Historic H3 methyltransferases are involved in the epigenetic control of transcription and heterochromatin maintenance. In Saccharomyces cerevisiae, deletion of a histone H3 methyltransferase SET1 leads to the induction of a subset of stress responsive genes in a Rad53 dependent manner. This type of induction was observed only in the absence of SET1 and riot in the absence of other historic methyltransferases, SET2 or DOT1. We show that the increased expression of the stress responsive genes results from a lack of histone H3 lysine (K) 4 methylation. The loss of mono-methylation on H3 K4 is necessary to increase the expression of the stress responsive genes, while the loss of di- or tri-methylation induced by deletion of either RRM domain of Set I or the upstream effector molecules hardly affected their expression. These results suggest that mono- and multiple methylation of H3 K4 have different roles. The mono-methylation of H3 K4 might be required for the global integrity of chromatin structure, which is normally monitored by the Rad53 dependent chromatin surveillance system. (c) 2006 Elsevier Inc. All rights reserved.