Epigenetic research discovers how the environment communicates with genes and educates their activity. This communication includes a system that uses specific molecules produced by cellular metabolism to modify the histone proteins that organize DNA chemically. An international collaboration has just highlighted a new way of communicating with genes by characterizing the function of chemical modifications of histones unknown until now.
Our cells organize the DNA carrying our genes into a compact structure within the nucleus of our cells using specific proteins, histones. Intense research over the last few decades has revealed chemical changes in histones that constitute a real language instructing the function of associated genes.
Specific molecular systems have been identified that implement, recognize, interpret and remove these changes. All these systems cooperate to direct the functioning of genes according to their molecular environment. However, cellular metabolism strongly conditions this environment.
One of the first chemical modifications identified and intensely studied is acetylation. It is placed by enzymes, histones-acetyltransferases (HAT), and is recognized by proteins with a particular domain, bromodomain: it is removed by other enzymes, histones-deacetylases (HDAC). HATs use acetyl-CoA, a small molecule produced by metabolism, to direct the acetylation of histones. It can directly modify the packaging of genes by histones or signal the action of other proteins on genes. This system therefore directly links the functioning of genes to the production of acetyl-CoA in cells and, as a result, relates gene activity to metabolism.
Modification of histones, these specific proteins
Collaborative research by French, American and Chinese scientists shows that histone acetylation has a competitor, butyrylation, a modification that also has its source in metabolism. Surprisingly, it has been observed that the most active genes are not only marked by acetylation of histones, but also by butyrylation of the same histones. They also show that the enzyme that acetyls histones also directs butyrylation.
Butyrylation, like acetylation of histones, directly activates gene expression, but on the other hand, prevents proteins that recognize acetylation from binding to histones. As a result, the researchers discovered an aspect of active gene expression that is based on a successive alternation of different chemical modifications of histones with opposite functional consequences. This system creates a dynamic state of return of factors at the gene level, necessary to maintain their active expression.
Better understand the control of gene expression.
The discovery of this system brings new concepts to understand better how genes work and how the environment communicates with them. Indeed, a change in the ratio of acetylation and butyrylation of histones, both from metabolism, could durably affect the state of gene expression. It could explain how a metabolic disorder could drastically alter genome expression.
The prospects for a thorough understanding of the control of gene expression, the effect of the environment on gene expression and the occurrence of diseases, as well as the identification of mechanisms for the transgenerational transmission of information from the environment, stem from this work published in the journal Molecular Cell.