Establishing epigenetic domains via chromatin-bound histone modifiers

The eukaryotic nucleus harbors the DNA genome, which associates with histones and other chromosomal proteins into a complex referred to as chromatin. It provides an additional layer of so-called epigenetic information via histone modifications and DNA methylation on top of the DNA sequence that determines the cell's active gene expression program. The nucleus is devoid of internal organelles separated by membranes. Thus, free diffusive transport of proteins and RNA can occur throughout the space accessible for a given macromolecule. At the same time, chromatin is partitioned into different specialized structures such as nucleoli, chromosome territories, and heterochromatin domains that serve distinct functions. Here, we address the question of how the activity of chromatin-modifying enzymes is confined to chromatin subcompartments. We discuss mechanisms for establishing activity gradients of diffusive chromatin-modifying enzymes that could give rise to distinct chromatin domains within the cell nucleus. Interestingly, such gradients might directly result from immobilization of the enzymes on the flexible chromatin chain. Thus, locus-specific tethering of these enzymes to chromatin could have the potential to establish, maintain, or modulate epigenetic patterns of characteristic domain size.