Release and activity of histone in diseases

Abstract

Histones and their post-translational modifications have key roles in chromatin remodeling and gene transcription. Besides intranuclear functions, histones act as damage-associated molecular pattern molecules when they are released into the extracellular space. Administration of exogenous histones to animals leads to systemic inflammatory and toxic responses through activating Toll-like receptors and inflammasome pathways. Anti-histone treatment (e.g., neutralizing antibodies, activated protein C, recombinant thrombomodulin, and heparin) protect mice against lethal endotoxemia, sepsis, ischemia/reperfusion injury, trauma, pancreatitis, peritonitis, stroke, coagulation, and thrombosis. In addition, elevated serum histone and nucleosome levels have been implicated in multiple pathophysiological processes and progression of diseases including autoimmune diseases, inflammatory diseases, and cancer. Therefore, extracellular histones could serve as biomarkers and novel therapeutic targets in human diseases.

Figure 1

Histone structure and nucleosome assembly. A nucleosome contains an octamer of histone molecules. An octamer contains an H3-H4 tetramer and two H2A-H2B dimers.

Figure 2

Histone modifications. The major modifications shown here include acetylation (A), methylation (M), phosphorylation (P), ubiquitination (U), citrullination (C), sumoylation (S), and biotinylation (B). Asterisk indicates that the modification is from S. cerevisiae

Figure 3

Histone location and function

Figure 4

Release and activity of histones in response to stress

Figure 5

Histone-mediated tissue injury and disease