Pleiotropic Functions of H3K27Me3 Demethylases in Immune Cell Differentiation

The trimethylation of histone H3 lysine 27 (H3K27Me3) contributes to gene repression, notably through recruitment of Polycomb complexes, and has long been considered essential to maintain cell identity. Whereas H3K27Me3 was thought to be stable and not catalytically reversible, the discovery of the Utx and Jmjd3 demethylases changed this notion, raising new questions on the role of these enzymes in gene expression and cell differentiation. Recent studies have demonstrated critical roles for Utx and Jmjd3 in the development and function of immune cells, and revealed both demethylase and demethylase-independent activities of these enzymes. I review these finding here, and discuss the current understanding of the mechanisms that underlie the broad, yet highly cell- and gene-specific, impact of these enzymes in vivo.

TrendsH3K27Me3 demethylases Jmjd3 and Utx are essential for a variety of cell differentiation processes, notably during hematopoietic cell development and during intrathymic T cell development.Jmjd3 and Utx are important for the dynamic removal of H3K27Me3 associated with cell differentiation, rather than for its steady-state homeostasis.Jmjd3- and Utx-independent mechanisms, possibly demethylase-independent, contribute to H3K27Me3 homeostasis.In addition to their H3K27Me3 demethylase activities, Jmjd3 and Utx display demethylase-independent activities, which are also essential to their functions, including in early embryonic development and effector T cell differentiation.