaches, the SSG formation mechanisms, its structural impact on the nucleosome structure, and its combinatorial effect with acetylation marks will be unraveled.
This research will provide the very first structural insights into histone oxidative modifications regulatory role on DNA compaction and gene expression, positioning our group as an international pioneer in the field. It will set an important methodological framework to initiate new research aiming at unraveling the mechanisms of action of other oxidative modifications, which have been largely ignored by the community so far. Such knowledge will open invaluable perspectives for understanding oxidative epigenetic changes and for the design of new drugs targeting these key-processes against several diseases.