Fat nucleosome: Role of lipids on chromatin

Structural changes in chromatin regulate gene expression and define phenotypic outcomes. Molecules that bind to the nucleosome, the complex of DNA and histone proteins, are key modulators of chromatin structure. Most recently, the formation of condensed chromatin regions based on phase-separation in the cell, a basic physical mechanism, was proposed. Increased understanding of the mechanisms of interaction between chromatin and lipids suggest that small lipid molecules, such as cholesterol and short-chain fatty acids, can regulate important nuclear functions. New biophysical data has suggested that cholesterol interacts with nucleosome through multiple binding sites and affects chromatin structure in vitro. Regardless of the mechanism of how lipids bind to chromatin, there is currently little awareness that lipids may be stored in chromatin and influence its state. Focusing on lipids that bind to nuclear receptors, clinically relevant transcription factors, we discuss the potential interactions of the nucleosome with steroid hormones, bile acids and fatty acids, which suggest that other lipid chemotypes may also impact chromatin structure through binding to common sites on the nucleosome. Herein, we review the main impacts of lipids on the nuclear environment, emphasizing its role on chromatin architecture. We postulate that lipids that bind to nucleosomes and affect chromatin states are likely to be worth investigating as tools to modify disease phenotypes at a molecular level.