Mechanisms of Chromatin Remodeling and Repurposing During Extracellular Translocation

Chromatin is a highly conserved molecular structure that provides genetic information to regulate cell function. Comprised of DNA, histones and interacting proteins, chromatin is inherently dynamic and subject to remodeling. While usually conceptualized as an intranuclear event, remodeling can also involve extracellular movement. Indeed, chromatin can translocate entirely from the inside to the outside of the cell during cell death processes that include apoptosis, necrosis, and NETosis. During these processes, DNA and proteins can undergo other changes impacting on their activity. Thus, during apoptosis, DNA can be cleaved, histones can be posttranslationally modified and a nuclear protein called HMGB1 (high mobility group box 1) can undergo redox changes. Outside the cell, chromatin components can display powerful immunological activities. These activities result from the ability of DNA and RNA, once taken up by immune cells, to activate internal nucleic acid sensors; the likely function of these sensors is to recognize nucleic acids from intracellular infection. Depending on redox state, the prototype alarmin HMGB1 can interact with a variety of immune receptors including Toll-like receptors. As such, extracellular chromatin can stimulate inflammation and drive the pathogenesis of immune-mediated diseases; in experimental models in animals, agents that bind chromatin components can block disease. Thus, extracellular chromatin can have far-reaching biological effects involving a form of molecular repurposing.