“Under conditions of chronic inflammation, tissues tend to show altered differentiation,” Natoli says. Chronic gastritis, for instance, can lead to the formation of intestinal cells within the stomach lining. And in a rejected kidney transplant, host macrophages turn into endothelial cells, creating new lymphatic vessels.
For macrophages to adopt new fates, a lysine in histone H3 must first be demethylated to relieve the silencing of cell fate determinants. One group of enzymes that removes methyl groups is the JmjC domain proteins, which includes JmjD3, whose exact function has been unclear. In the new work, the authors discovered that JmjD3 was up-regulated during inflammation and that it demethylated cell fate genes.
Jmdj3's target genes included late HoxA genes, which are powerful determinants of cell fate. Additionally, knock down of Jmdj3 inhibited the demethylation of bone morphogenetic protein 2, thus preventing its normal inflammation-induced increase.
The existence of a system to erase controls on terminal differentiation may seem counterintuitive at first, but “it makes a lot of biological sense,” says Natoli. In situations in which tissue regeneration is needed, and local stem cells are exhausted, there may be a need to recruit other cell types. New lymphatic vessels, for instance, may be needed to increase the flow of debris out of an injured and inflamed area, Natoli suggests. “Inflammation loosens control over differentiation, and Jmdj3 may be the molecular link between these processes.”