Inhibition of demethylases by GSK-J1/J4

Arising from L. Kruidenier et al. Nature488, 404–408 (2012); doi:10.1038/nature11262 The recent publication 1 of the first highly potent and specific inhibitor GSK-J1/J4 of the H3K27me3/me2-demethylases JMJD3/KDM6B and UTX/KDM6A provides a potential tool compound for this histone demethylase subfamily 1 . This inhibitor was used in tissue culture assays to conclude that the catalytic activities of the KDM6 proteins are required in inflammatory responses 1 ; the generation of the inhibitor is intriguing, because it provides a strategy for generating sub-type-specific inhibitors of the 27-member Jumonji family and for the future treatment of various types of disease 2 , 3 , 4 , 5 , 6 . Here we show that the inhibitor is not specific for the H3K27me3/me2-demethylase subfamily in vitro and in tissue culture assays. Thus, the inhibitor cannot be used alone for drawing conclusions regarding the specific role of H3K27me3/me2-demethylase activity in biological processes or disease. There is a Reply to this Brief Communications Arising by Kruidenier et al. Nature 514, http://dx.doi.org/10.1038/nature13689 (2014).